Cl i n i c a l Pha r maco k i n e t i cs Con cepts ond Ap pl i c o t i o ns

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I""1111111I11111I111 1111111: 111111 11
ALOS- 706- NZWP

Cl inical Pharmacak inet ics Concepts and Application s
third edition

MAL COlM R OWlAND, Ph.D.
Depomnenr of Phormocy
University of Iv\oncne$ler

fvlonchester, England

THOMAS N. TOZER, Ph.D. School of Pbcrmocv
University of California

San Francisco, Cclnormc

A Leu ..... Febiger Bo v ok

.e1~ LI pPINCOTT WILLIAMS & W ILKINS
• A Wollen Kluwef Company

Philadelphia • Ballimore • New Y ork • l ondon
Buenos Aires • Hong Kong . Syd ney • Tokyo

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To NIorgarel ond Down

PREFACE
PURPOSE 01 TIXT
The rhin l l"tlitioll. in

\\i th a n

kt 't' pill~ wtth tilt' fi o t hm ("l;lilions. is a pn nu-r in p harmacokinet ics clhucn l applica tions. 111t' Ix)ok should hl' useful to ilny student. pmc· tulom-r. o r rt'sl'ard lt'r Willi is in f('rt'slt'() o r t 'llga~("ll in til(' dt ·" dopllll'u t , e-...uluutk rn. o r II!\(' .

t' llI ph;l~i s 011

of nu-dn-im-s. SIl('h !W n;O Il S illdlldl' ph annac1sts. physicians. vete rinari ans. pharmaccuuca l scn-nt tsts. Im:ieo lo)..,'i sls, al1 al~1 i{Mu1chemists, luoc hennsts. and d ink'al chen us ts. It is a n in-

troduct ory text ami tln-n -fon - pn 'slllllt'S that tilt' n-ader Im. littll' or no t':qx' n t'IIl'(' O f k n " owl( '(I~t· i ll lilt , an-a. Previous ('xposnn' 1 certain aspects of physioloK and pharmacclogy 0 \' wo uld ht' 11I·lp(1I1, hilt it is 1101 ('Sst·utia!. SOIllt' kllowlt'( I~(· of calculus is also dt 'Sirab!e . Our intent h to ln-lp tilt' n-ader lenrn to apply plranuacokincncs in therape-utics . To this r-nd. W I ' I'lIlplJit\il l' {,(lIll,('pts t l ln )ll~h pro blem solving \\i th only til(' essence of requtr ed marlu-nuutcs . In tllis respect. til(' hook is a p ro~r.lI n m {'(II t'am inv; text. AI the bt";ll11i n ~ o f I';u: h d lapll'r, ohjt'(:liH's art' !-pH'n 10 itll'lltif)" lilt' s aln-nt poin ts 10 b learned . T o furt her e aid in !e;ln-illl-: tln- man-rial. examples art' \\urkt'(! oul in del ail in tilt' text , At tilt' {'ud o f t·ad. chapter, t'Wl'pt tilt' first. then- an' problems thilt allo.... I!l1' read to v;r... p tilt' (,(JJl{" pts . er ' o f tilt' chapn-r ,Illd In lnukl 1)1\ man-rial ¢ H'n ill previ ous chapn-rs. nit' u n !t' r of tht, pro bk-ms in I'a('h cliapter n ·III'(1s cousuh-ratiou of both t1HIi(111 and how WI·I\ tlu- problems 1)' apply tn chapter principles . TIlt' questions sta rt wi th theless difl tult O Il('S and those thai i t·. llplmsi...x- tlu- principh-s.

ORGANIZATION AND CONIINT
As in tilt' s('('(md t'(lilioll , 11\1' I)( M is t!id t!('(1into fiv(' St,'<.1inllS: AbsUlVlion and Disl'll,).'i itinl\ )k Kim'lil'S. T ll{'raj'll,'lItil' Hl'¢Illt'nS, I'hysinlo¢ c COII('('pls and Knwttcs . Indhi tluali...at iou. ami SI'!l'(1t, ! Tnpil'S. T lmst' \\i sllinl-: to ~<ti ll a ~1· Ilt· ral oH' nil'\\' o f tlu- sllhjl'<.i. 1It(, ! on ly siudy ' SI'('tiollSD Ilt' alld Two. fl,!-:t'lllt'r \\i lh Chapter 13 , Variahi lity, and C hap ter IS. \ Ionitoring. epts relevant to an umk'rs tamli ng of the S('('lion Tlm'(' dt'als wi th til(' phys iolc ~(' co nc Pl'Oc :t'Sst'S o f absorptmu. dtvtrthution, and climiuanon. T his section fo rms ti lt" basls for an app reciation of tilt' mat{'ri,tl ill Sect ion Four, whid. is conce r n \\i lh the idt·nlifieltion. ed c!t'Sl'riptiOIl , and at'('(llllltilll-! o f "Iriahility in p atients' rt'SI)(JUst·s to d rugs. Coven-d hen- are ~(' Il l'ral ;I' pl·(.'h o( va riability, (ollm\"(, 1 by {,(lIlsidl'mtions o f ~(,IW lks , age uncl w(·i ~h t . dist';I<;t', in lt'mdi lll-! d m l-!s. and lI\(milu rinl-: of dftl.e: concent rauous. SI'('linll Fi\"(' contains sch -cn-d topics . These- <tn' ill!t'I\(II'(1for Ihust· rt'a tll'f1i wi\()wts h 10 ~aj ll a mon- t1f'lailt'(l i ll si ~l lt into cu rious uspect s of clinical pbannacokim-tics . 111t" topics an' d istrihulioll kim·lk'S. plla rlll an Jlt ~(' rt'SI)(J!lS . IIwtaho lih ' kim-tk-s, doS(' and Iillll" dt·t' 1)('IIIII'I1('II'S, t U nJO\"N l'()IIl'('pIS. ami di:J)" sis, Eud. Inpk' is K{· .lt' rall~· st·lf-<.'(lIlta int, !; tllt'y ImH' unt 1)( "11 arnlll~l, 1 in any part il'u lar st'lllt·m'(·.

CHANGES IN TNIRD EDITION
T Il(' fl.y('a r ~a p hdw t"('11 tllis thinl ("(filion and tllP st,(,(lIld . puhlish,"(1 ill 19MJ. is shurt t'r tlla" tll(· 9 Y I'af1i hd \\l ,,('U til(' st'(u nd alltl firo;l 1, litiol\s. nlis shUl1t·nillJ: o f tilt' Iilllt· spa n

Pl!EfACE

IM 'tWl'i 'lI ,·d ilium rd ll'd s tln- l'\ l' r-J,:atl... rill ~ P,I( ~ ' of p" ~n'Ss alld a pplil'atioll of ehnical plla rllla(~lki ll d ics . D,"pill ' IlIi, J,:m\\11i. which Ila, n'( lllin "(l Ihe inclusion o f 1I111ch new \ ruatr-rial. ( '\('1"\' dfort Il,L' IM"( 'II matl(' lu (~lIIlaill tln- over all Si"A of Ih.. book. This. in 11101, ' lias meant Ih,;1 SWill' lIlillt' rial llas lIad III Ix' ('o llde llS( or dd t'lt'(l. It IIlLs also n's1l11("( 1 ill "(! a muc-h j,(n'all'r u,,' of "hhn ·"ia!ioll' . (·'I)(... · ial l~ for un its . T Ilt' 11I1I1l1M 'r . topn-, alit! S(" IUI'lll'(' of chapters have h('('11 kept ('Sst'lIl iall)" lilt" ~1 1Il (' ,L~ ill 11.1' \('('(Illd , -c Iiiion , IIIMl " I'r, r-ach chapter has b("('11 ('l\lt'nsi\" )" n-visc..1 am l up(lalt"(! 1 d 0 I'IlSUf(' 111;(1 IIII' I',-,unpl,·\ n-lnn- 10 l1IITt'lIlly prescnlx-d dmg) , A part kul,lr (' Ilu rt h,L b '; e-en IIMd,· III ind lill.' vtr-n.. It' I I I· lII i~ I T\. n,( ~~l1 i /il l C: Ihal Isomers ma v Imn ' dillen'nl kinet k-s and a(1i\ily. Tl l('n ' h "I"' l ('t>I I ~id('r,~!ioll o r til(" iJl(:n',l~ill~ Il llmh(·~ of IXllyp','pti d, ' am! protein dmj.(s ,·IlII·fJ..,'iIIl! [nun advances ill mol ecular hioJ, ~ and hiol ('('hlloll 'K\-" ' AItI Il)U~h the kiIwl k· (lllll",'ph an' lilt' sallw. 1111' phy, i ll lu'~i ~' halllllilll..:: of macmmoll'(11 lar comp ounds is ' lui'" dislilld from that of I ~pi('al slIIall lllol''(' lIlar \\t·it.:lll dm ~s . TIlt' pn-wutation of lilt' 1M h'LSa["'1IM'''II ruar]« .. I1 ~ illlprowd through Ih(' Ust· of (:olo r. 10k TI ll' mort- nuportuut ("Illalions art- IIOW lIil..:lllighl1'd bv means of color. C hapter number ;111.1 ~'('1i' 1I 1 Ilt';\llillg IIlIWalllM 'a r al 1111 ' It Ip 'If ( '01(·11 p'I,. ::" b~ nu! to assist ill (' mss- rt' fl· n' lIci ll ~ . l .-\ lahll' of fn 'lllwnll.\ tN·d '~'llI buls hlL.. IIt·('1l pb( ~ "(II It 'I;lTt . Chapter 1 10 fad lil;lle n"tldillin ~ w mlltlk wln-n IH "~ 'S"IT\ ' . T he ralll.:1' alit! uumla -r of p robk-m-, al Ihe e ud of ('adl chapter and Appendix I (total o f ";7 III'W pruh[('Ill';) Ilan ' 1"'1'11 , " h, tallli,illy extem h-dto itssisl in 1 ('itm illlJ: p ruh l('m SU "; I1~ ill l)haTlna,~,ki lll 'l i('s , 'I(lsi Ill' lilt, addilillllal problem s an' taken Irmn hterutun-, rather than Sillllltt"'i!. Ib t" , T ilt, thtrd , -c [itiou (1J1llaill\ 102 IWW fig ures anti 20m'w tables, n:'l1('(1 in~, in large P;lrt . Ill,' atklllt'(', ilIad" ill n"t'('111 ~" ;I rs ill 11liT ~'ll lwll'(I~(· o f 111(' pharmacoknu-ttcs uf dn l~s . Tlnmun-rtal 0 11 "S mall \ 'UlllllW u f Di ~ 1 rihlltiull " thut compns,-d tilt' ttsl chapter of tilt' second ,..[itlon II '~~ 11t"('1I illlUTJMlTakti intn C l.aplt'r W . D istrihulioTl , atul :\ppc.·lIdh I-F. \\'1' (~llIlilllll ' 1 adopl a umfonu st'l of svmbols 11m! 10 II...• lIlilli.t.:r.ulIsIliIN (mwLl ,lS 0 tlu vtaudard 1H,'a lW of couceutranon. \\'e do rt"l.1lj..'fli7'(·. however. tht· illl'n·,t\i llJl; trend Sl towun ] tilt' atin plillil of 1lI0lM Illlil\ lind haw' pn l\itl'''tl a fad or for conversion ht'!"Wi'('1I tht· two lIllils of nu-acun-uu-nt ill til(' ('ll'rt iIlPIlI fiWm· captious. \\'t' shall un l~' il(' convtnced of , IIII' virt m- of ,,,I,,\y lISi ll~ lilt" molar s~"Sl p lIl of mcasun-ment wln-u dm ~s an' pn-scnlx-d in ~ Ild l Ilnih.

ACKNOWLEDGMENTS
\\'1 \,;sh to th ank all tilt· Ulall)" silltipuls lind rea tlt·rs w!lu pn l\itl l"tl inpul thai Ilt'lp' ''lllis ' sha pt· Ihis Ihinl ("(!ilio n. Their 1 ·lllhIl Sia.SIIl ami {"m"llll r.t~{"IIWIlI haw ' 11t'('1l lIl,mlillllal st.ltln't· of salisfill1ion . To 111(' 1It'\.\· n·ilde r. Wt· hnpt· that 11... IItMlk \\i ll su('t.'t"("f. 1 in IlI'lpin~ ) U U <I....-dop kil)('l k- r..a....mill~ Ihal ....i ll hI' of personal \,.Iul' ill ) 'tl1tT p m f('ssio nal p ml1il"(' , \ \'(. hOI\"(' h("('11 (' llorlll(msI~' ~nllifi l"(l hy till' \\;de allli d i\"l·rst· n ·mlership of IIIl' fir.-t Iwn t"f.lilions o f tilt" h(ltlk. \\·t· ....,) \lld lik(' 10 ht'ii('\ "(' Illat lIlt' IItM ha.. 11t'l'1I ins lmllll'lIt ai in lk fllrtlll' ring mliollal lllilllav;en)(' 111 of dm~ t1lt"rdp)', Wt· sinl'l,Tt·ly 11Ilpt· tlml Ih.. thi nl t'(!ilion \\i ll l'tllltilH l(' 10 do st.1.
,\loltcllt'-d t"r , £1IJ!l m/ o

San

Fm'irl~('(J .

Calijonl;(/

\l a!t. ,lm H()\,·land 1 l1 Ullll ll'i~ . T oz('r

CONTENTS
Definition!> of St:ibols xi _ _

1. W hy C1inico l P ormocohnerics?

1

SIOION I. "'SORPTION AND DISPOSITION IINIHCS 2. Basic Ccn stde rcno ns
3 . Intravenous Dose

11
18

4 . Extravascular Dose SlUION II. THIU'IUJI( IIGI.IN5
5 . Therapeutic Response and Toxicily 6 . Constant-Rote Reg imens 7 . M uhiple-Dose Regimens
SECTION III. PHYSIOLOGIC (ON((PTS AND IUUTI(S

34

53 66 83

8. 9. 10 . 11 . 12 .

I'v'lovement Through MemblOnes Absorption . Distribution Elimina tion Integration With Kinetics

10Q 1 19 137 156 184

SECTION IY.

INDIYIDUALlZATlON
. 203 220 230 248 267 290

13 . Variab ility 14 . Genetics 15 . AgeandWeighr 16 . Disease 17 . Interacting Drugs 18 . Concennctio n Monito,ing

SECTION Y. SEU CTE D TOPICS
19 . 20 . 2 1. 22 . 23 . 24 . Distribution Kinetics Pharmaco logic Response MetabOlite Kinetics Dose and Time Dependencies TUfnovel Concep's .. , , Dialysis .

..

313 340 367 394
424

,44 3 463 469
.47 3

SEUCTED lEADING APPIHDIX I. ADDITIONAL CONUPTS AND DUIYATIONS A . Assessment 01AUe B. Esnmct.on 01Eliminalion Hall·life flam Urine Dote

CCNTENf5

C . EstimaTion 01 Absorplion Kinetics F,om Plm mo Concentration DolO " .. ,."

478

D. f'.h:Jon R esidence Time E. Amount of Drug in Body on Accumula tion

4 85
4 90 ,4 Q4

10 Plateau F. Oislribulion of Drugs Extensively Bound to Plasma Proteins "'

G B!cxxi 1o Plmmo C o oc eollO tjon Rolin H Esllmorion 01C,eohnine Clearance Under Nonsleody-Stote Conditions
"rINDII II.
IlIIlI.L X

50 2 ..... 504

uswn s [0 PlOIUMS

SOl
- "110

586

DEFINITIONS OF SYMBOlS *
Amoullt of dnl~ in hody. 1lI~ o r

A...

umolo.
Atl

sit(·

Alliount of t1nl~ at ubsorpnou n' m ai lli n~ tu he.' absorbed, 1ll~ o r "UIIO]t' .

Amount of dnl ~ ill Ixxl)' at steady state.' during con stant -rate mt rave1I 01lS in fusion , mg o r IJIllO]t' , A\'erdge amount of dnlg in Ixxl)" during a dosing Interva l at ste ad}' state. mg or umole.

A......

C UlIlulathl' amount of dnl~ I' Xe.'rd("(,1 U1l('h atl ~('t 1 in th(' urine,
Ill~ Of j.tlllo le.

A d (", ) Amount of lllt'ta!xl iite
1lI~ or

ellmtnan-d.

umole.
in rlu- urme

A..,......: Mali:imu m and minimum amounts of dnlg in Ixx!y during a dosing Inte rval at sll'lld)" state on administering a fiu'tl dUM" at a fixl-c.1 dosing Interval, m~ o r

A . ... ....

CUlIllilati\'{' amount of dOl!,!: ex{·rt'h,,( ! ll n{' h;U1~(,,( !

IJIIlO!t· ,

A. ...

dllrin~ a dusill ~ interva l at sh ';ldy

stun-,

111 ~ Of

umok-.

Amount of drug in b ody at lillie t \\ithin a dosing Interval at stt·ady state O il ;u!millish'ring a fin-d
dust, at a fi\I-c.1 t1os in ~ Interval, Ill g O f umole.

C umulative amount of d m~ ex(: rl"lt-c. I II Ile.·h;U1~t'tl in tilt' urille to lilllt' infinity aftN a ~i ll~!e duse ,
mg or j.tmolt,.
A (", )

AVC

Amount of md"hulilt ' in Ixx!y. 1Il ~ Of j.tll1ule.'. • TI\(' min imu m umouut o f dm ~ in Ixltly required to obtain " pn-detennim-dh-vcl o f n'spoII ~' , m ~ o r
"U Il O!t ' .

Aft"a under the plasma drug con centration-nm e curve . Total un-a fmm tinll' () to infinity is implied unless the lo ('(mt('lt indicates cal a specific time Interval. e .g,. dosing Interval, mg-hr/l , Of 1J~I . h r.
To tal area under the blood dnlg concentrutio n timt· curve , mg-hr! L or p ~ l . hr . lite co ncen tra tmn time curve. mg-h r/L or IJl\I ·hr .

AVC"

A y ...... : ~l ll\i ll1 11 m am i nununum A,\',.."" amou nts of d m ~ in I)(ltly afh' r th e Xtil duSt, of fi.'H't! sin' ,wd ¢\"1'1I at a Iixed dosill~ interval , 1l1 ~ or

A UC(m )An 'illlm l('r tlw plasma rm-tabo-

AVC..

umoh-.
"\\'.,

Amount o f dnl~ in I)(xly at tilllt' t aftN till· Xtli " O\t', 1Il~ Of umole.
Amount of t1m ~ (t'maining to he t'xI'n'It-c.! ill umn- arkr a smglc dose-, mg or umole.

An'a under the plasma drug ( '( )IIcen tranon time cu rve within a dosing int erval at steady state,

mg-hr/l . or

IJM -III'.

,\ V.\lC Total an-a under the first momont-time curve . mg-h.-2/L or
1J ~1 -1 1 .-2.

c

· C."..I ""iI' " n ' 10"''' .

Co ncentration of dnl g ill plasma. mwL or j.t ~ 1.

..

..
C (O)

Df fN1X)NS OF

s,r.w!O.S
lI i~ht', 1 {Im~ ( ' U ll ( 't' u l r.l!illll lll .. ~'nl'tl in plasma follcJ\\ill!{ad-

Initial plas ma eoncentratkm,

lISU -

C_

all)' obtaintod b)' (' d r oiplKdHflll to time 7...-ro. mw'l. or J.l M.
:(m('('I1C 1:C2 Coefficiellts with units of < trarjon, m ~'l.nr p M.

milli,tralioll of an t'xt m''lL 'ol'1lla r

tic .....•• mWl.llr JI\ 1.
e l m)..
C Olll't'n l rd lio ll o f a IIIt·l al. llih· al

C.
C"

Ceucentration of t1nl~ in fluitL.. 011 the ;j,~lTptiOIi ,itt·, IIlWi. o r ",\1. C.tllK't·ntrolltnll of dnl ~ in arterial

\tt ·;"ly ,t.aft" d urin£: a ('(m..tamrate illt rd'l'IKlU" inf"sinll o f dnl~

IIIWI."' J.I\t
C_ ..
\ l illi u llI lI l ('1ltK't'nt r.tlin n n"Cluin'tl
10 ohtain a pn'tIt.It'nuint"l! tnten-

blood , IIlgfL or J.I \1.
('.ou('\'ulmIKlIl of dnl~ in h lood. mWL or J.I \ 1.
CotK"t"ll lmfinlln( b ound d Ol I-:: ill

C,
CINI
C 'J
(;1

"ity o f n~llClIIs(·. mWi . o r J.I \ I.
C ,\ _ .: \I.ui lllll lll anduuniunuu ulII<.'(' n C\' ~" tnutons of d rug in plasma afll' r Iht , X III doS{' n n ;td r n i llh ll' ri n~ a fi.\t'tl d o S{' al cquul dos i ll ~ inh'r· vak IIIWL or J.i \ I.

plas ma, IllWI..o r ~~1.
Ic'a\i n~ d iOllp N .

D nl g l'lIIK"t'n lratinn in c li a l)~I I (' mWl. o r J.i ~ 1.

CtJlK't'nl rllfiun nf inhibit or of II1t'ta bohsm. 1Il1i!. or ~ \ 1.

c.;
C.

CI.
CI.." Cl ..",)

Tot.al clearance of J mg fmm plasma, l A ir.

CUlll't ·ul r.lliun of t1m~ ill Ill'rill.. lll'lll l'a\i f)·, IIIWL nr J.i \ I. CmK't 'lIlmtiull o f dm~ ill plil-\IU;. al ,11';11.1)" stOlf(' during a n msla nlran- inlr.l\1:"IlCItIS infusion, mWJ. ur J.i \ 1.
,\\l' r~{' tln lg conc eutra bcu in

To dt"ar.lIK't' o f Jmg fn)lll eal hlt:n.1. l A ir .
~'5is clt-anuK."'(" ba.~ 'tl Oil dmg .ttioo in hluu{!. LAir. l't"K'(·ntr

C.. _

CL" II
CI.~

Hepatic d(~.udIKT of dnag from hlnnc.L l A ir. Ht"taI d('llrdlK"t" o f N\·dlillillt-. Illl/min eN" l A ir. Dial)'5is dt'drdlK't' ba.'\t'll 011 dmg couceutrateon in pla. Illa.. l A ir. S

pld.\lIl4/, clu ring a dosill~ i'JlN\~J al stt-....I)· slalt· 011 d(l lII i n isll' ri ll~" fi\t"d diN' a t t'{!ttal dosi ng tnn-rvals, mWJ-,. or I-I \ t.

c t.;
C/,

C..._.: ~ l a'{i lll lll n and nuninuun t'(lIl(,'I1C.. _ Irdfiems of dmg ill pl.tSIIl;& af
Slt';lcl)" slaft' em adminis!t'ring;& fi'{{oe,l dust' .II equ a l clus ing int e-rvals, m!ifL o r J.i \1.

Clearance a\sudaftoe,l wit h Forma lion of a mt1a!J,olitto fmm a dmg.

l zhr.

c t.;
CL""

Hepatic dt'a mnn ' nf d n lg from plasm a. l A ir. l nt riuslc ck-aranee of dm~ ill or~an of t'l im inalioll . l A Ir. lAir.

C,

,\ \'{ ' m~t-

courx-utrutjon of d nl ~ ill

111li,L uutshh- plasma, IIlWL o r s

JA M.
Cl'"
J) n l~ ("IJ11c't'lIlmfifn) IIl1hollllcl ill lol al hoc.I)· wate-r. mWI-- or pM. ~1 a.,i Ill U Ill a nd m inimum limits for p la.lIIa dnl~ ("Ilnn ·n lrdfMms. ' 1llWI-- or J.I ~ I .

CUm ) Tot al d (';\mn("l.' of a rm-t abolitc.
CI· ,.u
Peritoneal dialysis dC'ardlK"t'

C.",....C".......

based o n dOlJl: ("II1K't'llfrdtlon in
plasma. l A ir.

C"

CI." CI..fl C(m)

Renal clt".uaIK"t' of tlmg.

tAn .
CII, C,_

Unbound dm~ (·ollll.'llfr.t tio n ill plasm a, mWJ.. or )1 ~ 1.

C k".u-d1H.,· of unbound drug. l A Ir. CAIIK."t'nfrdholl o f ffi(1ahofil t' ill pLaSIila. '"WI. o r 1-1\1.

Unb ound plasma (.'t)lK't'lll mlioll of illilihilllf, mWJ. or 1-1 \ 1.
C.tIlK"I-utr.lIM of dna,:: ill lIl hlcMII1lIIWl. o r J.i 'l .
\"(' llt MIS

lilt'. tal dm~ rono-ntrations in intrat. I"' k. no units. Shapl' fact or in conce nt rat ionrt'Srx)IJ ~' n-lanonship. OlIl.lo .t~(' tl. I E" f:.I.(· du!>(' 10 r-u. 'lIl1lar "uids .. IJ" U Luadi ll ~ dose. Hatt' constant ilS-\lldatl'll wit h l1... te-uuc-ally .l\ illllllll ('lTl'1 . t". of a f!Wtl.no units.:t' llt' mlcir- k (m ) Am l111 liou us a nu-tabolin-..1 t" fi· FEV.lunt·han!:t'll in urine." constant.. l'uTt'!l.\plnt' lltial coefficit'nls.1do!>(' or dnl ~ that l'nh'f'!i ti ll' J. J I~' . 11 1J1olt' . 110 units.~ IJ. v __ \ t u i lllll lll mai nft-ll<.tlOSl ' n-WlIll'll. nil units .I. Ratio of IIllhoulltl and to tal dm ~ conccntranons in tissues (o ub idt' plasma). .. 1111 units . M k hiU'IiS ·uh 'u coust aut..K1illll ratio.IIK. "" ' Jm f ill kJ /.r. Frat. Ehnunatjon r.onn'ulratioll ~i\i ll~ one-half tiM.1l1'.K1tonal rate at which dm 2 ko""'S tis~ut' ."". ft·. t'Uullililll\s or a1tt'n. Eliminati lln rat e constan t.1tomll tUITMI\"t' r r..'lis·\le ule n constant. Ii mils tillrin ~ a (k)O. hr .. no umrs .lt' r.d tiM. uutts of re S XlII M' uu-asureuu-ut . i ll~ Interval at st eatl~' ..1. )... IIlWl. TlU units..I... no units. 11f ..un... ltr . F"rad:iull lOr IlnJ!!: sph" Illit-.\IlU pron-iu.dllrill~ a (Ii al~"is In'a lll M no units.'iLil.UII~ \.. ka k" k. Inhihitio n t"fluilibrimn constan t....I. t'Xpres sed in te rms or lot al plasma concentranon. IIt'pal ko l' \ l md iull rutio .IK.(JlK . hr . n tissue and hlc..ma Ulld("f' .t ' formatio n of a m etabolite.- I'm ' F • Fraction of filn-n-d and !>('(:rt'It't! drug reabsorbe d ill tilt" renal tu bu lc. un uni ts .Jl.tat e.. E. EqUilibrium dist ribu lion rdtio or Kp ft· dmg ht1\l.. \ laintl'llalln ' dn"".eeu a. h. Ratio or un!'numlilut! hltal dm R ('OI K'('llt mt ioll~ in pla.lIltl and toral dm ~ ('OI. WL Ralt' constant for th e d ilUina! ioll or a lIll'taholitl' . Glllllwmlar fi ltration rate.bk fo r bint lill~ nn a pla. h I'.II {. no umts. k.liLahlt' 11Iat i". hr . 111' .'ntranou in blood. I ~ Frecnou or tlnl~ t'likrill~ tht' live-rtha i Ml'ilp' -s l'limi rlalioll 0 11 singlt' I'la. .dion~ in plasma. Di al"''iis cl. . " I' ~ \ I .Ssa~l' t llnlll~h th ai o r~all . 110 units.\ lUiI and lotal dru~ (.tle .I .aram'e. )-t Fr.. mgIL or p \ l .ill. 110 uni ts.tr:.lIt' constan t whilt' a P"'tiMlt is undergoing tlialrsi' In-aIIlM..th . \ I.. lin uuits.as a rrd(1io n or tUlal' cleamno.YaQlS . m or ~ ~1. Ratio nr I XIIIIIII til Ini al d m~ conl'Ol'lItmtilllls ill pl..'t . m~ or ~. no un its . \ l ichal. k /. mWI.1Ir . 110 uni ts .. uo units... U rillal)' escn-non rail.I. Fract ion or . 111 11 mill or l...l\'ailah lt' tha i h t'(lI\\'('r11' ! to a IIl1'l:llx.. F ract ion of t1nl~ "'~. 1Il~ or ~Illlllt" J"ff f liT F. Ahso rption rat e co nstant..IInClI(' .and C. 110 unit s. Rat io (If unl . Forced (·xp i rdt () ~· \UllInK' in I second.d min i. Ratio of unhound and a\'('r . P y GfJl H illa\~li bhi li ty fir d m ~.'. F.' plasma dm~ con('OI'ntrat ~ >II " 'III. • AS\lx1ali oll co nstant for tilt' biml · i n~ of dr ug 10 prot ei n..DEfWlONS Of SV.in C.'nt. 1Il~ o r ~ullolt" Ralio of unbound co ncent ranon in pla. hr ... IX :'..I.1 bintlinR. ·\h o r ~\ I .1 or plasma. Ralio of unbound and total sih 'S a...'n t r.' ma"iIl1ll1llI'lT('1.

" . I>i 'lly~. L ~1 d. of di strihu tiou (appa n . no unus. ~ 1 a.1. hr. inten. ". '11 10 thdt IIllhutllltl in plasma.tliull S}' h 'm..l'lii Ill U Ill d ns iuv.Tt1 km) into Wllm tnlmM'.lIK't'UIm hull in pl. . r. hr . (llIK'l"ntrollitlll ill ptl~III'l.. v f 1. limits . hr.is ws n-m .K1iun u f n-ual d flllK..".' l'll Ull (:lI VI.'lJlK't'nlrut!on in p!.'nul!S infll ~ioll .. L BlocM volume.'\(. L...r. M ~p- 1(" Itt.. \"olllnl(' of di strihlliion (ap pan'lI t) o f a Illt1 aholite 00. " Iltl (... 1ll~/1. e I' blood . \ '( m ) o f in itial d ilution ( 'lJIIl - partme-nt. J le-patu. n 'nl ) tlm l?. I/ m in or of ( Ii~t ri htlhon (al'lp .. lUI -' S/\ units.-una (' "K't' ufrdlkm .n l ) uml t'r sn-edv -sta te C't)fuliliom 1~l-'l.. -. . L.111 1'. Iv OE fNllCl!"iS a S¥MaOlS '" . hr.. V {>" Blood flow.1011 ih pb.. l . inh'1"\1ll ln n-lII11i n " i th in (.." lu ln(' Clllhic lt· I' • II. t \'I IIIIUl(' '-. Tu rm wer rate.. I . hr . I " ollllllt' (If d iah'!lall' solutio n (111· It'(1t. ~ 1 .. '''' "' I I' H alf-lift'. 1) lII ill CIT 1. min IIr hr.'".s 1 tre-atme-nt .blond 1l11\\' (port al vetn plus IU'p alk ark !')') ....IIt· n -skk-s ill . ~ con('t·n l r.infu sio n. "&I 1ft' Ratio o f u nhuulJ(l c k-aran o.lioll o f an extravascular cl.~lIla I 'r \ 're volume-. mediated n''''''' lion.U lll llln rate of IUt taholi. ml Jmill (II' IAlT.lSmOl.of an Individual patk'Il1 In that or a KW panem. Hall ' of filtm lt·lI11w fmlll ulu-ru ofiltr. nu mbe-r. 1. (11IK't·ntr.m I.ah· How in Ilt·lIIullilIJ~ . m l/mi n Ill' l zhr..U Ill II Ill rolle of tlm ~ t rolll~pllrt (w't.l\l. rm/mln 0 1' lJ( Jl.ma tuto which dru ~ distrihules ." Tm DumtMlII of a constant-ran..)'Sioll~c . units of re. it·nl a. I)o sinv. \ 1t~. 1I~~/hr u r ~mok~lr. 110 uui t.I11 tin"" a 1IIC..dit·nl. ' Duration of ('fTt't..'l1nlar fluids.:.l'\ot .\lRT Slope of Iht' center of It. m Z. Turno . I ~ Pt..1iou in a t~'Pkal l). '_.~·.r.1KIII in .. 1'11111 .. :\ unilk" .... IlU units . Ali"t·tlIlS " U llllll(' of illll'al. I ~ \"OIIlIlW of dial)"Satt'"ithin lilt' pC'rilulJ(·ll! cavi ty. "r "• \ ' rw plll-'mla in ln whi(·h dm~ dtstnbli lt'S."-q ut·o tls volume oulsklt· pla. 'J Tillie "I which lht' h i ~ht'l>t dnlV.'oC'l1 011 unbound tlnl~ C't.1. I ~ \'olulllt' o f dlSlrihulioll (aPlldn -n u \ '" 1Ja. 1IlW'1r.... r.' ' all r-nzvmati call.. Surfaet· urea.. mwllr . L • • \"ululllt' of (listrilK ltMIIl (a pp a n 'n t) b ased on ( l rtl~ (1l1l(1'ntm fio n ill V/ V.d ioll ('1II'H '. L. '. 1 o n ll~l~ (.lI'.olfiu (imlt·'d . duri ng ~ helllo(lialp i...\ ("(.er time.nat fUl K. Hiltin of conc eutra nou ill blnnd (..uma. :-':1111I1)1... \"Ullllllt' \'" lA.'11111111a lio l\ r.. Salt form factor. It l le uf l'tlll~tani intr. PIa. lnte-rvnl. \ '".~ a fr. . no units... I'I'nnt'abili~' {'tIll·ffi dt·llt .III indi\iftual p.~polIst· \"t' nus t... hr..'" o f ( 1tN-~ .i~· of n. \"0111111(' ha.d ion occurs follu"ill~ al lmini"il r.

\lon 'lJ\'t 'r.es the importance uf time.L~ not 1)('('11 illCrl"l<. tilt' an swers to lIlany import ant tln-rapeu tlc questions were obtai ned hy trial and error .("rTed s. succe ssful dmg therapy is "d li. un des irahle. 1)('I\\1. Al the other extreme are tho se who laJ.L~(. Bot h tI\I' duration of dmg therapy and the dosage regimen depend on the t1W T· apt'utit· ohj('(1iVt's.lli1A'S that a cos t (in term s of side l' rT('<. the se quest ions can not 1)(' dt\lIn1't1 Imm otu.(· "q~j"U'II .'a .'.lpy..(· 01 si ll~l l' duS!. anti if nec essary. this ('1I1p irical appnJl\('h contribull's litt le . .than ofTSt't hy all increased incidence of toxicity. \ \1 1 . Interval between do ses. for exam ple. our hasit' unde rstand ing of dm~ h.WHY CLINICAL PHARMACOKINETICS? T IlOSt' pat ien ts who sufli-r from chronic ailme nts SIICI. dryness o f the s mo u th. TIl(' qll('stioll Hew oft(' n? ~i7. Bt'('illl'>(' all d m~s ('xhihit undt'simble d T('(1 s. or the pn. F mm Iht·S(. afte r considembl!:' experinu-ntation n il .. n it' qu est ion 1I0w mudl? n '<. 111(' mann e-r in w hid l a dmg is taken is called a d tutl /!. Till' fillest ifm lI ow long? n't"tlJ?.diseas . as d iaht'h' s and t"pilers). d ro ws iness. towa n l estahlishing a saft" I'rTKi in' tlosagt' n-gitllell of lInolhl't (In lg.:" drugs ( ' \ 1'1)' day for the res t of their li\'l'S. Ilu."(1by opti mally halandllg til t' dl·~i mhl(· and tht.l' !lalil'llt's pn~rl'S S followed. 11l(' durattcn of drug therapy is Ilsu ally IM ·tWI. This decision implies an accu rate d iag:uo~i ~ of tlu.nnon of M e t1iSt·.l\ I.. TIl(' dose . fo r exampk-. the mitigation. such a. (JilSt'l'vations th e snggt'stion might 1 mad e that thl' tllCnlpl'ulic Objl"li i\'l' ('all 1)(· al'hit"\"t'll )(' hy maint aining an atl('ll uah' t.'ts.n nously? \ \ 11 is mo rphine mo re I'fTedive giv int ramuscularly thall wht' n giwn orally? )' en Furthe nn nrl'.I la~e n umbe r of patients.('U till'S(' (·xl n ·lIlt -s. hut not without some rt-gi UW llS p nxi lld ll~ excessive toxidt)' or p n J\ing ine rTl'('1 in'. tCl\id l)!. III rifm and i 'l ri t:t) studies show thai the ma~lit utll' of the rt'SpOIls(' is a fundion or the l1ml1-'ntralion o f d m g ill the fluid b<lthing the site(s ) o f aliion.appn ~ui at(' "d rug o f chotec" mu st he select ed. rt'a.L~ achieved .ldl allli to anS Wl'r S lllllt' o f ti ll' fllll'stions miSt'll. In practice .1('(1. doS(' gin'u.\" . doe s tet racyclin e have to be g tcc n l"\"(" )' 6 to H hou rs to I)(! )' t. and ro ute of ad ministration wen. TIle desin 'll effeceend an)' S i~IS of toxicity we re ca re fully noted. ("(111l1ll1lit'S ) is incu rred with con tinuous d rug urhniui stration. a knnw!('tlge of Ihe climcal state o r til(> p atient ..'(·n ti ll' desired erred and toxici ty ""~. To adli("\'(' opttmul tllt"r.' uf a tlnl)!. whill' diJ?.5(. it i~ fll"( 'SSllI)' to dl'k t· fnrt llt'r into tht' t"\"t'llls thai rollow d mg: ad 1 ministmtio n. the alxJ\"(' em pmcal app n "ad l left lIlany ques tions ummswr-n-d. Tn 1J\·('ft-'UlIll· SIlIIIt' of ti ll' limitatiolJS o f the e llipirical app m.man agement of thl' disease .rTt'<.1i\"f. and h)l x)k m ioll.Lstruin lt-sti n.ltioli . hallUll"t.('t1. if all)t hing. thl' convenience or g:h i ng a larger dn"l' k-ss fn" I I I wilily lIIay he mon.. )!. and tl. lIlay han ' to lal.1tgniz('s thai tlw ma gn il\l(les or the the rapeu tic and torte rt'spon St'S an' Iunct lons or tll(.1m('t'utr.auotln-r. lIlt· c1osaJ?.ltio ll of dmg at tilt' sitd s) o f act ion for till' d Ur. TIlal is. in thai tilt' magn itude o r tilt" effect ("\'('lIluall)' declines with tinll' follo""i ng: a single dose o f drug.t· rt>¢nw n w asad jush'll empirically un til an acceptah lt.J irritation.o\ in can he Wn' lI on ce dail)'? \\11 IIIIISt ox)'teK Ix· Infused tn trave Y . and a e s(lllml U1u le nlandi ng: of Ilw phartuaeotherap eutk.~onabl l· dllsagt· rt-giIllI'1JS were l'sta blisllt'll (Tablt· I-I). 10 n ·!it·\ t' a n occasional headache.. T hen tilt' questions How much? How ortl' n? and How long? mus t 1)(· answered. Eve nt ually. In th(' P. whith lIlay 1 ' t'itlll' f ti l l' cure.ll"<. 1l<1\ISl..

- n.I·Il"lo'iI-\l' (un llul.f .. of a fil.h.itt>of ou.. li'>e<~ 0 25-0 5 "'9 once 0 cloy o 2-. tI tv.1 iIImt ra te-s III(' cwnts occerrtng "ftt'r a tte~· of d nl~ i!'i ar.. tilt' ('OTK'I.• tMhm .... nntab~' tht· lh'N ami lIl(' kidneys.lt...k. on t ill' he-art .d becocse oIleduc ed ~ tl«.oon and ~e1oe1 '" """" rno. II n\"'{.. lIIall..... In il."l"ll.f "''''''l>lic''' " l ' ('1 h Iha l of t' h minaliu" .lui\.10.u-.han i.. tI ..1 o 12 24 Hours 36 46 ...n -d or. 1'i"1 (.IJIum llllCl.. . that eliminate it from the IlOl... SimultiUK'OIls1y. tI ralr of ...ni)""l. na n ·I)" is a d n1lo': plat..I/lrOIm fn .....U1iN . .n ArneIOOfO!oon 01 ~ cc-dcc fo. h unl .Jly..-r.. nftt'll . 0<.'d!{~· is Ilt"l"!t .'.. roth' uf its eleorption.ect>onl.-d. til t· d m g di"lrilmlt~ III all ndK'r ti.2 o f tlwrdpy .. In-r. lIl(l\1 d m~.! ul hN ttssues ri M:..4 .n 10 mg ~ ~ "'" Nor recom.. E . l)go>:. lnl I ....·.. and elimlnanon hilt a1 ~J of till' kineti cs of thl'\(' pnx"l'S<'('S. s. T_~ Trealmenl 01 lnf..· ad in fli t" b rain. r..~. R..Iore m O\"t" fro m tilt" .. Indee-d.."\'t 'r.d.. l~·....~ "'" "'" "--'-' InIrQI'nuSCuIa< ""'.. a n ' ' goen orally..".....r...... d therefore.. in hi<. To administe r dm~ optilll./ .J !r· I hn>rh~ tli..firf'..• orga ns... PL.JlIdi ll ~ ttN. Krfof't" lilt' 1 "'.d'iono( ."'"'\·...1 rD:T_bn.' and r Jjmination cxl'l..1< i\ " •• -I. distrihu - TIll' application o f phann'l("l.. f"hann. II.\ d Ol!.. \'w..lkl. ..ntenonee 250 "'9 ~ 0-8 lit I 5-2"'9 ..t th e n..2. St".... IWl..ntt>CJly o.kindk principles 10 tl. IRr<. .~... t1....e.lll)'.. ilml S-ch"k II U.. at the II t 'U n llllllSl'u !ar jUUdHlII.llllini"lrJotion 10 the sitt" ofaction....'Ii/rr"n by .to"f a " I'. l nnt o nly of t h~' 1ll 1.ut.h e re.I... ).. IK.(' to.. . 01 _ e po..t' 1 It....l· tberupeunc non.. F igu fl" 1.n' lt tnulrullo.... tilt' (1)11 ('t'nlroltions o f dru~ ill bit..'ntrJ..c:I.uffidt·n tl)"hi~h 10 d icillht' dcsi n-d tht-rolpl·utic t' lTl"( and sometimes even to pmtlll(. Dl1rtti..-. lmilli.. Al 11. and t1lt"rt·. · .].! }'('I tlM:.. m u. th 'll is..ilir... ' . an.''T''jr"......: f'nov-n l...4 Iv.. am.. .)'} s.ti(m of dnJ~ in " "til blood anti t&SIl~'S (1t'Clint"S a n th e e fTl"(1(s ) slIlxidl'S. TOlicul.."..t-d at ib silt' of adjoll.. knrM·I..00<- Ir. r... ellt' ro of d mg :h d....ms o f d n l ~ absorption.1WS i n<. " "1l' '11 ' '1I'' ' .. Ew:·n tu all)"..l~I'lI1 t'llt of 1 l<ltit'n h is r/lll ico!plwml(/('(Jkllll ·' lc..liull. 1-1 . n it' rate at whk·h dm~ init ially enters the bodv ('u't't'tu its rate of eliminat iun ..Iimi ljun Mt~b 1. A. llo. or t'!...

. ~ ~. aml most ull\ i lJus.lt...• r lT t't1.. _ Action _ _ 1_ ____ at Effects . ..K'!I...Jhtm Ul.l'i l... Om' pupu lar and ('tIll\t'llil'ut lI\('an".lated to d nl g k-vel-Hm e rdaliollships in the hudy. im h-ad til(' conce-ut ratiou is lI\('a..t\lol't'lI !(' ph am l'K'tl). Acl'(lTtl i ll~ly.. l lo: ~· " Wmt"fl t" lIt l.. . Flrs t. and a 1"l lln lw('Ilfl y" mll k pl lfls(·. . \ Vith n ".1' regime n miglll he defilll'ti as one th at maintains Ill(' plasma ronceutration o f a tlnlg wi thin thl' tbe rapc u nc \lo1lldow . \~ .J1(J\\111F. the pilarmal'tl). 11l(' dusing.l' re)!.nmgn il mlt· o f lilt' (·fT t"(1(S) pmd ul"('tl (Fi~.lsio llally snell all 1II1 rstalid ing has savr-d a d nl g th at otl J('rnist' llIay h'l\1. TI It'n.K'lio n 1 1)(· 1II('. a dlar..\ n ~ I'pr""... of 0I1t' linl g 1....tln lg coucentrahon at IIIl" silt'{s ) of 'K1ioll .( plals tile' <lOSt' ~ \'t'II ."('tl ing t1U'lOS.· fm m pn't.. . dusagt.. pnlC.t't'11 dd il\('(l.O'SIIIt". \ III IlMltli l)' 11. ghi ng int·fT(. . . ()('('.on 1lIi1)' 1)(' regarded us <l " tln-rap eutte wtndow..clinician ill anlidpiili llg th e op tima! tk)Sit~c n -W lllt'll for 0111 im ih iti llal pal ient am i in prt't:lil1in ~ what may happen when a tlOS:l)!. ~ ..·e Ihe 1!It'T. concent ration lie-s a regton a.'h In tI..1iou is n-luted to ' tln.lln 'tl at all ah t'm ati\ 't" an dmore al'('t'ssiblt.ocian-d wi th therapcuuc success : this n . Pharmacokinetics Pharmacodynamics Dosage Regimen Plasma ConeenIralion . I"..... when r-ither tilt' concentran on is too Inw..K II(.... ). : .~ nnat~ ok.magn itutk·s of hut h tht' tkosin 'tl rt''i!JlIII'>t' <lm l lo'l.\ llil\ ic tenet uf clinical plumuucekim-tics is th at the... silt'. .nu d roll: t'<M ItVlltnttlfln ·li mr data fir tI.l\\l)('iah't! \\1tll this appnlildl h~' (It'pk1 ing the I"(JIll't'ntrdlioIlS tlmt follow the ad mi nistnltit)ll of hm n".gs... 1.1 tI. .'Olld.'t in' . For lllallYtl m. Ilnd('rstalld i n ~ tilt' plum naco k tncncs o f a dru g oftl'n expl ains till' manne r of its list·. ~.idty an' fUII11iollS o f tln.l\t '(1 OIl tilt' fon 1:0illg conskh-runons..I.... . Il. am i mute o f udmuu strunou are rt. in which ti ll' 'KljllSta blt. .2). .CHAPTf i I 3 11lt" events f(l ll(J\\i n~ dnl~ admtutstration can he d i\1d("(1 in lo two pluse-s.... .. ill whidl th(· 1"ll1l(t'l1tmt iun of d nlg at tilt' sih'(S) of at. ~ ~I1 ." .lI)('utk ohy't... phartn. B._~ ~. iK'('lIIl1ub lio li ()("l...upti m. illfon llalioll ~ai l\('ll uh out the \kplmrm au )l.." Han ·ly can the co nce nt ration o r the dmg at II.empiric.(1in · IIlt"fiIp or is 10 0 Iligh....l\1I0't1 di rt't: Iy. 'S h.. rlt-tit ..."'"l(t rt.... II.IIt~1 11".. .·~ (o Lt. Om"(·IM.1I of these phases han' ).« to ad liMt · a plasma conce-ntration within till' t1lt'ra pt'uti (' window and then maintaining this coucentratiou by n 'plating rln." elements of du'l' .lgt· Tt-W lllt'll ca n 1 t!("!iig1lt't1 to a/: hi(. Be-tween these limib of y..--- Site ..tit-s of allot lJ('r...II1I'US.. L astly. inte r...11I ls-lp in . .al is tilt' same hut the dust· ¢ \l-'u in rt'WIIll'1I Ii is h \11'(' tha i ¢WII in n 16l1wlI A...(i mrn n it.ristk' saw·tc)()tlw'(l platt'au is tl wn adli("\1't!..-r.illdic allt l Jlll anllal't )(I~llalllit· causes of all unusual dm ~ Tt'SpOIl'l'. tht>amuunt !()'it t.I~·' - r. I o\"('r rlu. all optima l dO'i<tF. fir .· rLl... .' fi.' urs unti l.It' sill' of .-.tl app n ". plulllt't'd lIll' u"' '11 via p1... Se<.')'.' 1)( '('11 distlt' cank-d or lIas 'ill~t''ih'tl a more app ropriate dusa )!.. a dOS.. ti ll' ...1 c "·fillt ~ l .'itl" 'r Ill. Third. Fi ~ In' 1--3 illllstratlos tht·llil\ ic (t'atu n'S t· .K'<lki..llld ng unacc cptahlo tod d l)'.....illdil"'i I)f a dmg ititl\ tln.. witll hl <l dusing inlt 'rvd1.inw n.· is nu-t by ¢\1ng an initial duo... tlu-rapout ic failun.llllount u f dmg lus t with ttmc.I... a IJlwnlulC(Jki"l'I ic IJlww . Brt-aIlSC SUIllt' d m ~ ~'a'"!i « 'mains in the lui.-~ .. frt"'llIl'II(. . I)('spi h ' )(· tilt" grt'a h' r amount of Infonuanon req uired wi th thls upproec it has several ad va nlag.. of maill!t'llalll"(' is to ¢ \" a duS(' at d ist'n'!l' lilll(' inf(·rvaIs.lIl lici pal i n~ tilt' phann. 1_2 .' fon n .-~ t 'l " . .l' regimen is changed. .. dis tlnction l'im ht· III.Illit. "'.i nl'l it. i\ a ud B.K'tllciul.. . . this the-rapeutic o!ljt"l1in.!C" fir ~ ..." lUItl tI... IliL concepts o f phannacokiuerics an' co m mon 10 all dmw.Il1l'1l A..

111 utllt'r Illud!"s of ad mlnis tmtton. or in human s.·!'lop!.L~ maintained...'uli<: "1>.i. . '111l' S~l l t1 lt"l il' an timalariill aKt' ll t..lim inalt'(l wit hin minutes ..'ssfllll)"·.. .g is diminatt"tl mpidl)·> small doses mu st 1)(> ..(ft"'l1in' ami perhaps ahandoll('(1 pn. I....·" A.·" I.' I~· an d rdiahly ahso rl)('(1 t'tllllf'l"lllIld.>11 o r ally..F 11 requently. dt. Only afn-r its ph. . Sf. either iud T <...· . T his lilian· " '...l. ~> am i cousta ut rate d in't(1 1 into lilt' blood . l': . . IImllY of tilt" hll"je p n ll1. Hill! the rapy 1.. Mo rphmc is exe tt '"si\" y nw lalxl!i7A o n I). Awareness of tilt' ht'llt'filJi of llndt> r.1 shows thai ho lh IIIl' widt h of lilt' Ilw ntllt>Ulk window ami lilt' sp' 't"fl o f dm ~ elim ination gm 't'm IIIl' Si7A.<'('('{!t'{ l tllt' upp«'r limit of ti l l' tln-rap eunc "imln\\'.... th e dm ~ lIli ~hl have I)('(. 111is dt"gTt-'t of t't llllmi is nol )" · IXJSsih lt>\\. t1h i n"'I" ~· " •• Itij. foll"wt'(l hy small daily clo se-s 10 muintuiu ti lt' p l.1in ' at'l ltd y "'~..(. Also . sufficient 10 product.n in • 6"'11. Bt·sid t> had oX)1odn 11t'i:'n ~\1.In.t\. ''''In' <i " i.·.of lilt" Illainl t"nann>do~ ' an d 1111' Fn-.. quinacrine.>nlu ally p roduced IIl1ilt't. m lo\\'.1... Wil h ...1illll..IIISf...u ( e l holl~hl im.:h.'t)!cillt'lks had 11t'('1I t1t>fillt'(l W lL" Ihis d nl. 1 fairly pmmptly.lr o f a s<llIlt'\\'hal It> polt >ut hnl mort' (>xtl'll sh1.therapeutjc wi ndow. (' .J ly..>sIXJIlst> art· sim ilar at'm ss mam malian slx't.!it.. I x .landilig pbannacoktue-ucs and coucent ranon..~. all urgan I~. -hit'\. Ih is s.-I. fI{!ow is uarm w and the d m ..'t...U.L "llIa coucentratiou wn hiu thr.g l. i. ha n ' 11('('11 tried .l~lx-p titlt> hc rmom.. 1. .uly ad mi nislration .tble loxidly when a dnsill~ rate sllffid t'nlly h i~h 10 he d Tt't.g W sut't.. ..\1' i."\.re"I)tlllst>n 'latin nships hilS led in n -c ent )" ro 10 the exit-m in> app liC'"dtioll nf sucll in fnnnal io n t'il by tilt' ph arm m.1 )"1ic (> UZ)ll1t·S in ti lt" gil'"~ tminn-stinalfhuds .. is also t1t·s ln ~·t'i:l substantia lly b efore (>n lt-ring th e gt'lle ral circulation.'(1 by tln.1 . Ah holl ~h a th erapeunc rt'SPOIlM' " 11111d ha ve h"'('11 <tehit'\'!. (~lIl1l1lah .. n 'Kin. I' ' at'ult'1y a~a iTlS I u mb ria or .""'" H.'l"solge t hmll~h the liver.· lI"' r"I'. hUI hl 't:. O \)1odn is an ext reme exaruplc: it also h a. Qll i ll<ll ' rilll ' wa-.'l> ieal ind us try 10 d m g dl'si~ l . a IXIlt-nl t"flm lxl\Il\(l fOIlIlt! to l)t> pno rly alit ! un n > liahly ahso rh('(1 and iu lem lt'1l for oml ss ad m inislr.' IX'i:>n dt'sl rt'~1..m pidly than d i ~()\i n .• pI.. n g be tween lilt" g:Lst n.. i ..' t')'{:II)SIX)rillt>is e1iminatt"f!Ill11t·1I ' num. \ \1."". '1.. .'t· pl. rq~i llll'1I H.... 111t' allSV"t> ""l'i 10 ¢ \'t> 1 1I ~t' xh r t111'it ' S l"'l'r lilt" firol fl>w days 10 nt pid ly at"ilit'\'t> therapeutic Sll{..• 'i('n-ral IIm e's had to he ~n'll CHAYlH I b efore d nl ~ uccunurlatkui Wit.1 Therapeutic Failure Time .1.\\1Juld 1. ~ .· .for til t ' n ·lativd y sca m ..01\1.> mon.u ther- apt'lIlit' concent ranou.g IxlllI phannat"flkind it's alltl n. ~' ..'11 stop p d hefnre 111l'1l. is an example... " .. Altt·Olillin . . a !l am JW therupe-utic winduw hil i is t.. n ·'.> xInll x llated from animals to p n '(liI1 1Iu:lnl ilalh l... 1ti nK' inlo'r.ot inili. Bo th cvclosponnc.and h d i ~o'(ill lIa\'(' a narrow therapeutic \\.ly "ntil Therapeutic Failure .. titll' i.10.. il hils to 1)(' ..... Fo r t·xalTlple . il .. TI lt' plalt'au situation in Fi ~..IC. ~Wll orally...1 h1.. Regimen 8 "ilhin 110.p mlt. Q llin<lcrint> is t'l im inaf('(! slm"'!y am! it'(l at't. 1 (. ind '(1 n-snnal tract ."1 II.'{1 t1 urillK \ \'m ld \Var II to suhs ti tu n.'!l ofkn 10 ..111 l u ntillll('(l admin ist ration when lilt" cone-utr auon ('x.. toxicity woultl lmn' ensued \\. ..'t. 1.-l.. ..'t.1Tl"....>Sst'S l'tilltmllin." • •Im )/. hu t fo r a reuson <IilT rt'nl from that of oxytoc i n .. 11"" "P""Ii<' " KU .'SS.tlltl tilt' gt'lw ral circulation.. mltl d l'\"t'lopnwlll.tnll.gi\1.. ot. pt 'I" " " ' 1..\tioll llIay lit' sl1('I\1...'hit'n' therapeutic s m't:'t·s~ . II. qm> IIl'" o f administration. Will...)1.'lllllllb lt-s t> >nsi\..~ .'11 ill fa\1..·maturt'ly. 1-3.·'> larxN closes lIli~hl '.1 at Fi".I.1 l~' II.t i.quinine. ~t Olllh i ll e . 1.ly tlte likely he h.(-ly wnh n-pean-d d. TIl(' s 1I11 1~' nwans o f m!("fillatt'l)" l> llS ll ri n~ a Ilw mlx 'utic concentra tion of oX) 1ocin Ihe rt'fort' is 10 illfu ~> it al a p rt'(." .i('S sllcll lhal dala eml II(>. \ \1 lt"1I the \\.> ut lt't.

1.: TIlt' serurn 1t. pham.. 3.. II.:7 Assessment IAnimalTeSting) PhaseI ~ Dosage Selection Patient Variables = = PostMarketing Surveillance "lit. l .3 ".. This S('tillt' nce of events in d m g dt." TIlt' d' '''''~ '1l11 '''llt and ".1. some com pou nd s pmvt' to ht· of sul1k i t"llt 1 )('llt'fit and safeI)-' to ht· approve-d for a particular clinical iudication hy dmg rt'gu latUf Yaut hori ties. Enr... 1. usually in he-althy su bjects. dma...· I' K!I'D inf"mla li...If..Ic (... b'id u...1 '0 10 5 o N OJ OJ OJ OJ OJ OJ OJ Ol Ol Ol V ~ ~ ! 1 I ~IJ:~~ Daily Dose (mg) .odl3lloll from K()(·h · W....m "p'nK I I" II.::::J fi ~ Population PKlPD Characteristicsin Large E fficacyTrials PKlPD in Special Populations Efficacy Safety <::::..a11...its plmnnat'tltlwnlflt·util' pro file..... """I" '(1i". .r~· n . I'I"' nm. pot''''''''.lata l. '1 l1allt..Ie. TI.". 1'...t 1:..' ..... o lten i ll\ul vi ll~ ll1a n~' t1lollsalld s of patit·nts.l\(' II stud ies aft> aimed at de fining the most likely safe and e ffic-dliolls ' d()54I~t' rt'WnwllS for use in the subseq uent larger Phase III clinical trials. elin.•.".·6.". uf dnJli: ..1i n~ not only tht" most p mmi sin~ (.sdlt·matim lly in Fig ..S \i rtually continuous postm arkt'li ng surveillance to Iu rtlu-r n -fim.."" . Il:l7S. and h..s. .• 1a1'):t4" In. "'ic"'~" ( I '''WI ...rtllli/: .ln' lI: .iui.oufan n n'(l"in'(l l" p". J. .. in huma ns.. Evt-n then tilt' d m~ n ndt'~ot. .lo it"'lI lifnm"ni~! nl:. d FiK\lrt· 1-5 Illustrates an impo rtant problem idelltifit><l du ring t1mg dt..f ".I"."I t l K..fu l..CHAPTH 1 • titatiw fnllllt"'\~lrk impro ves rhe chance-s o f sdt't........1. If I"'hlll:." .1. " .tU ..tu ri>. Ultimately.""Ssnlt'ut 1:. for "pli mal i". ''P'' '' '" I t.tiKI . \\i th assessment of any sidt· effec t s produc ed.lt' I" I. ~ o D ~ ~ 25 20 15 "'111:.1.. 9:1-'l .· ' ' . "fJit:i" n'I~' .'S I.10.. helps to define candidate d(Jsa~t· forms and rt'~i ll l('IIS for evalua ttou in Phase II studies conducted in a smal l 1I1111l!Jt'r of patie-nt s.<lio'nh ..( 1 1ll 1)( ltl ll{ l~ h ut also tilt" corn-et nmgt· of safe doS('s to first tes t in hu man s.11<1 II.. Tlu-n..· 6"" "...·61.1illll: uf II ... '''~. imilar pn>lh rornhin Iim. . . II. 4. TIl' pn ·lml1lall ..oct!.l ' lOt'.I lll.'''t "'..·11' ..'11..~'r ..Jp:. lncorpo ranon of a clement wi th the-se t·arly Phase I stud ies. J. .n.. Th e M ph....Ic""lll-t·.·II" ..'S in 2lXl • •dnll p.I~'..I (W'arm" lyruunicc (1'1» .... {·1ap1 '' _ '10 t.1 urinli: ...Iruli:.'(1 .Juah" u I" ..I".ls..... 1'•• .'ali(.... tr>lli.tlio>llUf ..-elopmen t and evu huuion is dt pil1t... Iai ~' ...4· . l '''''''I''MIIKL.. Pha. alld III or human a.· ..t'1lt" r.l<ir.·rnl...I.1k (1' 11:1 . ..'Il1 lIlark....is a " i de ran~t..' of daily dose requt rem ents o f the oral anncophan ll a('t Jkin('ti(~ h~t'tll(' r o PRECLINICAL TESTING CLI NICAL (HUMAN) TEST ING Dose (Cone) Response Trials PK-gui• •• Dose escalation G=v In vitro PKlPD Animal PKlPD Toxicity c.. jIKIi'-ic I"a1il..JI I'I..e lopment and tilt'mp)". vuriability.

..·L.' . Il~(" in phamlat-"t)!..agt· n ' ..M. an. '~ ... IIl' ".. ""\'((('111.) n it· 1-6.• cu rve....... ''1M .. .. . thi s 1It 't"t! is clt-arl) ' Wt'at~t for d mgs that han ' a narmw t1w nlpt' ul ic "imln\\".l'On\lll!iion!i....t· c.. p!-""" ..j 1l"'ll1~I . lIin Irt.1. D .. that p"."d. Ihal ('xhihit a slc't"p concent...t1llnalk".1ist·a'W '.Ktic:t·.."...)jd of iIllIllUlKlSuptln ... rt"I.. 1 to dinunish d lTonic airn'll~' n-si!ililIKT in a.·lopllwnt l~' j:!... . I II .. alltl ('·yl'Kt<r>pJrint>.<!lIaJ rolli" nt i.hili ly in tl m~ n"'p:lI1'it·.~r.'l..tIlK'(.... \\i tb tl..hilily).1: u n iIlH'!\l. .-.u. nn. • • ••• .. ....S.\ It l. allJt"it lilllitt'ti...Ii. nmmt'ut al Iactors.. 1 ill lI~an tran"'planta tion ..... ~}.m 1.·...lIlt is thai a sta ndanl do . I n KI" It". I). th"'Il.. . ~ C.. ~ pL.IIKI wt'i~l1 t . M.It)'l...1:kl.r :\ h l OW... il\ in man y i o tllt'f'.(. Tl a.lIion . IN.·n . •tla ta in a t ug. II"" . t"\(· t l m~ ...... ill te rms of sud.. C...wi~llI .1i\l.a lt·n t in chuk-al prdll.."".!J•••: •• • •• • • ··. itw ff.\in¢y l'Ofll...· of total \1Iri:.. 1 ~ ""I..\.. III th is in.s 'IIIK'I. Itl it.I. '>1)(> alKI dt-. ... Ketot"(IIIaJ'. • ••• :!... U173 ...' >II1 In TI lI" r 11. li ILu.'tli ctilhlt·. SUlln:t'lIo of \" riability ill d m g n "!'r n!'iot' indmk' tilt" p"titonfs agt". I't ~ sihle t'UII'it'S uf thi s lind of e !Tt"t1: art' U14U1)" .1"ulntilm l') a n nal '01J1K-ticl pI Jdn nal"tKI).· ill otlH.nOIl to v. 11k "\( ' IJ>t."l· a sim ilar pmtlmnnhin ti mt' (an md.h WIlt.~t•• n in poo' " . ti lt' Inn-n." ii .n t c hardll. ..dit'nl's Rt' Jwtk lIlakt'tlp.Ir-.\ionall).ullplt"i..10 I" i' ~ .'IIJd t·olK"t"lItr.1.llt ac.....:n't· o f M"-'{'ri l)' o f tl...'\it~' . t1 n fn. . e dTt"t1: o f t..tion In I '''' Iwlth ..ok· ."U'll: r.\laIK' ·.l.y In ~ ....IM ""'" E.. II...t M I~' tht· rt"lip lllst· produced by f"'"d('" h dm~ alrnw rna>' ht · pn'tl it1:aIJlt·.>1 ..ihlt· t1l1riult dm~ tk"'l.li "i fo r h \ tic.lx . .. u<ortl 10 t reat WIlW l-anliac di ".In' tllt'lI 11I... a n illlllllll1 o"iupprt"S.• I I J d ini<"aJ t ria k At lt ' fIlph ..."S a dw...t· · .d io ll.atht·rillJt.. am i tovic ill ..1:t·risl in il. d t.. IIH'II of a dru~ for an indi\...n"..1i\it)•• plllh'ntia tt'S tt.. .Tt':'ipem.1 ( Ro... ".. II re. ". I .1 I~' tilt' t'(.Ir.. It . a nti with rnan~' oebers.( 1 ~t. Coatllllillidmtitm of \(·n:·r.. t!t"P'''C' " _ (If ol: N.'\il1l1 11. infonna tion o n va riability a'\ Ixn... pn.uk til at'("tltlllt fo r th is \1lriahilil~.. h .till or hers The Iwt.' (lllJlulal it m of patit 'll t".rillt·..~ ..unk' n . .&/.-nhlr >. (IIr t·""mpk·."...II " ..t . .l dm gs til a pa twnt . pa t.-d 10 p n"" 'nl ('pik-plic...! ("m. uJ.· 1IIlpn. p:lII. . variahi lilY ill phannscoktre-ncs Is a majo r "iOlHU. SUlllt' t1 nl ~ stilllulatt" drug- t.I .. I'rlt:l ". • n-.""It.I.'( ~ o 5 DaI ~ ·:-.. (O" r m~ •• 3.. :fT 1~"( Dn'lt' I" ft. ut!K'r ( I OI ~' ("II IK' IITt'n l l " adlllinL \ll -c..·Ullli ll~ iIK"1l·a..I..... tlllli lll't Ph. I ~ : t:lT 'h o( I'hrt.~ • ·1 • • • •• • • 10 15 D (mglkgl ose ..t. I'l" 227-2. can IXJ!i(" p mhlt·llI"i. tI"" 'PI1~lI i nl" !I!iol. hll'l. mhillatinn mOl>' IK' 1l"">S certai n a nd (It.\ aV. 111 1'1..""" "('''1...l.IIII·U recomna-ndatlons in di nit-a! pr.I.• on O WTUI a~lIlalll wa rfariu Iw('(I('d tn p n l(lm.IlH"1l d dOlI{ lIla~' p rtl\'t" tberape-eric ill 'iOIIW patients.indit:s.lli~n:in . am i that an' ('ritkal to (I m~ t1H'rdI'Y' E..u K.T1Clm k shKlin Iorm a Il.I......I..1 to adjust the (1oY.ain a.. pI M·"~1 oin . Iot'. 50 • • • • • • •• • •• • ••• ....-x (If h1()oc:llua~.I~ ('(..1. . ilKIi\idual pla.'..IIKI n.~(' «'. .

sis ulotn-. In this ch apn-r..().I' ha. ~n'll in slIllk-it'nlly high doe-s. tln. Dnlg st'!I'l1ioll an d tl ll'mp)' "a\(' Iraditioll . of tlu.)"Il1l·S a nti slow ('Iillli· nation..'ltlm inish'nr-d.pharIllOll1Ikillt·lir. It 1l('W1lS ""ith a consitlemtiull of kinetic cOlIll'p h IIll. Fij. ..l bt'lwfid al.wl'< llo 1)(· (.khwtil'S and r-nds wi th a Sft. therapy has bo-n iIlustr<lh 'tl. rt· 1-6 illust rates a sil lml ilJll in which lI11m itl l ri ll~ of the dmg concent ration Illay ht' 1l. 1 "I1t1 20 Illgll. H r-re again.. are kno wn . Inde-e-d. h.ma ccncenrration n f tinilltt' nK1i ng dm~ am i IIc'II('(' wil h tum -. lrllll'ly wln-n 1 plasma d nl ~ con ce m rauon d.. I) 'S it questionof dt"grt'l" Ultllt'rstamling t ilt" lilian· lilali\"{' elernents of interact ions ('I\Sl1n'S tlw more rational use of d m~ lhal may .t. It h al. Bu tll appmadws an' 1\('('11 1110 ad'!I"'" optim al 1' dm v.iOIl n mlaini nv.fn"' llIt'llt~· c N. almos t allY dm g cau intr-ruct with anot he r... A p m~IJl <l t it' appmaeh 10 this p roblem wo uld Il(' 10 adj ust till' dO~I~I' until tilt" des tn-d objl"l1i\'(' is uchh-ved . 7 to 20 IIlW[.." and the <legrt'. therapy. s 1 ~· I('(1('tt topics . Control 0 11 a t!os. pbe nnaco ktnencs o f 11 elm !!: va r ies ('on li llllc)IIsly \\ilh llit' ph..)lJlt'S and hasn-u lim /{ loss: o t lw TS Inhilut I ht"~· {' II7. T his b ook emphasizes tlu.t' of tilt' daily dU t. fi ll' S plalt·au ptt.autu-plleptlc drug p llt'II)1uill.IUy lll'('J1 llit. pharmuc oktm-ncs is tlu' major SOUn1" of variah ility.lt (' II7..il' II) phann:Jl1.."l'll so ld y 0 11 observutlons of tlnd Tt'<.s pr ocr-d difhcnlt. hnwt. tht' d lilll ~t' in tht.p n ~n'ss i\'('l)' wit h coucent ranon.. Still others interfere with drug absorption. Ch'N the narrow mllV.\?..~I1l.vr.aV. lill" ap plication o f p ha rmaluklut't ic p rinci ples 10 t11'li siu n makin v.7 1Ilt"lal x llizi ll.. 1oin is nar r ow. SUt'1l iutr-ract ious are grad ed.ala an d the pl mn llal'C lkind it's of the dm.n "adily and 1lt1.l t1m ~ l'C lIll't"lItmlio ll varu-s 1ll00rketlly ""i l hi n Ill(' p atient population .: approach. Yd till' tlwrsp unc ""indow of pht'n. in d m v. Control is achn-ved mon.15 produced.• of Im:id l)' iuc n -ase.

.

Section I ABSORPTION AND DISPOSITION KINETICS ..

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n lond rece ives dm~ Irom tl«. dermal. subcutaneous. Disom the limilolionsro interpretation of phormocolinetic dota imposed by ouoys!ho! fo. inkO'oU5Culor cod ell.1 10 diSlinguish berween cceccords odminislefed le.. ifit. \1.'wlo pIlWIlf. and in iLsS('ssi n~ risk ilssot. administratiul l n'(t' rs ftl tIlt· :tly place ment of a drtl~ t.sift's lIlay 1)( .lroYo:Iculor odminiS ll"otion. metabolism. n llllll('lIlal and tll"{'ullilliunal Sl l hstill l ('t~ . R· and 5-isomet'sl Of between drug and melabolite IX"""·'" 3. Tht ·~ · con' . in mld itilJlI to hl'i ll~ a p ract u-al and l'o nn'n it'nt sitt· of nwaxure-ue-nt. absofphon. ill I1JUlnllll nikilll'til'. t ' lt m n I. ant i n -c ul mull's. n llJfltl lIr pl ~l-'Ill a. t·itllt'r inl 1a\'I'nlJllsly or inlm-arh'rially. ind uding IhoS( in whkh tilt' d m g ' ads anti those in whi< it is ehmina tecl... This scheuu. int nuuuv lps t cular.Ul<tlo lllit' · and physi ()I(~c ft. NOIlt't1wlt·ss. Sudl !lSt. fif$l-pOSS effect. d m g ad 11 . if l/o:z.'terillary medicine. excreeon. Extmnl.y. 111is cha pt e r sllI:'l fieall)' dt·filws ! ('fIll S and i dt' S('rillt·s a basic model for d nl~ ahso rp tiol\ and di sposition .t'xplaillt'(l hy . 2. IIlIM of administration indlltll' 1111' oral.l-s u n' 1I 1('1I 1 of 11 dmg in til(' " ud)' is lilll ih'<IuSlIlllly to hlo(1(1or plasma. The-se.ofl~ 'li llc." .1l it'<tIl~ ' :h in Fi ~.forms a basls for " /.lin-c into the hllMJfl. enteroheparic cycling. SII("h " Illnd('l in~ has applications not on ly in clmical p hannucoktue-ncs hul ill d m g d. cepts a rc dt. Sites of Administralioa Then.an' several sites at wh ich d m gs an' I'(JII1 ll1tmly adminisll'n'tl . ANATOMIC AND PHYSIOLOGIC CONSIDERATIONS ~ 1 ('. mall)' uS{·flll llpp lk liliu llS that skill from ba. il· L'tJlll't'pts.. sllhlillWml. buccal.1.BASIC CONS IDERATIO NS OBJECTIVES The reooe will be able 10: Define rhe following term~: Phatmocokinelio.tu ft'S lha l aOc'('t u dm~ follll\\in~ its ad ministriltinn. pulmonary.·t>!0IX'l! in this ~'Ct iOllllf the !XX)".sun's to ('lI\.g. Thi s 1ll00'I'lllt'lIt uf d m~ is dt'pk11'(1 sd lt ' lIl..fuh U'ss can b .. Show the general contribution 01 moss balance concepts to drug ObSOfpliOn and drug OM melobolite disposition _ Phannacoldnencs hit. drsco sirian. distribJllOO.{'u /a. lilt' infonmllioll obrahu -d has proved \"t f)· uS(·ful. d 'ls. To enn-r Iht' hllMJf!.ic ". com- 2 .si!c' of ad ministration us we-ll us {'a nit's it 10 all the O~im s .:iilh'(! \\i th t'xl'll.'tl us t'illlt'r int r ava scu lar or extravascular. is III(' most 11 ~1-al nue fo r t1t·ten n i ni ll~ d m~ in III(' I M lt l~' .Sl1l/u .'.

.f.Im( .'" '''' II..rilt'..h"i"i.'tI I~' hle. all ' ilo'" "irl .c •a Other Tissues Kidney Renal Excretion •b .1:"" lro: """ I "" t! 1 .In'lt in hle .. 2. 1 li'K'" ..· " ..~. O f III l("han ~t " l...·I ly i' K'hlllill lt .' " f .111 li~I'I ..Il• . ti lt' kidneys S t am! other n f~a ns can also play un im p ortant metabolic 011(" for {. wlw n ' it is lIl'('(lt'(l." Ir."" " f .. Disposition O lin ' ubsorb ed.' uf .·lim i" . . d m~.' III(' pri ma ry sih' for excretion of thr." h...·n ·ilsin ~ o r p lll(lnd np.k i d n(~ 'S a n.e \'t'ssd l('ad ill~ to a tissur. comes alMlllt by i!wn '... " ..l'olll"in i ll ~ a ( 'lUll't' nJUS tu mo r.·.s<:llla rly... "....l'f :n·hmspi nill ll uid. Tilt' lin'f lIlayal....l ll "~' "". into IIIl" p le ural o r p eritoneal cavi ties or intu tln. It is 11 0 p on-utialnwans of ~ai ll i ll~ a sd l'l.• ..d i" " I" " I.e kidlleY".lr"I'''Il.. "S. wlll'r(' i t is not w anted.1 "f vrr- .111 bloo d. oltn-s ~.. organ is pt' rfllS('t1 \\. Tlu. ...'lt'{ l ll ndl..6. 111is ad\'allta~l' . [mi"i' I ."lh "(· tllt'ra pt·ul k· advan tage.Ul~t'{ l .:Jly. 1"·" pl..1.1 in 1 "Ie. Io rnu-d art' elther furt her lIlt'f ahnliZt'{1 or t'x("rt.. f"ll... .. l' .J fnom ..... 111(' h lll ~s an'.. t' '''\1~."...lsing d mg ('ll..pm urt· !oe. ~i l.1" 1)" h .. tittle or 110 d MIlp. 11.1i"·I).."" n'f"r I " Heart I" .! hy how w('11 ('at'l..I.. (). .·.: a . c. ami pl.-rt ain dnl j. Ik ¢ o nal mlmuustration includes iutru-artcrial injection inlo tl. · .'rnlt'ahility of liSS1U' 1llt' lllhr. """" ".·. .UI~ )i h'~ "f ..lIl S of elimiuatiou. Site of Administration U • Enterohepatic Cycle Routeof Elimination Gut Wall Gut Lumen Fecal E xcretion and Decomposition Metabolism ... "I .Ie.i ll 1I.t· in (-'l)( ls lI n' tllm up. a n.1 fru". 2-I . mu..Iml..livt'r and Il..·.li ll ("f)(.us ua] orgall for d m~ lIlt'tilIK.K" a/ N .dwmi t'al ly unaltered.IKltly.ill. a nd dt'1. tln....in i. Sil . nil' IIl('lah. Tlu.TIONS CHAYlH 2 m in i"II'n'(! e:dJ'<I\"<l.l.. or llIay b au important route for e.~' .."" .1 "f . """·.III '11 1>.lu lIll til(' n-st of the IM ltly.11 Iar ly IIIm t he absorht'(l: :\'0 a bso rpt ion sh'p is n '(I"i(('(1 w ht' ll a d m~ is adm inislen'(l inl ra\"\. .t'{l d nl~ illtn lilt' hi ll' .(i "..ul('s. .12 BASIC CONSIOU .1.t M11 sc purately in Fi ~..!i Ill.I ' II.l!.ill ' : c. 11.. D isl rihlllioll is iullueuc. .....! i. a t1m ~ is d ist rihllt t'tl to tb l' various o rgallS of tlu.I" ' II't. Dm ~ llIay also hI' atl llli nish'(('(! r('Kinnall)".'n. t·'R..1 he treated..I -.I "...lin 'r is the.~ . 111" ·1.Ltrk_ " . T Il(" two prtm-ipal O ~. l."" . hilJ(li ll~ of d n l~ wi thin blood am! in tissue s.....l".' sl..I . orgall sizt'... i'Kl " .I.tI.· ... ill comparison \\i 11l ut lll' r routes of ad m inistnllio ll.uWt'\" 'r...IlIY of 1111' (lI.S<."" St't'n'\(' llll{'ha ll. . " i l h "m".n .

·ular stnll111re allows for simple alld n ·ad). .13 dilllilliltilllt \ulalile substa nces.lIltify the various pnx'('SSf. utlil'r tunes Ihe difTl'n'IIl-('S l'lUi ht' therapeutically important. into the llIolt'(. mallYnew prntein and pol)llt'ptidt' d nl ~s are b(' i n~ intr oduced that may.'par. {"Il1lSU Ill('( ! in suffkit"1l1 tlua ntit}" to alTl"<.'tIH'I) ' o f . h nl nol Ilt'(.{. ~a.'S anti to n-late plasma coucentrunon to respClIIM' has llIallY p roblems with no simple solutions. eXlt. Ap on-nttal pmhk-m ex ist s wheu using radiolabeh-d d nlgs. a major thru st of till' pharmace utical indu stry has b een to produce tlll'rapt'llli e agents that art' not on ly as safe and dTt. a 50 :50 nuxrun. This particularly ap plies to ste reoi soun-rs am i protein s.x·ation of d n.1 tilt" slIc kling infant. und er Illest· cirx-umstauces.l't'tl dntg. 1l. TIlt' most com mon stereotsomers found tc~d lwr in medicines are optical isomers.ltioll of 01 1(' Ill' mon ' rudiouuclidcs. is lISf.stroinlestinal tml1 . lIlay IN. dext roamphetamine (S..III ord lly ac.'llall~' H and ' II. o r compounds for which their struct ures an' mirror images: tilt' drug subs tance is usually a r acemate. Ove r tilt' years .<. sten-oisonu-rs an' hei ng produced as smgle chemical t'nt itil' S. Oll\iously.l.of tll(' H. a1 ly . and coup led wit h specific analytic techniques for their det ermination in bi tJlo~ic fluids. t'xample . dcfinitjve infomlalio n about their phurmacoktnetics mil 1 ~ai llt'tl. n -c. In contrast. miltll' about th t" dll'mical pu r itj-of prescnbedmedicnes . a la~t' numbe-r of d m~ substa nces art' not si n~le c hemical e ntities )(· bul rather uux tun-s.)u ~h l whenever possihlt·.'util) ' lIlust lit' ("Cmsitle rt" Sf. An added problem exists rollll\\ing d rug ad nnntstration .' dilTen'll('('s an' small ant! inl-'tmsc·cl" elltial.'() to ('lISure rcproducibk. lilt' for m ation of metabohtes. these suh stauo-s an' o ften measured by assays that lack Spc.i fk Informat ion about eac h chemical ellt ity should he Sf. D islinK\lish l"lll't·full)' ht'I\\'('t.qualities. h ll·n·'L\i ll ~]Y. Another pot ential route of elimination is via a motln-r 's milk. such as S-n<lproX)ll . Ahhough an i llsi~ni f1 call l route of elimination ill the mot lu-r.lll. Each d\{' mi(-d1 !. A b:tsic lesson is leanlt"(l liNe."('ssari l)' o f tht' ad minislt. mall)' commonly s ('mplll)'('ti clu-mtca l :L\sayS do 1IC11 d istinguish [x-twee-n stereotsome rs.-d from natural products or Ihmu~h fermentation . ~l allY lIIt'laholilt'San' of in!t'n'Sl.lt.d mg suhs ta nces contain gpOIl1t'lric Isomers .lminbtc'n-d d m g lIlay han' !ll. hut d ll' Jllieally disttnct. aud t ill' spt·t:ifki ly of cln-nucal 'lsSily S. To 1)(· of value.III of a md inla!)(·ll'd dosc' in UrilW.ey art' ad!\(' or toxic. For example. n it' majority o f admtntste red drug today s art' tlwrt·fon· ('sM'llliaJly pun' materials. Desptte such differences .(:t i\'t· as poss ible hut also an' well e!la rat'leri7. Somethnes Iht. spc. jso mer) is a pOle nt central nervous stimulant. and still others. molecular weight dl'ri\'t. d nl K in till' mi lk ". a\uid tln-se problems. whit-I. especially proll'Ins o f h i ~. l'S{X'(. ill mallY instances . if tl.Sf. IlIl"CII'Pn r. Today.\cn·!t'tl illllrint'.. COlllplt.' a mixture of struct urally n-lated . am! pimnnal'tlkilll'lic profile. e de!t'dioll \\i thill a lumplex bio]oWl-' milieu. l'tIIllI'N IUmk Each dWIllil"a]l'ntity wit hin the dnl~ subs tance ean haw a d ifTl'n'nt pharmal'tllowe. namely.(JIIS anesthetics .u dnl~ ami IIIt·taholile(s). fm m whil·h t hl~ dt'gnulatinn pn ll!ul1s c'IIIN Iht' hoch' alld an ' ('\'t'nhtallv t'. lad purity. Notwit hstandin~ Ihest:' problems.cJ matl'rial bill lIlay prmide liUlt· to no information ailCIIII the' dnlg. Furthe rmore. all a l\al~1 ic' proced ure must dislinguish b etwe drug and metahen olit l'(s).'Cifil:ity.ltt'ly for kine·tic d dat a lu he nlt'anin ~flli.'(. Soim. g-rt"latt. Fo r .tIIy protein s and !'Nllypt·pt idt·s. CHIMICAl PURITY AND ANAL YTlC SPICIFICITY A gt'lll' ml stah'lI ll'll l 111"('(1 to lit. follu\\i ng urdl llmg adlll inistrdtiun.·flll in i dell ti~\i llg the lI]timall' ]. II 0wt' \'('r. a1mosl all of . most assays 11:1\ '( ' t1lis des tred speci ficity. a~' lit.p t for some of those 115( to '· 't1 nn-axnn.and S-iSCllllt'T'S.'t'n dt>slrcJ>·t't l in lhe ga. toXil'tl]o¢ e. alk mpting 10 ' lu.. when-as the R-('nan tiollwr is alm o t d t'\uiclof such activity. fo r e xample.

.IIll-tI'l! d nl~ pnM..p rnn ·s ~t·s of aleorption ami e-linunation l ift' dt·M ti\'(· and their II1t·allillj. 10M' hll"I I'.. ill ih "'~ I'H'" li.. .!t..· "' 1 ""'11 11" " r I. 10'S ut allY silt' p rior 10 lilt' sitt' of measurement contri butes to . ·rip ~ an.. G t'llt' ral dcfiuutous of tht' P OIl"-"St·s follow.. ' Absorption i I. (. Taktng Ih is a r~"' I IIlt' nt (lilt' ~ II'P fu rt her. ...y ""~ . make Ihe extent o f s AbsOI iull is dd il\l'il vt "t' Gut Wall Portal Vein Liver To Site01 Measurement Metabolism Metabolism To Feces HR. R.I.. . however.:hillg: tbl' silt' o f rm-asun-nu-m .u lt's of the ~."." "'1'1. SlIp pllst·. " tlnJ~ "" " 11 a. 1 " M "j ' 'Io..14 CHAPTE R2 DIFINITIDNS " h htlu ~h the..d " " " 1'T.lst nJi n lt'st i ll al Ira ti .' 1>. 'lst that a t l m ~ sll "in'~ dt ost n l(:tiun ill IIIl' lunu-n n llly III1M ('(lIllplt.... tln. I " I..I ""1..'rK~""'''''' "..of ad lIlin isl m t io n 10 silt ' of IIW. 3.lSst'S 11J"..{! ' lliI"A i/l .-. tln.answer \\lII llt1 IJ(' IM)sil in ' . 11{)111' sill ' is l ilt' !{ miute-st uml lunu-n whe n . h lond or plasrna ill all arm vein is lilt' silt" of me-asun-me-u t...<~.d rug is nul absorbed sysh 'm im Ily.l'S lllg: Ihn)lll-':II tlu... 1'S. p rio r 10 rt'al..1:.l..\. in II..l""'1ltit"..li:l :lS it p.... f"rllo .'... it w ould lIu t t11'1t'{...rri<·n .. .. H..llio ll tha i th"y (~UI ht· '1IIillltirit'd (Chaps.III"l' nu dm g: wfJllltl lM detec t ed.....{" .u ~h till' me-mb ranes uf l ilt' ~.. 111t...I~t..tl t ract inlo the po rtal vetu o nly In 1M T1lt'l a IM 't1 ('(lIl1plt' tt'ly 011 j).... ~\'t" ll mall)" moves fm m " IIn.lS is ('(IIll IllO II .. One \\'lIl1ld as k. a lld 6).ly 1I1l't aIM . "".a n" S(-"\'(' m l pnssih lt' s ilt's Ill' los s. I1t'J1{1.1 ' d l'{"rt'.d t'l"lllllpns il io ll lIlay oc cur. ". -.·.p li" " .S. tlu.'.rt't I t1n l ~ wen.t .. .I('".1 o f ad m in ist rati u n tn 1111" !{t'llt" m l ci rculation.!:I.t.'wills dt'p itkd in Fi ~.S\ tln..J h.'r.~ystt ' lTlk' ahso rp tiou. n. Then.It'd in t ilt' gencml circulation..til 1l<I' S Ih mll ~b ti ll ' 1llt'lIlh r. fi.. it 1"'"' . a n ' o fIt · II silt 'S o f d im ina lioll. f PO'''' .t't1by t'liZ)1 I1t'~ ' . 11l1ls itll' r the.t !{hUll.f iI d m~ ..lin ' r? In an t'·' Ilt'rilllt' lIl p t' rfll rllll ...' ~ " li.01 "1""'1lti.d rug ahsnnM't ) if all of the orally atllll inistt... 11\1' ~... 't'r \\1Iu ll! ' 1M III"gillin'.. f . 2-2. 11 .lSlIrt'lllt'nl wi thin till" hutly.. ·n''' ·''''ihl~·...l'il' ill tlu. 4.l'S l " nJtl~h Iht. To illm l mlt· why llhscllVti ll1l is dt·61\('(1 ill Ihi'. IlIdt't't1. ill w hi d l l ilt' 1 ). IJ(... n ~ I. n ''1ui n 'lllt-nl for a n orally adlllin ist l' rt "<1 d n l ~ In ll. . Wot)'."-r...1thlli ul: ".' ". 11In.illtl-s li ll. . h tlu.'tls fru m stn..a llw.l ". itn..I "f .iu!t'Stin al lllt"mIJnlllt's is studn-d !'> t'j). 1"'....:0....'j" .1.lstmill!t's l i nlll tract .."l' liss\lt.L a t1 m~.' III(' pm<:t'SS lIy "bid l Illlt:h... in particula r.. If.1". II. it is n nly wit hin lilt' context of expc-rtun-n tal o h'I: I"'. h tilt' dm ~ ahsorl wd ? E n ' n I llo ll~h lilt' d m~ k-aves lilt' ~.. tlu-u.... 2-2 .".tm ld y.I' lnJ i nlt'sti llal tissllt 's and ti lt' liver.' app an'll! at fi...."o-""". ll w. how t'\1. ill tI.

md frnm the sih' of measurement .l from om. Dispo. t·f" ' or .~:l~t mi n lt'sti nal membranes and the liver.. 10 .~ of d Ol ~ fm m tilt" site of meas urem e nt . Fur example. · doing so.1 not he the sann. ~Ion itori ng Intact d Ol ~ in hl(1l 1l1 or plasma olTers a IIst'flll nwan s of a.·i('S. il is a simp lt· ph armlll'()I. ill tilt' intest inal tract is t'\"("l1tllull)"excret ed in tilt' feces . Th e pa thway fo r ret urn o f d r u 1 g 1("('1.s a d n'mil"ll (1lUu'rsioll .ers'5. Ck. Ill. for the firsl time .!)("{1t·S to anothe-r. n i l' situa tion is analogo us 10 Ollt· in whic h water is plllllpl'1. th rull~h sites of d illlinatioll. By d t·finitioll. ~I on' ('()mple x 1Il(IlIl'1s art:' IIt'('('ssaly 10 t!(·Strihl· till' pha rmiK1Ikint'til-s of SO lnC dmgs.ml)()St1. am i t' xert'la art· d t·arl. D ist ribu tion. ami bt· rea bsorhl'tl int o the circulation. Biliary v -crenon is tr uly a mu te of climmntion only 10 tilt' extent that the t1mg fails 10 lit.1). An exemple is dis tri bution !Jt'h\1't'n blood . Elim ination is ti lt' Irreve rsible los. d ll ri n~ abso rption is knowu us Ill('jin t-IH t1Ji...l. B.:-II follouing tnt ramus<'11Iar.small intes tine.. is rt'absm !J('t1 in this manner. As with eu.lt·. 2. Elimination occurs hy two p nx"l. If all tilt' dm ~ 't. Disposition As absorption and d imillatio ll of d Ol~ art' juterrelated for pl l)'Si (ll~c ami anato mic n -aso too art' distrihutioll and elhmnanon. It occ urs as w.K1('ri stit'S..S(' im"'1:'rsih ly lost from Iht' b ody. incl lldin~ organs o f elimination. 19. Th is Iailurt.nt'tit· !Il()(lt.'l1 . \ln ihle Inss of d lt'lIlkall" IIl1d lltllgt"t1 d rug.-d F · rom tilt' ~all hl :l( !l lt·r ... tht' IJ()(J:.( I('mlll'pal k l. a d m g is delivered sim uha Il('tlllsly hy arterial hl()()(1 to all tissue s. 2--3 whit'll ha~ pm \'("{1 use ful in 1Il. depil1:t'1..PTE R2 " ahsorption dcpondeut on d iminalion. O nce absorbed ..origi nal n -w rvot r.l..."(:ling.CHA. Uncha nged drug in hilt' thai is nei ther n -ahsorl x-d 1 nor dt'l'(.lLS that !t'a\. p' xJr absorption d Jar. the l'tl tf'mlu1H1tk C1Jcle (S( Fig.~it itm lIlay 1)(· defiued as all Ill(' pn x'('Sses that occur subsequent to the absorption o f a d m ~. rm-tabolites are conve rted hack to the drug.l in Fig. 111l'sitt· adm inistra tion..sess illg the ('ntf)' o f d m g into the syste mic circulation . t mllS i t into tln. Examplt·s of sud l llltlllt·ls an' : <!t'sl'rilJ('t1 ill C hilps. SOilS. E limina tio n . sto red in and rt.sl.circulation.l.'(l lhm ug!lnul IImd l of Ihis " t)(lk. tmns ft· r 'lIu l d uolllit'ai. alld 22 . usually Ihe blt)()(1o r plasma..'sS( excretion and meta bolism.(' lII<1y lx' rt'fem'tl to ll\ a Itx'lliion or tra nsfer l'Ompartlllent.·. ~ of hu man anato my am i phrsi o1 0r0' "'11111 ap pt'a r 10 make it difficult.. D i still~uish in ~ lx-twec-n e-huuuution and drstrthutfon llS a ('U II st' for a decluu. Illis nu:ttllxuic illlrmml'f'nitm is a rou te of d imination only to the t·\ tt'llt Ihat rln. In l'OlIlr.ill concent ration in blood o r phsma is nfh'n t1iffil11l!. Ihl' ult'tal)()lile in tltl" I)()(l.I1lt'l al)( llill' is excreted or oth("m. lu Absorption is nol res tricted to oral admiuistruno n . to 1II1)(ld !low Iht·I)(IlI)' handles a dOl ~. sll(:h as tln. Distrih utio n is the pn x't"ss of rt's" ersiblt" transfe r of u d m . and other extra vascula r routes of ud mi uist r ation . 1':xcn1io/l is ti lt' im. lIlt' l11mpu m'Ilts o f disposition art' d istrihu tion and elimination.'01II is tht' conwrslou of one l'ht' mit'lll '. I't'rhaps surprisingly then. ft·ahsur llt'1. if d not impo \sihll'. and in t·xt'n·ta art· IllI'rt·fort· in l111T11Mrtlllt'Uh tllat di IT dl(' mim lly fm lll the d n lg. T Il(' loss as d Ol ~ pa~S(·s .. lIg tln.lsionally. hiliar:v sccn-ttou is not a m ute of e liminatio n: till' ()t·ling is then a component of dist ribunon. 2-3 n:'p n 'S('ut cem II Hlrt r/U' /l ts Ihat logi('lllly fall into two d'l~S(·s . 11lt' I)()\l's in Fig. BASIC MODEL FOR DRUG ABSORPTION AND DISPOSITION TIlt' complexiu. only 10 drain hack into rln. nt Eal' h plal.llld musek-. 1Ilt'lah ol islll in\l lkt.llIay result fmm dcc omposttion in IIIl' intestine. til(' t1m~ complet es a (")"(:11'.. • aboli.n -senotr into unotln-r. dm~ llIay he excreted in Ihe bill'.1II) ' applieatiolls ami is t' mplla\i7. slll)(:lItall('tllls. · d im 'no plat'los. lJisIXA \·ltioli is tilt" term IIS('(! to em brace b oth pnx'(·§.l. or otln-r complica tions.1.

. ..llllro 't' fo r 01.I I"'''' . for .. )UI'1'e of a d nJ~ am i its llH'talxllilt'S in tt.(·IMKly Drug at Absorption Site Drug in Body Excreted Drug Metabolite in Body Eliminated Metabolite nil:...n. II to.. .poort "'ilt.\ ".. anuoo..ol'.'I.1 or 1m! in th e (c"( 1. · int lin't11y from either hle.L "{1 U ll a mo unts o ( dnJ~ a nd nu-tabolue.1 o f tilt" ra te-s o f dlall!2:t" of Ihe (Im ~ in th(.n l .dv.\ . n lil. n~anlk'Ss of IIJI' narun. 111tum. ...thnhlt' ('l UI nlJ l~' lit.h ip'" (·\ p n. DnJ ~ at d lt' aho."h.i ll!2: drug absorption ami deposition . 11 It' clu!>t" ts al'l'Ul...".\lJ lIlinbt rJ.r ..nl d "'il...o unplex IIl(Mk-1s for clua ntil). .·u-m pl..1 au)' O Ut ' trme..)..' llUstarK'l'S. n tn<Jt oh<..".. F~\· lilllah'~ of t lm~ ill III(" ahsurvtiull l"Olu pal1 mc'n t art" ..is SIM"' 11 in Fi ~...tso mually mad. a...' equal to 1111 7~ ' nl 'Io() th'lt : Rate of change of Role of drug in body "" absorption Role of el imination 2 n it' n ·latiu lI'l. that w hidl is IIt"'-'t"r absorbed..:.. 1-.. t"._ 1 in (-:'1'" I am i 2 apply lIIKIN all ti n. ("\("ft'f.. !II(" I. <:t .Ifh"r oml ."d . . a1 orf.. ..I"'lo II t. Dose . ." lil.·' is rt·.na ('U IK't ' n l ratiu lI .J I as el inunated fro m. t1H' amounts of dnl ~ \t ilm l lllt' t.._"".__ dtffi-n.oLl. \1t1.....Iil. "m"II"' I....Ii"'" rn ...t. \' in ( ' al-ll of Ill(' ('u m pa r1nwn h : .· f...\'(' r.. 2....... t n " 1""" . haldfK'f' nf dm~ a mi related mat erial \00. n. Phar-"llln...t... ~.'1! illdmlt.1 . c.lrull.. 111l')' an" part in lldrly 115(·flll in dl·n ·llIpi ll ~ mon.h · .l.ite Amount Amount + Amounlof + rnelobo!ile in body Amounlof + rnetobo! ile el iminated + of drug in body of drug excreted 11M ma.·.'I. _ ~a1.. lI uwt..tiun ... ttM' '1.. CHAPTER2 Tln.....\lminh"s lirwl trolC.It.(Lila. .'tal n' ~ i.nf 10 ohrf. Amounlof drug 0 1 o ~ .. nort .t 11K-tal. ."S ..t .. measured in urin e din'C:tl)'.inC'llldc".llly dt"lt>mlint"(! {nlln measure ment o f Iht> hlond o r ph.qual to tiM " lll r'l..".Illudd is h."visuahzcd from mass haliUK ('(lIIsick· rdfto lls. '111' tnt"I IUIllMlIlf of dm/... n p" '""" ..t"'''I'h''ro ~ 1 ...c~¥ is tiM' quant ttanou of the.:I Ilf1 . IIlt'hthnl itc'!i in ..uf tilt' absorpnon and eliminatio n p nx'-~'S ..10 n-pn--.~: til(" molar amo un t o f suhslall(.oL .1.. nit" a UK)U1l1 in the h()d~· is mll. I IIT urne ..tune. ".()rptio n sill.... d nJ ~ th ai is 1I 1 I i lllah'~' de c omposed in tilt· ga.. n it' mod. SiJl('\' tlie ' SIIIII o f ti l(· 11K"''' a llMllm h of d rug in transfer anti dM'mie-<lI rom part nK'n ts is r.(.·."\C' l·ulllpart nk"nts m ust IN..l.

1 in th p fi" t o" jt'('fiw at tlU' Ill..·]s In dt·S ll· ohservatious and p rt'1lil1 out comes (. llIi ~h l inllllt'I\('(' a cc rrela tton I)('t wt't'll p!'lsma concentrauon am) tlwm p' ·lItit· n·s lxlIlsI·. \\'l lt'li dOI ' ~ ran.\l'n ume Ill.rl I... \\ 111'11 dl x's d m g in lxllly reach a p eak fnllO\\i ll~ admmfst rat ion of an oral do. mlTlp"rfn"'llh ... U...CHAPTER '1 17 100 / Drug at Absorplioo Site Filt.· ...'s nol v .'t l? . Ilf absllrpti()lI? 2...\ ".illJ: F iJ:s. STUDY PROBLEMS (Answers to Srvdy Problems ore in Appendix 11 .. 2-4... Follf)\\ill ~ oral ad millist ratioll of a t1 m g lalx-led with a nlditl<lt'fiH' alo lll a II (If tilt' mdio.· uuunmt of dm ~ ahsur lll't i up 10 u h ".k·.. n ...mpl... .~· 1 . I and 2.... In "'i' M.ilrnl. "f tI.1 aud 2. a. .. wlak h n-late to F i~.x ly apprna..1.I Excreted DrlJ9 " •.L SSilY thai measures tilt' .1c ..... di slill~ui sh IX'h\1't'1I n· and S·i· SUIlI.. i" .II' .·ly :1'" so rlll.of ('h a n ~t' of dm~ in h... 2-1 aut! Eq s. Can on ..."· l. D{ll's a 100'l n'{'(ln : ry of luwh an gl'tl dnlg in urin e ftlllowi ll ~ oral adrn lnistranou illlli('ilh ' IhOil d nl ~ is t1ll1lpll'll·ly ahsn rh:'tl and not 1I11'Iaholiu 'tl? h.nning uf thi s chapter.. i.11 111 of d m~ and illat'fin' 1Ilt'lal ll)lift.'rs can I" atl lu pruhl" lIls in ti lt' interpretution uf plasma data follo\\inJ: admtntstr at iuu of a met 'llIk mixtu n-.1 ' 1i1..• 75 8 ~ Eliminated Metabolite / Drug in of .' det ..ld i\ily is n -covert. conclude that tht' dm ~ is .o.~ d . Brit·lIy sia l(' why an unalyncalmethod thai do!. 1"·n~·"I. Defino' 1111' tenns lish .. " u ~ ~ ~ 25 o 4 8 12 16 Time (Arbitral)' Units) . Till. . .t slx'(1Ib l(' 011 how an .5.·. '0 50 0- Bod~ .1< lOIl I i"i. Answl'r I'ad l of tilt' follO\\i llg fllll·stioIlS..1. \\111'11 is mho of d l'llIJ:t' of d m~ in IXKly equal to nih' of dmg d iminalinn? P. :2-.. l? d.'ri! in otln-r situatio ns... 3.. lit ""li'....1 I . '~""I rtn ll Ii . mnnc.t.uu l tilt' ck-velopment (If appn lpriah ' lIlotl.'(. 1 in un lit.'? I" C'\l1 lh.'h nit. rnc"lllt ..• t~"l"" of tln1 "' . I" Flit 2--.

\!· larion. lI uw thi s infonnation is ubtaillC"tl fol h""'i ng a rapid injection of tilt" d rug for ms the IllL~is (If thi s cl. Th ereafte r."tl for grllphkally d ispla}i ng p llL'ma conce nt ratton. 111(' pliarmacokim-tic informatio n so dt'ri \'("tlfon ns a bll-.L culur rou tes.v..v.scah.rt' lIlaini ng chapte-r in this Sf.lint' b ecome s 11111<. ..·("(1 fur situatio ns in wh i(:h dm ~ lo cahza non in a spt"t-. ad m tnist ra- :\d lll i ll i ~h'ri ll !! non.' f'<llx' r (F ig. tilt' intravenous [ t.1:1IIar tlmI.' as prolllptly am i {'mO('IIt1. renal clearance.t'\l'(1: bv infusion at a coutrolh-d ra te.. tilt' plasma {'o n('('u ! rat io n is nhst ·.:l-' lx-fo n -.1in ll d('als wi th (. a constant eoncentratton can hI.th e ('()11('('ntriitiflil falls 50% to 9 mWl. Intra-arterial administration. DISPOSITION VIEWEO FROM PLASMA St"n· m l ult't hocl. ti lt' ra te of t!1 "(. " is n ·S(·. 3-1A.. which 11a_ gIl'ah'r Inherent lllanipu lat h'(' dange rs. re-quently (omp lo}'("tl. tilki ll~ almos t a n other oj 11I's b fo n.-ents folloy. plasma .. 3-1H).u uu..'(-d. (iispos itiull charactcristlcs of a dmg lift' ch-fi ucd hy allalFjng tilt' tem po ral changes ' of t1mg and meta bolites in blood. an' t·lJlp lu)l. volume 01 dislffbutiOn. 5 Cokulole rhe concentration of drug in the plasma and the amounl 01 d". shown wit h t11lt lpl. ond frocliOn excreted unchanged f10m ulinory excretion dolO following on inllovenous dose . ng an e xt ra\1l-<. D l'pit1("t1 in th is manner. and clearance from plasma Of blood ccecerecnons 01 0 drug following on intravenous dose.'<. O m' t'(IIII IIIOII method. li/$I-Older prOCMS. and f'ocllon excreed unchanged 2 Estimore the vo~ 01 holf·liIe.\ ionally u rine follo\\. conr mlled.' rnalntalned.'9 in the body With lime following on inlToveoous dose.'h slower. c!c"( sic)IJs in tl ll·rap(·utks.?.4 Estimate The value01 !he reoclclearance of a drug from conbioed plasma and Vfine dcrc.. clearance.alUM 101 the phormocokinehc pClfOme!ers. ts to p lot concentration ' again.. The. hut nnw till' ordinate ( '(lII('(' ntmtion) scale is It~ari th lll il" II .'.) one is the most F .)'lIill(' ill Fig.is for maki ng ra tfoual . eliminatiOn rcie ccoscot.data. Anotl lt' r c 111t'!I1od u f d isplay is a p lot of the sanu. a d nl ~ illtrd\1l-"C:11Iar ly ensures that 1111 of till" d OM' enters ti ll' ~l·Ilt'm.. fic o~all o r tissue is desired. eliminatiOn rOle conslon'.1 d R. ele vated co nce ntrations of dnJJ. given -. 3. til(" sllhj('t.1 of sllhsc'tlllt' nt se-ctions. n it' ttnu. ng i.. am i ot.t tilllt' nn rt':'llar (C llTIPsian) gra ph Illlpt·f..INTRAV ENOU S DOSE OIJlCTIVES The leader will be able 10: 1 Deline rhe meaning of holl~ife.dat a o n M·m iIOKdritlulli<..of aduuuist ratton can blood co ncentruncn Ill. T ill.epn.. of tln.. Uy rapid injection .·('t l to fall rap idly imm("tliat d y aft e r a 500-mg b olus. elimination rote ccoscot volume 01 di!>tribJtion.two illtm\'. in tile hloo d can I){' promptly adl.is till' sanu. Esllmote Ihe vo~ of half-life.r.. \ \ 'ith /ltl ot lw r r oute. . in th is <:a 'i(' [rom appm\illllltd~' 2~J to 18 IIIw'L wi thin 3n min ..

in all otilN tissues and . 111t' ea rly phase is l'll llllll(m ly r. and t'\"t'lIhmlly.'.lll~>kin.time n f tilt' firstmeasurement.' \U\h "i13..illl t l~· I"'·t·1l hy tln.19 S ol il't· t il(' sha rp hn-ak at ahoul I hr wln-n tilt' plasma conce-utrut tou is ubout 16 IllWL.. 5 min ... . Then-afte r.. in lilt' amou nt of d mg in the IM M. ..~1 a' .. tilt.. must han ' elreedy It'ft tilt' pLL\rna und Ia-cu d islrihult't! into et her t tssncs.. As dt't'lillt' of tln.le containe r OT s ('(Impartlllellt ..<".. 3 L.~ '1"I~lli . Distn'bution Pfluse TIlt' distrihutioll p!l...l!.II~ tilt' hi~llt's l plasma concentra tion..m...tioll (\ 'J.5 /1 \ 1). rapid e <!ed im ' in plaSIIl<l concent r atton.' . Oil thi s wnulo gan thmic plot. l11(' . tilt' fall is ra pid . il sill..ar. D lI ri ll ~ th is propo rtionality phase tilt' IMXly ad s kin('ti('ally a.l!.r.. dlan.. sometimes flot clearcut ... .. ruther IhlUI loss from.lh"lIl..II"" ~ ' l1. in plasma ft'fI("('t pri marily movement of drug within.(UlI("('ntmtiollSof tim . d ist ri buti on is ('xtrt' IIlt' I~' ra pn l a mi occu rs siKll i fi{..1. ila " . yll ulI·..'tK" o( i"I""""II'''' t lw. Distrib ution Kinetics ... th e e!im.lI11('t('f!i. - 10 E " ~ • • • • • • • a:8 ~u ~ 2 !1 10 .li'lnl> tilll' p1w. For Ilwophylline. 1l1i3.: Phanll... e g ~- ~ -~ ~ c - \ ... 19..wtioll Iwlf-/ifi' (t !12 ) aud thr tJp1'nn'nt uAtll/U.1ltin ll of tilt' atllllin ish·ft't! dn..and mon.) .. >' E_ ~- . lilt' l'/illli.plasma volume.nrt . 10 l'tmtilllll" lim·urly...l... Th e Illiljo ril)'..Il't('ri7. .(""I IJ)· h ' 11 p<tr.L ill" an' " "" li'rla~.20 . by tln.of d.L. Amoll~ these tiSSUl'S an' till' hvr-r and tilt' kitlrlt'ys.\-.~ 1 (" ' 111 tl. tht.. di stribut ion ("fltlilih rim n of drug ill ttssuc with that in plllSJlla is t'sla1J1ish('t1 in mon. hence ..i~'lo:"r1II""k r~ >t . ( \I .'~t riJ". l 'II.!!. . an ' <'' 1)('(1 more compk-n-ly d ist"IIS'i('(! in Chap. n it' eliminatinu half- A 40 ~og. n it' elimination phase is d..t d ll rin~ tilt' dis tri bution ' phil"l.is s IO WN and .tisslles. E lim inati un lI a lf· Life.>t.uh Ii" . I'L "" "" Il~· "l r"t il " ' (If tl.I)'...' (I "'WI_ .'1 ". whtch also clear d rug fmm the body.to I Ill~ or 80% of tlu..· .~'1.. rr..' ts small for th t't)phyllint' andlllan)' ot he r drugs...c 0 E u ~ ~ ~ ~ - ~ •• ". with time . >-E ~~ c 00 ~ ~ 8 ~- 30 } • • 100 ~og. S .h . d l 'i . This must be so b ause ec lilt' amount (If theophylltue in plasma lit tilt' end uf this p -rto is onl)' gtJ 1Il~.'.r a 5ln-mJo: 1. f. 1.. 3-1. " Ii fi.."ast'..''''' i1111 into a 7O-l~ "" 1 1 ). PoO' " 111111 ( ~"w.... 111is di stinct ion i.. Ho weve r. 0 0 2 4 Hours 6 8 0 2 4 Hours 6 8 . (·arl)..l'i(' is so ea llt'l l b cause distribution primarily dct emnnes tilt..t . Bf·fon· lhi ~ tune... "'"..total (500 m~) dose.. 33 mw'l.. RI .t's in plasma concentrat ion rd lt"( a proportional dJan~t' 't ill tlu.... althou~h some dm~ is eliminated dllri l l~ 1111' t'<trly monn-nts..plasma coucentranon is 1J(J\\l due on ly 10 elimination of dOl~ {nun tilt' 111M(1)' ..llIl'() the tlhtrl· Imtion plum· an d the latter... el i".. appt..\.. tht' hnt ly. H.. Ho wever.I .hm. lhr . . this phil'>t' is ofn-n called t ill' elimination pllll"l... n lis value is d {'a l('ub led hy lIlultipl)....\ 1".• In. aft.. Elimination Phase D urilll-: till' dtstnhunon phil~" changes in tilt' concentration o f tim )!..ta "f \1110"111.Flo titlll I..

thc' volunu.l!"f'" ' \nllllllt· illln whi!'h a d nL~ di. d istribution t'f!lIilihrimu ha s nnt yl'1 11l'l'1I adlit'\ '/'l!. Afh 'r :2 half-lives ( Ill hr ]. tilt' \Ullinit' or di.5 lllP. AflN I half-Iif.'UlSt' ('C lIK'C 'ntra lio n dt'lC dc'(. tilt' r-hnunution half-lift' is illtlt .!lt'IIt1t'nl of lilt" a mo unt of lim p. Do.st'('n ill "l' till' sl' m i lo~a ri t i ll n ic plol (Fi~.l concentration tlmt wuu ld h. All t'stimall' is Ilt. a' d ilution spa('('. tln-nfon-.l' .'I!lIt'lllly. n-quin-dto al'('u unt for 1111 lilt' dOl ~ in ti lt' b ody. remain.('. te rm C (l l) is an t'xtrapn !llh '(l \"alm' lind is all t'stimatt' of tlU' (1 )Jl t1'lIt m!ioll wllil'h whl'll llHlltiplic'll hy th l' \"ulllllll' It'nll . al'l..' hr)..o. In otln-r words.t. for theophylline at till" dost" ad m illish ·rt"tl.'t"t·d ing haIr· lift. all the dmp. Tilt' amount uf c lm~ in tilt' hCIl!)' is kmJ\'11 illllllt'(liall'ly afte-r un l. Oll . ill Fi/{.'IiIU ' in plasma roncent r at ton dunng tbe diminal io ll ph a..t. Calt'u b liollllf \'C IIUlIll' or d islrilmt inn n-qui n-s that di strihutiou equilihruuu hc' adlie\l'll ht'twc'('u cln l/{ ill tis'llit'S alll! thut in ph~llla .) lllg n-nnuu. di~lribu lion Amount in body P1a~ma d rug ccocentrcfico Volunu. !>C 'l. list' is madC' o r till' linear c!C'l:lillt' d ll ri n~ the t'!iminalicm plul. C.IPIl. ca n II(' d mra< rin'l! hy o 1t' thl' linear t'fj1lalio n InC _ lnqO) _h 2 wlU'rt. In pratiil. ho lus: it is the dost. admlntstr-red.~trihlltiOIl o r tht '(}ph)'lIillt. conc entration u btail\('(l \\ilh a known ' amount o r dm~ in the hody.Ale Volume of . conce ntration in p l'l'lma adlieH -'(1 ufter t1istrilmtion is ('(Im plt'l c' is a rum1 inll (lr dosl' undexn-ut or di stribution or dnl~ int o ttssu cs.'C lllllt s ro r Iht' duSt.v. TI l" . Ihl'l'phyllim' . i. A /1 v . . 250 IIlg rem. is 2S L.1illc's \\ill.l\'(' n -sulted had all d rug spontaneously c1htriblllt'll int o its final volume or distri b ulioll. is tho \" lllnlt' o r plasma al tilt' dnlg ronre-nu tm lioll. ' 5 (H7%) lIIil)" I~ · n-gMd t't! as " <Isi ng lx-en d imi natl"tl by 5 halr-IiVlS (2.. Plasma..') hr ).1B). rather tha n b'OIM!. 62 . It follo w . V. TI lt' half·life of th eophyllilll" determined by the time taken to fall (m ill I fi to " 1Ilw'L.. t.11 !In.or di strihllliCJIl.\·l'r. IIst·rul ill c'stimatill/{ plol ma concent ra tion when a known s amo u nl or dOl ~ is ill till' IM or. 3-1B). C (O) is IS IlIw'L .· (5 hr ). K Ilt J\\i ll~ tilt' \llIUIll(' or d islribution . 111is extent o r distribution can 1M d l'h 'nnilil'(l by rl'latin ~ tilt.tn hun-s in 11ll' hCMI}" at C'llllilihri UIlI is ca lk-d the. l'()IJ\'C 'rli ..t. " Vo lume ur Distrih utio n . am i after 3 lla lr· lin·s (1.. Ilcl\\·t.~ati\"(' s i ~ 1 aris c's Ilf'l.c'm tilll('..V · qOj 3 In tl)(' c':\<I"l p lt.1l!m illh l!'TI'f! ln " tit" !liltit'llt . .son 1Il~ Wll . 111t' nq.un. tha t k-ss dn l~ is l'Iim inah 't ! in each su('(.-'(1 is.li\ill~. reqnin-d to uchicve a llly t ~\l '1l ph\lIla e uu vntranou.((lI' / lIm 'Ilt) ( "( 11".. CC III.that it lakes for the (1111{'(' n t ra t io Tl 10 fall Im m 12 10 fi IlIWL. 111t' \Ullllllt' IlW'l. a. 3. in c'stimal ill ~ lilt' dost.. TI.s well as tbe amount of thl' d rug in Illl' IMM ly. l 1lis is tilt' s am e tmu. 111t. in dTc·l:t. In itially thenare SOlllllg in Ihl' hody. k is thl' J>lopC' or tlU' lillt. artt-r t ll(lnm~h ' .. mlm ini stt 'rt'll.20 INTIlA'/ENOUS rose lift' is til(' time taken for the plaxmu concentration. " i tl. is usually measured. rru m this t'filialiou at .'!y. tilllt' . 12. \ '. This is analo~~oll s to lilt' ck-n-mnnattou or til(' \ 'O IIIIllC or a n -servotr bv d i \idin~ tilt' am oun t o r dn ' ad dt"(l to it bv the resultant conceutr afiou .' c1l1ri n ~ Iht' c·limi · ' . ( Fig. Sint"t' . To dn th is.is 5.('l lc'l! or III(' ph~Ill. In fall by OIlt··half. in the hody. 3-.ur. ti ll' amuu nl in thl' hotly ( "II IInw 1M {'stimah'(l al any tinu. /11: d istriJ".or d istrih llliOll i.18 am! C (ll ) is till' n mn' ut mtioll /lIlC' wu u lel 'nJlint .

ih .iw..'('n trdholl or amount in tbe btJti)· l'Wl lit. n ""'I'M "l·· th't"I. gn-at thai tbe \'olunlt' of (Lst rilm tion is mall)" t illlt"S tht· total l.mi n i ll~ tl H rat e a l ".. on ill\l' rsioll TakinR the natural Ic~aritlllll o f buth side-s.. is dlan~ll~ with time.1 t't! dnl~" an' . F in t ·O roc r E liminatiun.·ttlt-cJ.. SilM. • _ b 4 "------'- 5 silK'l' C ' " and C(O) .693 7 constant k is i ll tilt· t'\ pollt'n t in F.0 . ~ Oi l«' . Vohmu-s o f di. l'<lUM'S for dl is "it!t. tli\trilHltion ma~'lrll ' to al l)" utlt' o r a comb ination of tht.-d ont o the cha rcoal.lim' in tilt' pl asma tUIt(.. tlt~I'M"'I1 h. ~\l'1I II)' Etl s.693 nh taill5 t he important relanonsbip.-:. ' 1 ' ht1tt'r uncL'nttoo lJ)' ex. Why tilt' r-lhninatton fill' tl woph)'lIint' (and for IIK".(CIu llt for all lIlt' dnl~ in tilt' ~ .)...>n.· a sinJtlt' MpOlIt·ntiai n-rrn a.· l.. (1lI0IK)K'xporw ll tial.l(]lIt·ous pha.0. would ht.+ -I and <-III II( calculated fmm F. 10..t". VnlUlIIt" of w stribllHoll is 'il Jin"'(:t IIWClSUnc.. 'In .lIalf.. Equanons -I a nd 5 t'nahle the concentranon and amull nt ill tlte hod)' at ioUl" h lllf. it fol1.IIIl1t'h Jtn'alN tha n that uf tilt' total ' 5)".~· . M. in tilt" IXKk {'1II 11'l'n l m t iull of th ' 'l'phyllint' in pWTJliI is 5 mWI.....1.ou ltJ hI' n "l lnin'll to lK. Tlikill ~ ~ the an li lo~arith lll of hoth sltlt'S uf Ell. For esamph-.o f tht" ('" II'nl of Ib~t rilllltjon..t " IIIN dnl~s ) is hneur when d ispla)-t'(l st' m i lo~~a rit h lllimll.• fn JIII C (O) to 112 C(O)..nil''' the a mou nt in tilt. such as plasma \ulu nM:' (3 1. o r total hod).. ('o nsid(' r the di'!>trilmlion of 100 mg o f a {Inag in II I· L system com posed o f .Alt"ou~ t he lIlt"a. 'In . nanon phase..'l' ti lt· dimimll io ll half·lift· (frl2) is the time taken fo r t he ('(lIlt't' n · tration a nd th e amount in tilt' IKJti)' to fall by OI1(".h 'lII. \\l l('n til(" charcoal has !\t.-ate-r and 10 R o f al1i\'ah'll d lan 'o al and . 3-2. nit."'· t"I1·r.te-rn. lhl' roncentratson of tl n l ~ in tht· ..rbe. n.' tn Iw. I' . .of dm~ is lIlL 'il. himhng 10 lissm' l'Om porwn ts rna)" till' . .:. ap pn-cian-d a.cl' 7. ra n~t· (If values an' di scllss("l! in Chap . Disiri llllt io!l . :'1.II"C...<1II lit. " art· tlK" illll(KlIlt in th t· IJ(JtI)' allli tbe t!tlst' ad mmlstered..-" A _ Dc». II ran-ly.2.. \ \11t'1I tlt'(. ' It..i7."""\ from Efl_-I that : 6 o r. w h tilt' en 'hNt' art' 140 m. ntis is ohtaint"ll ll)' t1ifft'n'lltioltin~ 1' 5.~ .. To appnocialt" th e dTt"(1 of ti' SUt· hindill~.. ' A . wate r (42 L ).a.: th us.In 2 . 2 .. it is sait! til ht· .-...' esti mated . 9'9'1. ·. -I anti 5 .. 100 L I)f tilt" a1 1 1lt"lK'S phasot' . DnJ j?. 1..i l'ltl~ c -qol ·.. corre-sponds 10 a real volu me .tnbunon fo r M.tissues and fluids o f tilt ' bud)" F urtbe rmon-. a vnluun. I mWI.t rdCt"lIula r water ( 16 L).llin~ may 0 .h U\\11 ill Fi ~... Follows .

T his is also tlU' mit' of clnninatkm o f dnt~ fm m tht· heM Pn xx-sses such as this.000 Drug Quinacrine liters/K g 500 200 100 20.000 5000 Chloroquine AmiodalOOlI Doxorubicin Onipr~mine 50 2000 1000 n Jt.05 3 ..rit~ "'itlo·I~·_ ChlOrpromwne Nortriptyline 20 10 MlfIoxi<!11 0'001. in which Volume 01 Distribution liters/70 kg 50.Inol:' .ra il' (If (:hanKe' uf lilt" amount i ll tilt" hud)'... ..000 10.111 500 Qiltlaum 5 200 100 50 Verapamil Morphine Raflllidine DiazePim EryUlromycin Phenytoin Theophylline Ampicillin 2 0..\ = D cl'il.• "'I'I>.I""".Ih ln h" k .k· A dA 8 9 Tln.5 20 10 5 0. mt" "'~.' .2 tbupreten Warfarin Erythropoill'1in 0. .22 INTRAVEf'.kll . .U'O'nl ". 9 is rln.1 0. it (nllnw<ithal dA di . 11..0U5 D05[ CHAPTH J di but ~i nl't ·. 3-2. l)'.h .term 0 11 lilt' left-hand sid e of Eel.

10 Eq .. . Bec ause I... 1("((' is 11 Ill't't l to ha\1' a p ararm-tcr to n-late rmrce-nt m tion to rate o f dnl ~ t>l imillalioll . Ortlillllrily.do ">(' n' lIlai n i ll~ ill the body (NOose ) varies "'i tlJ tiun-. .doS(' remains afte r ' ha lf-lift'.14 h r .CHAPTER3 INaAV INOUS DOSE 23 Ih". 'S.lS the pa(.. Rate of e limina tion ." pm('t'Ss n f theophylline.k · V · C 15 C omp arison o f Eqs . 14 and 1.('(! ructional mil' o f r-limlnatton is C). tile va lut' o f its e limination ranconstant is 0 . art' known as ji n tofmler li me· The pm pmtiollality const an t is know n 1L~ Ih(·ji n'-t.I .-' lfll('t11 111(' jmctiOllfl1 m re {if dn.IiO".doS(' (('Illai ll i ll~ is. us the. then al a concentratiou o f I IIlWl.kin etics of dru~ e ln nln anou lIIay I I(~ . Sillt't. r ate of rt'ac:1:iu ll is pr o portional to ti l(' amount pn-se-nt. 'l S k :::: O.: cha racn-nzes till' eliuuuation pnl('t'ss. S hr. it is known us t!J<> r [i mi llotil m rate n m_~t(m t .rt:'lll't. 9 to yk-ld l'_n~'. ' Frac tion of dose A remaining in the body ..CL· Conce .1!. .mil./ 'r rate n llu to " t with dinn-nsions f o f tuue .. k _ Ra te of elimination Amovn t in body 10 til(' eii nuuatjou rate L't mstanl lIlity sim ply 1 ft1!1 "..lr.conccut renon of 11 dm ~ i1wn '1 S( so dot'S its mit' of dillli1I111iull . il follow~ that » .o.. if the w.Dose - 11 111t" [ruct ion of tiu. o. <lJl( l l/~ (1/2 X 1/ 2 ) o r 2. Jml . A :::: v C. dt'(Jot('t1 hy CT. ls Fo r e xample. llwrt'fo (('. like Iho ">(' o f [lo 01(( ' colunn.(If t1istrihulioTl is 11('('(1('1. . 5. w/JI onl!. tilt' rate of dmg d illlina tiull 1.. . lilt" sp('('1.I . . Fruction of Do<. Tlltl s. o'''el imino tion . Fu r example.!. o ""' ". ~\1 '1I hy {. d ('amn('(' \111ue is I l zhr . o r hy sa~ i ll ~ thnt tlte F .. Cleumue.(' Remaining. and SCJ on .l u f tilt' d im illati. F r om EII. Sill(:t' ti l(" rute consta nt can also he denllt'1. Another view of tln.'>% n-nuuns afte-r 2 Imlf-Ii\1's. By (('ft. 1/ 2 o r SOli u f tjn.:: SCI is S('(' I\ by letti ll ~ II ht' themnul e-r of llalf-Iin's (. it is !I'w ful ln ( ':<P (('SS time ft.(Iotal). ch-amuce rvmafn s ti l(' s ame. TIl(' valur.~ .l"tin' 10 the ha lf-Iifl"." e ""' .I " (o r '4% ) o f l l l(' d Ol ~ ill III(' bo(ly p('r hour. Eq..' o f r-lhrnnatton :::: k . is I JlI ~/hr .o f dn in.69:Yt 112:' JIIiS 2 Frac tion of dose re ma ining in the body - 12 Fracti on of dose re ma ining in the body = I 1/ In 2 13 111l1S. A . II t. Total C le a rance .mlt'l('r vnl uuu.1 10 n-lanconcentrat ion to amount ill th t' 1)(1(1 so 11 )'. sint't' Ih(· half·li ft· o f IIlt'uphylliJlt' is 5 hr . Sorncumcs.. 14 111(' uut ts o f eleanmce. From Ell.'5 !('lI<1 ~ 10 tlw n-lattousbi p .::ai.l hy ft'arnUl~ n/. is that p ro p rtionalit y f'Ki m . I.IIt" .c-an ht" dlamd eri 7 ('itl wr by its half-Iif('.lapS('(11Iftt't a IM tluS(' ( II :::: tit 1t )' 111('11..I)('r unit tune.wd by l''tlUnillill'::how tilt" fraction of tlu.

It is mo re l "Ollll ll O Il to refer to tilt" lI a](·Ii f(· ruther than III thc elumnatton rail' cons tan t uf a t1nl ~.-slimalt.. wllid l for an i. Clecrc oce • k . 3-. To show lilt' app lil'< llioll o f Eq.lflc(' by: 0 . 17.U1Ilt'f to stn-ss th ." .ulily ralculated .1' . tlu. so tha t V half-lift· is n-lan-d to d t·. and therefore..lIh" il is n. Inag that has 11('('11 .can he better t'slilllaftotl iu OilillthN way. Fnun limt' 7. . t JI hy dt'amlll1' ~\'t's lilt' amount of . I!O Wt"\'N . 18 whe-n.JIl" obtail l(.. IItKly d uring Iht. t'lim illah 'l l. Furthermore. clearance is rt'.d. l-t..11 hillf·)if(' {and d illli· mlli on ra il' constant } rt'llt'(1s rat her than contro l.llt'(l.ra lt' of d ill1inatioll (If tht'oph)1Iillt" .Interval. has lilt"sault' t. . Arc" .Itolal) dl·amll(:t· of t1lt'ophyllint' is calculated to lit· -I l Air o r 67 flit /min. 'a. of"'''11 111(' \. h r. mlmillistt. Inulin.' )6 L u f exlm' 1'Iluiar wa ter. l111lsidt' r the lise of creatinine..-'.Ul ~t '(l in Iln.... )m'sl)( md i n~ small an-a under the plasma co ncentrattonlim!' t-urve-.'C''''::'''= = = = Clearance 17 Equation 17 is p Ulvosd y arr.~ .'xtr.(! by . :\l lt'mati\".."""''---'-.concenr rutton. two ill(l" I)III(I"nl pammdt·rs..tln.unu.lII b seen th at d \l rill~ a small interva l of time.'amllt" of II ..' or vnlunn of t1ist rih ulilln 10 calcnlan...' 1)(. if the.'-\ (mill t ill' hO: N is -I ly III Whr.. h.. :\ml th.A L'C is li lt' lolal a n-a und er th r.n-d. dilllillalio ll pha.uf tll' 'l)pllyllillt'.!t"ulatillll of d ear unce is imlt'!w lltlt'lIt o f the shape' o f lilt' coucentranou-tinu.) Fnnn !lalf· life alltl volunn. I m~ is I l z min and lilt' lIn'.of d isiri butiu li.2 1)111" am i is t-n 'nly . \ 'nl ulIl.tri(1. \.hnunan-d up to that lillit'.abo\'(' 1lI.t'm 10 infinite tim.1.t\\"' '('11 flO and 6 1 mill h I 1ll ~-m i l\/ l ~ tlu-n tht. IIUIIlI' of d islrihut inn ami cleara nce..product C ' tit is tilt.it"tion of til(' Inial art'il hl')uud a g1wn lilll(' is a 1ll. th is l.. 11111s.. tnt al AVe . For r-xuu ph-.693 • Volume of distribution . As t'X))('(. a n d Volum" o f Distrihution.· arance. t· .1 l1ml'('llt mlioll to amoull I of dmg in Iht. o f th ..u!t' th ai IlwIT is lUI needto \.2.'!illlina!t'() in each finu. 17.lr.Cl ' AUC 19 when. V U sill~ CHAPTER3 16 ElJ.'(1 to Ih. . H)' n'arr. 3lXl mg ha~ )'('t 1 ht. in tilt' eoL'it. [A L'e (f).\-\ creatinine. C n 'alln!IIt' !la\ 11 clearance of -:. it lV...t.alllllllnh . inu lin hlL\ a half·lift· of nu ly 1. Hccallthut ' \12 "" 1I.'tt>i1 hy calculatlon m inl-t E' I.~lI n' IIf tilt" fmt1 inn o f dllst.lt·. Ti ll' rdatillllsiJip !K'I\\'t'('n are-a lind ehmluntiou ran II(' applied al auy linw fll!lo\\i ng d mg mllllinisimiion . 11l11s far . as Illust r ated in Fig. 16. So 11m! at a (11 111<1 coucentranou nf I mJil .\t"t1 to a\M'SS n-nal fUlld inll.clearance.' is . tit.Iy.'!illlill. is .l~ 11('('11 .. allt l lll:'lIl't" 4O'. C lt. or 2()O mg. k .cnrubohsm.lr. C learance and E lim inatio n lIa lf-life .5 lrr !1(>i'. hy . its half-Iif...t IIl1d r-r IIIl' l'll r. IIm llipl)illl-t tilt' an-a up 10 a giwn rinu-.1IIt. mu-e AVe is KIUJ\\ 11 (Ap!)('mlix I·A1. a mo unt Ilf d Olg r-lhnlnat cd ill th ill mhnnv is I m ~.l\st'ssc'(l hy m ld ill~ "p 111" inftogmtillg tlu.v .. listrillllh>il t hmll~hullll h.llllp lt·...pmfil(-..tpolalioll (1': '1' 3 ) " .curve. IIIit' o!'taillS 111(' fral'tion o f tlw d oS(' d imina lt'll.' also 1I. : a product of ruusch.6 11 1" tile an'a is 4U% of lilt' tul al AVe .• t jn. a pn lysal'd mrid. n 'lIIain ing In l)t. Thus . 11w lulal amount of d Olg ('n 'lIll1a11y ('lim ina l('(I.' 42 L o f total hudy water.69. cleurunce has )1('('11 .tt1iull of II. l. Clearaue . Fllr t·X. as a marker of n-nal fum-non. e Am ount elim inated in interval dt _ Clearance ' C · d.' half· ' lif. Dose . fr..·f('(l 1 0 5()()-lllg lIost. ..110\\' til.' o f d islri lm lio ll { \1 is IIst'() 10 n '!alt' p t l\lII.Jiminalt'll fn uu Iht'! I(KI)'.U1¢ n~ Eq. wlu-u lilt' area is ('xp n 'ssc'll a~ a fr.1/ 2 . b olus ("(Iuals the do \(' atllllinisl.

con stant v . n·. .LoI.h olhl'r voluuu. ·nh . t·stimafe.Ie · "'lmini..t· (u llt'1... i'lI .v.I . h.1 o 2 4 Hours 6 8 .. Urine.sllally IWpiltit: IJlt'lall(llism ...1Il hc' usc. "r..ct I I ~' 1I.lhl'l.ullint't! in Chap. SI. RlNAl ClEARANCE Elilll ina!iull CI('(· U "" hy n-nal excn-t ion ..c rfl r 'I"'0 l'''~ lt i ll'' .. The lM. b olus situation hilt l'.. · is n-nal r-xcn-non an important route of t'limillalioll for lIIany d m gs.( 1 "~lJ'MI · .' 1" '1'11 .t'Stimat e u f excre-tion mit. Tlus is l·sl)(-c·ially trm.~ . howt'\"t'r. n it·.. Ot't'l. n-ual d t'a nlllt1. .1throughout th . is app!it. ~(JI onl.t' ohtaillt'tl [roru analysis o f urinarv dat a..fur urine..CHAPTE ~ 3 INT RA-Vi NOUS oose 2' is a rt"L\(mahlt. 1 . lilt· total dl·ar'U1l't·.LSiOmllh·. lin alilll: IlwI 411'. .) min .I..md extmn-nal piltl l\\1I)'S....l~ma coucentr anou h' ll iu(·n·.. lilt' valuc' of \ '. A li".. . t'slinm!l' of this \u11l1l1l' tcnn. . I· . infusions .·li". ·n .. Pnldil'al pnJb le'ms ari se. o\\ill~ 10 incomplete hladdt' r t·lIlpl)ill ~.'l. .6 hr rtllrt.v.. . 3-1." lip In 3 6 Itr i .• ..·c1 ill t"i" ."st 1I1("IIIoc1 of t'ak'lIlatin~ \1IIUIII(' of distrihutlou is to d h id(· d l'anllll.IIlJ f'!nlnlmY' .U·C i. ~ . . 1unde-r a \'ari dy of conditions.(' lIh l lt' n i ll~ tilt' ' rt t'l ~.. Dose 1 AUC ·l 20 Unhke extrapolation. Cm lsc'C!IU'n tly. tst·s till' IIIlt't·rtainly in tln.. C 21 lh-na l d t'a nllll'l'. "i tl..cininj( In I . long-tt"nn i.'..LL....dislrihlltillll ph'N" it is not .ls nnits of flow. :J-I.is lu llt-c 1l't! cvt-r a finite IX'n od . C analysis is lilt' t'l)JIl'!.' (CI. 1 n sill~ Eel' 20..tf"d llt'l'...cl<. t' .. when t'slt'lIsin' r-lunmntkm occurs in tln. n-nuunder of thi s hook.(u l1t'l1in rl inn-rcals of Il'SS thau (.'pl (If ". l m the l. of II.1 ha.'1II.·1i1rlin..c (~ "K ~·"lr.crt·... "\ l1 a l0l-~lI ll s 10 to lal <'I t·arall('!.·.1 as th(' proportiouahty n-nu l)('t"'I"1I urinarv excn-rion rate.. I..n-nus are t·x.·rt..' . sa. Jl1... this method of t'stilll atill ~ \ ' is not restrit1t..O]" pi".(lrtt ·lI ilJ~ II..(' bv r-lunmauon run. bul IIsc'ful .· fill'l. t1l1rin~ wllk-II tilt' plasma conce ntration is dmll~lI~ l'o lilinllu llsly. ill t's timalill)!. 411'. .. ~.. alt holl)!. renal d t'..s . Distrihution Kiuet k-s.... 19 ...1iI1ll pt 'rind reduces tln.. R ) is d l'fill(.Cl .dmll~l' ill. ""lllml lo this p llanllal'llkil1t'l k iuformutiou run iJ..."• .or ""Imin. usually m illilil(·rs!lIlinnlt· or hn-rs/ hour.~·Il.n..1.• -I hr.' k"H jl!"· n .ami plasma l'Ulll'('lIlmliull: bcretion role • Cl// . n..r"I II.

EX lt'liding E(I.ahst' lIl't' o f plasma tueusu rements.. in . tlt..l~t' plasma drug conceutratfon du ri n ~ the (1.('U I'\'(' . midpo int of the (d ll'('!iull interval . In tln.ttuu. 10 avoid t ilt" problem of iuce mpk-n. til(' Int erval sho uld ht. the pe-riod of tune 1I111s1 1)(' at lt'il-st 5 to 6 elimination half·li n 's of tilt' d m~ (st'(· Appt·nd ix I. that is. l"itll I.eurement o f the. lt. t' nd o f Ill(' (d lt"('!ion tum.l\ plwllolml'hil.(lllt'('!ioll tim e Sl' lll i l(~a ri t h Illi<. fmill t11(' slope o f t lit' stl'ili~h t Iilit' .Intervnls. ' l'slimah't l fmlll Urillt' data.lSto inhi bitor. AUe withi n ti lt' ti nlt' int erval ( St"t' Appt'mli \ I-A ). In pruet ice.ht. :'\om-tln-le-ss. . thi s assumption of linear change is reasonable oll l~' when los. The mi nt' collect ion int e rval (de llo ll't! hy t\t ) is compose d of mall)' slJl-h n'l)' sma ll lncre ruents o f time . By asslllllillR that IIII' p h SlIli' rmu-eut rution dl.' uc WI lth In mle rvo I) l 23 Th e p roblem in ca I('ulalill~ n-nal dt'am. In s prac tice. 111is app roa is analogous In th at tak('n with ch to lal clearau ce-. TIlt' a\·I'rl.rsihlt. si ll{"t' all uri ne formed on'T a I)('rillli uf at 1I'.B). such . if the Ilal f·lift" of it drug b in till' unlt'r of it fl:'\\' hOlln. 111 awmgt' plasm a (1.AUe is the total area 1I11dl'r tilt' rl.tj ll~ F. Ix" cause the plasma conce ntra non of drug is in faet dlan!-?Ilg t'Xpo lll'lltially with titue. (Jt is the l. St·\'('rt' t1iffit'ulti l'S wi th {1.1 Ilt'('!ion int erval is !-?WII by «AUC wit hin inlt'mt! )lN ). d uring tilt' tnn-rvnl ts small. in unli t' collect km occu r. df 22 when' C .hut at some inlenl\('tl iat e po int. can .' then-Ion . rt'(juin's II II1 fl(lifit '(! ap p reach for tht' estimat ion of renal clearance. ti l l' ap p mpriatl' concenrranon is that at tht. 2 1.mu st hi' taken to eusu re thut allurine is colh-cn-d an d for a su ffidt 'u t ('Jt'rind of tilllt' til gain a R OIIlI es timale of tilt' total amount excrcn-d u nd langt'tl.I1(1.A!.t·lll pl~.lsma t!rtl g concentratiou.n -sts with t's l ill1 atiu~ tilt. T o apply Eq.. Amount excreted '" CLI/ . t'xb l k in t' mllri n ~ urine collections taken 11\ '('1' an at!t'(lllah ope-riod of tum-. . TIlt' apprtliK is to plot ti lt' an'mgt' t'w n' lilm mit' agaillSt the 'h midpoi nt of tilt' (..)II{1. 23 11\ " 1' all t tn«.lInp li'lI\l't. C . TI lt' dilllinalioll half·li ft" o f lilt' ft'\1. C HAJ'T E ~ 3 collection inte-rval.lllgt'S lillearly with time . IlIJ p ract ical t1ifT ·ultit·.L~ lII a dmg conccntrunou-nme curve.ss than an elim ina tion hal f-lift' . 24.: CLI/ " ( A ' t Of\ In efV(] co 'lee.l\ 1 1 mon th must lxcollec t ed. o f sll ffidt~n t l)' sensitive ilnal)tic tec hniques cau and prt '\illllsly has prewu n-dme. 1I1ll' obnuns tilt' useful relationship .~ 1ll '("t' SSiU) ·.couceutrauon of lIIall)" d m gs in plasma. galallihamil u'. 1111I"'. DISPOSITION VIEWED FROM URINE ONLY Lac ].lI g . amount ( If d rug excreted ill a collection interval is thl' SIII II of lilt' amou nts excreted in eac h of th ese smal l mcn-men ts of tum-. duri ng a \"t'f)' small int erval of Ii me.(JlTt-'sp:m<lillg small art-a unde r IIIl' pJ. [rruu zem to infin ity.2. ena c ecro nce " Total a mount excreled unchang ed AUC 24 when.(1 with . ohlailJ('(l Irom u rine data alone.. however.. wllt'n sud l i. useful tnformanon can still ht. and . l'!IOIiIlt'sh' r. Amoun t excre ted .'lilly and .ht' w nnill g nor at tht. for d ru w.l half· Iifl' of abo ut a week. neuber \ UIIIIlI(' of dist rtlmttou nor d ('amn('(' can 1)(' d('It'nnillt'll.'IIis tration is neit he r the value at tln. By rt"arrdnJ.

.. Ol"ld-sionaJly... W.m.....a~ain s t tlu."Ih>imi l"'lt> .. tilt' value offi ' mn gt's het\' 't't'u 0 and l.... :\n ('st ima tl' offi· is most readily ohtalm-d [rom cumulative urinal)' excretion data Iol1 U\\i n~ i. inl/: .ot.u... ca n. I .. COII.on {·UII..rm". lilt.. AIIlUll ~ d m~s .1 11:. \\l w ll the \ 11111l' is low. collect 1000 ~ a: ~ -" 10 f: 100 u rin. uri nal) ' excret ion rate is proportional to p lasm a con ce ntra non.~.~ ) . .ft'. (R. is 111 fract ion (If II\(' amount (' n t(' ri n ~ the o rr-Illation that is elhnlnan-d hy extra re nal 1' mecluuustus.. KIltJ\\ing f e ajds in t'stablishing uppmpriatrlIlod ifil'atiolis in tIL(' IIsual dusa~(' rl".ug Ie _ excreted unchanged Do.l1. n. l'tlllsta nl'" o f renal clearance is Inferred. n-nal excre-tion is the on ly rout e of eliminat ion .fi'.ta ken to ens ure complete urinal)' rt"t.·h . J.. I'han ll.. II is a quantitative measure of the cont rihntion of renal I·X I'n·tinn to (lw r:lll dmg eltm tnatron.1 0 12 Ph.t".-Iwr...u\('n u f a d n lg for pa th-uts with \1u) i n.(!-\APTER 3 INTRAVE NOUS DOSE: 27 obtain an es timate o f till' half-lift" I ll t ll i livt'1~·. and pl ott in~ uri nal)' excre tion rate a~. tilt" approach is ('asy to see.... . 3--1.. the collect ion inte rval... I• .:t" ... T .. 1Y91. W..i!i.. i"I. ulj".ltio n) to fall by ollt··halr..'t~ or ~. w " " 0.· in I"".... since by defiuitlou.'R nn i/: ".."'1io mn 1"''''''/ afl.fract ion of the amount enter mg the V. ns . I lth~......\...I.e.u" Ih. II . in whic h l'a<.. CIi" . S ilT )....lr.B... TIll' half-life is then taken as the time for the urinaryexcretion rate (or plasma l'(Jm't·lltr."n.·t'~' ly .mid poi nt tune ... Totcl d.'h" T.l~{.'.cl.omi."'·n rm m 8i .il. paranlt'tl'l"is tln. I 24 36 Hours 48 60 72 ..should alw.. degn "t's o f reuul fUl1(1ioll. rat. 801("' no. '111e 11('('(1 for using midpoint tune follows fm m the previous diSl1lssiou.I.1 .t' ne rdl cm-ulunon that is exc reted U1ll'haug('(l.t' the value o f fe is 1.1.dn .ti ~h t lille is obtaillt'(l h)' plotting the urin al) ' ewreuou run .S fl : 4 :W. ' of 10 ml/:of1/:. Form al pmo f uf till' fu rt'going diSl11ssion is !'in'n ill App endu I..Ull't' is constant .(J\'('l) ' (i..v. For ~aJant ham iJw this is approximatt'1y 6 hr in a ht·alt hy subject ( Fi ~..·~ .O.tll..0.. subj .'ol .lYof dmg ehnunauon.og:n 't. excretion is a minor path\\N . admintstrutkm.n<I . usually me-tabolism . n .killt'lit.l\·l'r. By ddinition the difT ('f'('lIl't'.f'aI... p lasma conce ntration duri ng. U.. ~""" I . J . the measured u rinary excrclion r ate n -fh-cts till' . Renal Excretion as a Fraction of Total Elimination :\n impo rtant phan nal'(..4 2~. r lU' 1..' r.. Unlit' .' . R.d . wlu-n a st r. TI. In pract ice. Assullling that renal d t'a r.li.tillS t tune is likt" plotting plasma eoncent runon a~aill s t ttnu-. il7. .I~-s 25 lx.

A ().IMI UrI_ . ' 010 0 43 0 20 0 0 25 . esli llllt1I. l'lis is pa rtit'ulany useful in Il lOSl' situation s in whit-Ii totul u n l it' l '(IIII't:IiOIl is lint po ssihlt·.wI. Clear-lII('(' is t1t'lt-n nillt'(l by t1 i\itli n~ doS!:' hy AL'C.Io.dmppin~ p n ~n's­ sin.(!lIsi n~ Ihe trapczoldal m il' (Appe nd ix I. of SU Ill~ o( a d nl~... o ccec TWf 1NTf1V"I """" o .fjl\("tl ilS th e fatiu o f Illl' rate (If ewn-tion til till' mil' of elim inatio n._ .lS tll(' mi lO ()f n-nal am i total dt 'ar.I)(('1l a\ Ill(' tiul(' (or til(' l'lIl('('n lr.' ''' Pl. III p r act ice.x .lll)" id. •• I.~ '" 'NO.'(.v.2. CI.In.25 Ilf . 111<' Ital (-li( '. 1 follo\\i ll~ an l. is Ihe n -(on' 19 . hilt o nly a(h'r tln. .A). 'utiedllo Ihal calouluted hy ((hi d iug duS(' h)" till' Intercept l'tJ!l('('utmtin lJat IA'n l ti llle."t'll that 27 Thus.Je) . T his pamnlt'h'r can I" ..'allw no t1i \t ill('1 tlislrilJ1tlitlll phase is appa n 'ut..tr.2._ • 08Sf N AOClN TI1MMEM C# Dolo'' ' lJRf"..S.9 lA ir for clennme-... OW1H3 \II.J!NA!.how lilt' p hann<l('Ukindie ll.2. Plasma Data Alone A p lot o( p!. extran-nal dear-lIlt't' is ( I . it is Sl..(1.m' fllr 011 It'll" 5 t'limillatiull h..2 1Il ~.5 ) 1·1 til(' !tal(· li(t' 111 and elimination r.da ta an' ploltt'( l S<' lIIi l()~ari tl ll n it. "'roN 3 5 7 10 18 ' 2'1..12 12... holus doS!:.S hr . 26 .U to U.lt(' constant 1M.. "" 120 180 340 178 ' 50 ="".S 1lI""'1..lt". ..' n-adtl v de!t'rmilll.ll r/L and wlu-n di\itlt'(! into the dos<' \idds a value of 4 .ly 0 .'sl im a!('(1 From CU I. w!lt' n './l 11VI "'''' 133 50 63 10 18 2 Im .'5 in sllhjt"t1s with normal n-ual Imu-t ion . f ' ("'\J"/ll N"" .tlll '(' s . -<> 2-4 . and CJ.1."lllly (Fi ~ .13 ''''(}-2 '0" ~. \ 'olulIlI' of distrihutiou.~. d isposi lion ure l'slimah..We 3-001 . .. II(' t!.. Plasma and Urine Data Bntlt p (...>-8 8.' from I .l)".I.(().u :lioTlfi' Illay II(' d l.1 BO ' 00 226 14 0 0 66 0 80 0 43 '6 0 00 56 34 .Jf-liv('s)..."->.fi' is app m"imah.T lll. 111 Intal. constder tilt' pla_ 'imu and urine da ta in Tabl e 3..'''' . 3-.2 to U. 11: 0 1 of excretion 6 I!:o of elimination le Appmpriatt>l~· s ll "st it ll!ill~ (or IU... fi· liMy "lSI .. (' so that k is 0.A!.U : C . estimates of e l .·fillt't ! llmi l'sti lllah·d . .IIIN ato r am i ch-nouuuator ill 26 Eq .. nIJl:lim'(! {rom tilt' sln j'" of a plnl o( Ihl' amoun t e-xcreted \\il ltin a " 1 1l('(1inu interval . AI any inslanL t llt' fr. ~""-'" H C91flO 32 " 160 250 30 6 34 0 372 391 .1 • 0.L sma concentranon versus lime illdi("lill' s that IIII' \·alll('s an.6 L... ( I f U.1 oblai nl. is 10.N " (tfIl D "VCWlT~ C UYU. ESTIMATION OF PHARMACOKINETIC PARAMETERS To apprr-cian. !M..llil't' is dt 'h ' n uilll'l! hy d ilT l'T('!It't·. 0W-1. .0 """ N " " CCN:f:NTU .Io.lfillllt'lt'rs dd illi n"..mUl(" ... ex t run-ual t..Y. I" lilt' (~lW of ~al all t hillll il lt'.4 ••II. 11 111s. is 2.tt ion to fall in hal( ( '.L'ima anduri ue data an' n 't illirt't! tn ('slimalt' rennl dl'.. 1. 1'\. I mwL). (E:I. ..A...' u h tililll't i di n -ctly. Tht s value is \irtll. 20) . I CO<f.

0 H It. i S) (cf t:'I' 2i ).· li n M ..1--..tim!' i llft·.0 IJh r) hy fi ' (O.1Il ht· ohtatncd from either excretion mit' or latin' cxcn-t ton data.. so rln. is 39.(· of thi s dOl ~ is -I IJhr.. TIlt" stolx>o f tilt>liue indican-s that tilt' n-nal d t'ilr.5.2 0 u 0 0 0..3-4>..\. an M M".0 0.. §."lItialty the sann.</.. "" !V'•....ltlat" " . li' M·.. Da l...ug:ht Iiiit' implit'S thai n-nal \ dt·ar. TIl("{'u mnb th "t· amount t'xn t'l t'{l is 39.' uf II.. un.. TIl(' \t r.. in TaM . or lI..1 f"un 1.U1{.01 8 12 16 20 Hours HK ...." h~" tl.fraction of the delS(' t·X(:ft'tt'(l lIn(:han ~t"(J. 1 mWSO mg:..·.oralM..Ifl i1Moal In fiM' .CHAPTH 3 INT RAVE NOUS DOSE a~aill \t . TI lt' app r o priate nu-thods an ' dt'all wi th in Aplx'llflix I -H.1-. " 0. <' 1111 111 3.(' (. .lll('t· i\ con stan t and illtlt'pt'ndpllt (If plasma concentration .. " z: .iS.1.o (n" " T . g y ~ ~ ~ 1.f(' .J" .5 e c 0. L'C within tilt' sann.1 1Il ~. i.1.....-.. n.02 0 4 C5 E ~ ~ c. 3--fi).-c ' 1i<M' in l. n '"lralilM. ES. Urine Data Alone TIlt" elimination Ilalf.\lllllt' is o!Jt<lill('..\I.0 2. l " "'f"T 11 ' M ""'M tulJ.-\l 'e: ""·. 1i.1 0.liW<1h· r" '1M.il"Kantlullit' r~>t u(I Il .d hy 1Il1l1ti pl)i!l ~ total d t'ar. rt.. 11 (Fig:. :J.</ d.lift>of tilt' dOl~ ('..IIl{...I"p. Lola · Ki'n . 1 . o 1 2 3 4 Area Under Curve Within Sampling Interval (mg-hrlll ... .a] . ...5· St.05 0.

lIu l ht' illd ml t'(l ill tilt' Dt. Illtlt'l't.. Stril1 l)' sl)( 'a "i ll ~. tilt' . B-t'lM dUst' u f t'.. l/n.killt't i<' data alltl makt' prt'C.lst'S Out··. IIIis t1t-grt·'t· of illinum li\i tlual variat ion is <ll1.1I ~..'l1 upnn slalistit'lll ('rilt' ria.' phurmacokine-nc parunu-ters.pt'll i(·Il(')·... lin tlilTt' rt' lwt..LSUrt'II\I' UIs han' errors lLs s. all 1IlI' .limah'1. tl u. 0lwflit uf..k W ith ill hlcM dmg can biud to ma ny ('tlllslilut 'lI!s i ndlltLu~ plasma p mtr -ins ami IJltltKI ltl.. tht' pl ll1l\t ' ltl.. re-ader.SFlUI CC /llCt'Ilt m t/. Thi s is 1101 unusual and " i ll N U('(1Ir in llIa llY case-s when }llll dWl"k }llu r uu swers 10 l ilt" problems a l tilt.an.s the IN'sl t'\limalt' of Ilitf1 l11wlt 'r. This ('flllsistc'Il('''' (Mdllllnt h(' ad lit'\ '('t l h)' fitlill~ ~rdphi<-.tillS l tho S{' ~ n' lI ill Appt'ndix II..rt'lIt'(' is t1nJ~ ill serum Of wholt' blo od.. B.ulI fl. MOfl.ull l l l. Measurement Fluid So far.S hr. For almust all d illiC'lll situatiolls.l half-lift' ilia)· haw ht'f 'n :U hr instr-ud of 2..fillilio ns. In!l'g ntt iun \ Vith Kiru-tu-s).l\llla.. in om' d lap lN ma.(1.lltmlio li of a tl m~ is u ntl('r.!n. this plml"l' is oft ell shurtt. s doUi n!. In lilt" .ct i \l' I~· unimportant .1 s \ 10 he.'tJ\"t'r.1 t'(llIatiull."'l'n fu rtht' r sl.(ft' mml~· sih mliu m in p lmmm('tlkint'Ii<--s tlml ft'(lllifl' . :\l sc ).od a l l't ! \\i th all al~ t ie methods.ck-Hned. Ihe. ill "ltwlu/ (or hll N ~J..l.hook. Ilst'C. TIlt' majuf d aTt' f('II('t' " t'IWt'('1I p l'l-m<l ami serum is tilt' n -moval of fihrifl(~t' n ill the. INltl. 11ilt! tilt' sl udy ju st ('o llSidl'I't '( I IJ("('1I rl'pt'ah '1) suh">("(llIl'ntly .lll..: n mo. Ilwn'h)' )i(' l d in~ diffen-nt I vahn-s for ma ll)' phanna('tlkint'l i<-' Jlilflllllt'f('r.c1ll (o r b1of ~1 n IPu-" Pl t m t lo ll ) ill mall)' (Ulll('\!s in whidi ('tm(. alltl us mos t dm ~s do lIul h ind 10 fihri lJ( ~t' II .. Ih mll~hnu t ti lt' INM tilt' k rill 1"(1·\·" m is taL::('1I to illdllt!.n the "lllll l' indtvtduul. aflN 1 11(')" ha\'(' lx-en plolh'd.llt'(l lo .' data and eak u lalt'( I III. .'ul rtltltm . CnlJst '(l"t'ntl. To <l\1Iid l'tlllli lllmlly rt'tk' fi n i ll~ them ill t. ill mudl of thi s dmptN lIml t hn .. t l lTlllitium (If . I I. uul ike serum und pllt..'fit' l'ardlllt'It'r \·alm' s art' adjllslt'( l lo J:i\'t' llw I~'st fil of Ih(' appmpri. mu st an swers he ft' a ntllhmu ~houl tilt' n-maimh-r of ti lt' hook an.. an aSI)('1. Alstl.ClIl I~· ¢ \l'!1 to ! \\11 or 11 10"" Sij. h locltl allt l p l'l. han ' lx-eu t1t'fillt'(l \\id l n 'f('n'II('(' 10 d m !!: ill p l. 5 10 Il Yl variatjnu .! S~l l1 buls Ihal occur tllll.mpk-s prior to iUla l}1iis .ma. . To n-flect lilt' ."...t' p IJilnll1lt.lidin ns.'sn lts in tll(' Sl lllt' all\"\o\"(' r. 12.\ I)('rinlt' lltal da ta ..' pharma('tlki lll.'C..lS{' of ehmcal anal)'sis.o rlt' n('l l lo l. lilt' phartuacokinetk-s of tilt' t1 m~ wi thin Iht. Clllt' sho uld uS(' the h'rlll illol c~· n mt'~" l t rtltilm of (1m /!. t11t'f(' .u~ll(m l tilt' n 'sl \ of tilt' IUIk. A ("t't ll'tlin ~l..-tIM Simi larl. tilt. o r 1.1 dis<-'usSl'(1 ill some dept h SUhSl·· Illll' lItl)' ill ti l(' IU lk (part i('u larl.rt' u ~'t l ft>pt ·aft'tll)· I llft lll~hoU I Ilu. StJlJlt' iufrt'(jllt'ntl. III this chupte r.lx. cells . p lolh-d li lt' sa m. of hIIMK!. st'n llll. Ihis is S(lIIwti lllt'S e. an d C hap.t('t'C 'plablt. ll\ it is the firsl tune tlmt ti lt')"an. inclt'pt 'llllt'1I1 of Ihe l ('atioll of tilt' ~I m(' t'o lllp ult 'r p n J!..latte r t'a.'i(' h. .' equivalent.ma cannot I)(! ('tJllsidt ·fl.t·I')' chapte-r alltl to I"adlitalt' refen-nceto t hem. appli'T. ~' lll lIIay ha\"l' ohtaillt"tl a nswers that d ilT Irom t!loS{' ~\"l·11.' \ISl'lllo all'IIF. l'tlllfidt'!l<-"C ill t1lt'IIl..f( 'r.<lI d ata hy t')·t' . mall Y s~lu hols an. t(J"'~I' .·" u/ It·nt/'r). b ut also in('f('.Definition s o f Symhols ap lx'a r j ust IN'fo ft. 11lis appmad l 1101 (111)' pnJ\itl(. llr/u " m l ill hotll) n.. an t'\I)(lIIt'nli.. C hap . alld in roll lldi ll~-Orr numbers . Fur (':\.tw('l' 1I til(' ('tlll<1'ntnltioIiS of d m !!: in plll-SlIla ami se-rum is t':\..'C 'ptablt·.'t.30 lNn AVfNOUS DOSE Cl-W"TE fl J A Question 01 Predsioa Had vnu . mml measurements an ' lIlatlt" ill plasma.I)('(1t'll.. rut her than ill blood. Chapn-r I. Use of Computers Tt ltla)' (um putt'r. u ntikt .'11ifica nl p lace s. In addition . El imination... 11 1t'~' s)1llho l\ a n . SUlIll'l illll'S tlu' fl. ('11(1 o f ('adl l"h<lplt'r a~.clllUllllt tlf d ftl~ ill Iht' Iltxl.lft' t'(lllalion 10 Iht' ('. althc m ~h for man )' appl iedl iolls ill p lmnmK"tlkint'lics. 1) flI ~ ('o ll('('lIlm lio lis in whole hlotM alit! p lusma can d im 'r.'ft..<lmn (o r 1JIc ~ ~/) tlm:.U1d li ll ~ of . 111 reuson Iii 's in d ifTt' I"t-'IJ('t ' S ill th e d r-d"in~ 1' of a Iilli' th mll!-:h data. ti lt" dilTt'fl'Il<-'t:' is f(' I.N .

l'n-pu n .v.t· of til(' tIusl'. ). 1 II1g. bolus dost·. e . \i rt ilall~' impm sihll' . Xoucthek-ss. howt·ve r. Tht' f"'ll-tiol\ of all i.4 mg. 4 . A t1 m g tha i di splays OIlI··l'l Jlllpa rt lllt'1I1 disposition kmet tcs is adnuniste-n-d OLS a singll' !M dust.tlly M 'r\l' .5 g fllll c J\\i n~ a O.tl'li oll o f the admi nistt'n "ll tloS(' elhmnated by it gin'n tillle is ilJ(lept'nde llt o f rlu..)(l.foltfl\\ing: a. t1 m g ill 3 hr? ' .C HAP1f ~3 " t'l!u atinm. ' a. 111('11.5-g holm tIC a.n 'ud i l~' when tilt' \·alllt·s of tilt' plllln mu.relationship : C '" 0. is the tot al uri na ry excretion of unchanged d r u IAt'" "" 60 g mg]. ohta inillg a lx-st fit hy 1')'(' 11l"<. 111t' half-Iifl' of a d r u when IS% of th e dose re mains in till' hl xl)' -I hr aftN all l. t1111 ..0 3. lilt' Ave is 5 . p'lr.lIld tilt' at. the-refore. is II m~. Because of IIIl' ~n'al 11l'llt' fih lu I( 'an l ill~ ph anllaml. It takt ·s ~\in ' . 3--.'hungl' wt th either dOM or ume. IFIICT OF 0051 An adj m tnlt' 1l1 in dO is ofh-n 1\t'('(' sSilry to achil' \'l' optimal d m g therapy.l. 111(' t·lim inatillll run. whid l O1I1'(S) of tilt· follO\\i ng statements is co rrect? 11. 111l' pa mTllt' IN \11111t'S nhtailwd by t')'t· also gt·'ll'r..a st' milngari llunk pint uf till' f{)lIf l\\i n~ plasm a conceutratlou-ttnx.Il1l'h ·1'!i u f a dnlg dn lint ' \'ar:' \\i lh IIm l' or \\i lll concenrra tiou.hr/L and tilt' (11I11 ulati\l' amollnl l'"l'n·It"lllln(:h an~t'll.is in hours . G in 'lI IIlat till' t1isposilion l.majority of till' book. huwt"\. ' ' fo r ma ny reasons. T ht· fr.~ tIUM ·.3. holm dUM' to hI' clnninated.possibilif> for a dJallgt· \\i lll dOM exists .left -hand graph of Fig.quality o f the dat a and thl' ('(!lIation that is I11l l' 1 lil. 0 11(' gains a f('t·ling for tln. h. 3 . Co m pll'll' unnc ('lIIlI"l:lion np to 12 hr is 1 1"11 1(' 1"1110 pn l\itl l' a good t·slilllalt· of Ill(' ulttman.h rll ~ 111t' lotal S :\ l'C is 2:1.v. c. 3--.Tln. 71 where C is in IIl WL and tinn.int't il'S gaillt'l! by plntling data.. when lilt" half-lift· is 6 hr. 22 under th e utle of D UM' and Tim e Dl'pl·IJ(Il'll eit·s. pharmac okmc tic pa r."<. Tl m mg!1011t tlu.si.int'l it's of a dm~ is t1I'Sl'riht'l l h~' a one-compartment Illtxlt'l .f of an i. 2..9 e .tlu. and thes e an' dealt with in C ha p. Complete tilt" fig u by drawtng continllum lint'S thai t!t-pil1 Iht' fall of d m R n('('lltmlioll in plasma . F ru m 0 10 3 h r af!t'r a . :\ dj llsl lllt'nt is M' mad t.I.r .amount of d n lg ewn-n-dunchangcd. ' STUDT PROBllMS (Answen to Stvd y Problems ore in Append ix n. a ~n'ul d eal aillmi (Lila is lea rned by di spla~ ill g " W ill gm phil'ally.likillt·tit.1 atl1l1i nisll'H'l1 tIoS!' rt'mains in th l' l x xl~' a<. tht s r-h-ment is Inco rpo rated inl n lIl 'Ul~· p r obh-ms thnmglumt tln. h. Depicted ill till' ri ~h l ­ hand j?. Cuk-ulan.. tluS(' rell lajniu~ ill the Ixxly at 3 hr.v. It takes Hi hr for S' "S'.) 1. boills doS(' of dmg.-tly In thl' 1 '\I)('rill ]('lIlal datil.L~ su itabl t· slarting \'1III1(' s in a l'lJlIIputer pm~rmn.'i g folltl\\i llg a I .11Illulalioll of d m g ill u rillt' \\i lll tilllt' . 11lis limitatiuu does 1I0t ari se lISin~ a compute r: any equa tion can Ill' filtt 'l! di rt"<.t>ly til dt'S('ril ll' them app ropriatdy..s it doe -s 10 lS(' t'lillli llalt· ll.~s long to t'l imina!t· 0..rdp h of Fig. 1>t'pi(-tt'll ill tln. :\r " .book. are the plas ma con centrations IIIiS o f d m g ohst'!yt'tl initially ( 10 IIIWL ) and 60 min later (2. . mg ix . a_ \\1lal I)('r<"t' nl o f 11.. g. mon.l i 3 hr .con stan t o f this dm ~ is O.t· hal f-lift· of a t1 m~ follf)\\in~ tlw r apent ic doS(s in humans is oJ h r.5 IIIW!.'Olllto:. that cannot ht· hm-anzed.tl1ll'n-rs an' aSMIIllI'l! llllt to (. d.

'Im<l (~ J I K't' lItrd t i oll­ . c. Calculate tilt' renal clearance of Hu. \\ 'hen 100 III~ of a dOl~ wa s Ji!." y ~ " o 2 Hours 3 4 5 . holus. Ca l("ulafto total clearance.5 2 2. c 0 u y ~ 2. tune rela tionship (C in mWL und t in hr } was ub!it·rn'tl.i\'l'll a.14 6.~ 5 4 ~ 7 3 2 c .drug.5 1. all is." CHA PTU J II. 7.5 3 Hours 3.5 4 4. C ." c. 173 ' 10 9 8 °E ~ c ..5 5 ~ <> _E c _ ~go o~ o ~ ~ 40 30 20 10 0 ~2 > y E ~ o~ -" => u~ c:.. o o 60 50 0. d.6 .: 0. ~ c. tilt' foll(J\\i ll~ p la.0.\{'rd iull? fi. Eo. \\lmr's the fnl11ioll of till' dost" tlml is dilllill <lll"d by n"nal l'.

J'n -p. C lin .~ .. c..\U1 Il.1 m~ cocaine h~tt m('l.· 3--2 "U lll llliui7. b. .llc' ti ll' total A (:C of l1·ftria. J.J.ak' ilatc· tilt' . \I.l~ pla. and StcJl"'l.J..IIl~ i. .~') . T . Teltal . c. Amlin ' .. _ Tahl.fhoIw 6 120 AffMo I•• • &4.lkw) h .m a da ta uht aillc'l l afh· r a !Jui lis lie N:' of n·ft ria.-" 33 ..\UIK'." of d i'\t rilmtin n . B ow. ) . ' . d m~. Est ill\.."·whon! .. G i\. .\OIIl. _ 3 .!aoLlf·lift· of I.124. c. Pharmecol. E!otimah' ti ll' 1J1lIf·l ift' am] lolal clcaruncc of cocaine. . ) .r. _ C I ..tn· lhc· plasma l1 111l"t-n tnd iuIlS of l'K. l' n-pan . hull l" du'ol ..ltt" Iln . 38 :31S-. .we~..l~ .I" Alli nson. . Tl .loride· In a subjt't1 ..kinc1it'S In till' ... E.1 1_".we 3-02 • T lhrl ime 1•• -. •-liminatjou. al KI dlnmotrupk' d Tc'1". a.... a .J. m ll'IIOI h' Ihc' \'Ullllllt' uf d isl ri· h utillll IIf l"tJl-ainc' ill l A Jt.c'n tl lal lilt' bud y wl'i~" 1 o f Ill(' slIhjt'l1 is ... ~I . .." . n il' tlata !{i' 't"u in T abk.~IIl· a..H.) D.'i k~...v. c'. C. 'u lar w. .1 e·.c •• _IJ.· ftru.-nn~ll tlK' hc l1-pl.tn· a ~ ' Ill i~ui llllnk pk Jl o f Ihc' plasma l11IK" lltr. ElimiJl<ltinn hal f-life' c.. I g.lrihllhou ' h .U..-i~th l o f cocaine h)tlrn t'b1oritle' := 340 Wmn1 IUo lt" llar ""t'i~ 1 o f ('(Il'UiIW := 31).:522--52'\ .) . J. lI a~1e m .. 0. d .muK1· e. . "-.0 -. C .\lJIll".. \\".: Sinp c--tIcN:' l1·ft ria.1. . n Wf.tllm iui. C. 01 6 170 0."-'u l.. Tulal d e·.1.I ". Cli n .\\'....J. : Kitll'ttl'S of coc aine d istribution. Ilh. 1 9-~.I_ a . (Mnlt.tilll.II1 a coneent ra nou 20 min aftc'r a 2....la-r . allli Fi'\(:luTlitll. h. I 137 .oIl..Imllt.. . in a »cwbom iufan l. VOIIIIIK of tli.\ a flll"-1ie llluf tillW aftt"r I.lliou of 3.e.tr.llion of l't.)H.a '\('lIl i lu. V . n il' ple."'UC d .CHAJ'ff R3 Call. (.... A.ak·t1lalt' lotal clearance.: .dah' : 3.aleJ!Opo rin antibiulic. RUIl. Qo ~lmg/lj 12 103 24 76 48 42 n 23 12 144 37 s..5 122 10 74 15 45 20 28 25 17 Time lhrl ConcenIrahOn ~/U 30 10 Ol..~a ri l " lIlil' p lo l of plasma lt ml"t' u l raliu ll versus lirllt'. 11.\I'nll" tin K'. llapl t"C1 from SelliLltl. Wmo 1 (Adapt t"C1 fn un C IItJ\\'..lel•• .

given ei!hef plasma cceceotctce Of urinary exclelion dolo following differenl 005096 forms OIIOUIeS of administration . drug e1. Anhcipolelhe effect 01 oflefing loleof absorptiOn. {'spt"li. uhsorptiou is d l<lI"llli{·ri. AhsOIlll iulI . alltl a w rn'slx lIId i ll~ ha lf-lift.'S sorption uf drugs atiministen'(l orally in solution or in a ra pitlly di sillh~mtill ~ dl lSilgt' form us llall>' rdllR{' fmm 15 min til 1 lrr.fol1l )\\ill ~ .llly ad i ll~ dmh abso rp tion is a pn-requisin. The term IJ. III this dmph-r tln. s . and the di!felences between. of tht.male!toe renal clearance 01 a drug From plasma ccoceoecrce and Ullraory e>lCleloon dolo IoIIowing exfrovo5CUIo. EstllTlOle the relolive bioa. ur pcrwnt .t('(1 by an ahso rp tiull mtl' constant . aduuntsn-nd dust-. H fill" tln-ab w.{I(I lA'lilaIJllity is l'CJlIllllollly appliloO to IX)jh rate . Iher an' a<!minish'R'(1 exrravascularly. KINITICS Of ABSORPTION 1111' oral ahso rp tion of dm~s ufit 'li approxiruutr-s first-o nlt 'r kiru-ucs . tl. 9.i<lllall>'.lilt! exh-ut u f t!0l ~ inp ut int o tilt' sys te rmc em ulation. lirS/"Ol'der and 5Ofption processes oZel'O'OIde1 ob- 2 . 01 volume ofdislr'bution on the pIo:.un illt"t1: Ihl' spl n it" imp. OI"l"il.' conslden-d as the Fr ction.for t1l(' mr~ 'lIt i c adhity wln-n rs. ka.llly when Wn 'lI in solution.t( :okindil' paramet e rs fmlll p lasma undurinary (Llta foll()\\in~ e xt rava scula r udnuulstrat ion. administration. Fu r sys h ·mie. E~. Unde r these ci rcumstances.t' d Tt'\. Describe me choroderi5liCS 01.1 of a!tt'mthllls ill ahsmpliull alltl d isposition 011 hull y k-vel-ttunn -lationshlps.EXTRAVASCULAR DOSE OBJECTIVES The leader will be able 10: 1.minohon. given ei!her plasmaccoceoncrco 01 ullncllyeXClehon dolofo/bMng boIh exlt(M)SCUlo. a abso rh{'(1 int act .ooilobillty of 0 dll. 6 . 4. plasma ouux-ntration andamount u f dm~ ill tilt' hody. Th e sam e holds true for the absorption of dmw.L '(:b an' ('x. from llIany other extravascular sill'S i nd \l(li ll~ subcuta neous tiss ue and 1Il1lS(·II'. 111t' half· . EsllRlOle!he biOOYailobilityoi a drug. ami Ihe methods used to assess plmrn \. and inlroYOSC\JlOI odmlni~ohon _ 5.'9. Oeiermine wherher obsorpll()O 01 disp<»ilion role limil!.(:t o f rate and extent o f absorptton o u lJott./ferenl dosage lcems Of roulE!S 01 administrotlOn. factors that inllm'lIl't' dm~ ahsorp tiull an' {'( III ' sidt'n '(l ill Ch ap. given plasma (orr following d. e'denrol absorption. 11mm glJollt thi s book the term will ht· Iilllih'(l to tilt' extent of drug input and can 1M..ma cceceoectco and crrooet ofdnJg in the body ioIbMng eeo ceoecrcenee 0010 vascular odminislrohon . clearance. tilt')" an ·lflllgt'r .. 3.

BODY lIYIl·TlMI RIlATIONSHIPS Comparison With an Intravenous Dose Absorpt iull t1..". For a -ro-order absorpt km..of ded ine is constant for a first-order pRk't'SS.1<-. III cont rast.. Il. for a zero-on k-r abso rp tion pml'l' ss.rmlil'nt "it h tinu. " "" I'-In" ". "-I.lt'r am i first-on ll' r kim-tics an' fl lus.k~ . 2.I tllTll".". .i"lI: In h..f II./Iit l/ dl ' eif Ow Il1.~nlar .. 4-2. Ell.t'n lially a constant rail'. .. For til(' n-mamdcr o f th is chapte r..'ak {'OIIlIl.\ .. TIlt'S(' 1 ol ·0'1'(15 are portrayed for aspiri n in Fig.\'S 11('lwl"t 1l <'. tIlt' alllolint dl'C:liTlt's IiI1l'arl~' "ilh tum.Halt' HI'¢ ult'ns) llpply. 0 D ~ ~ 50 Zero Order ~ '" s 0 ·E ~ .. A. g. b us dost·.1B)."."dll Imm C hap.Irt"(1 to tha t s('("1I follel\\ill~ all t'(lua l i. and for much of the hook absorp nou is assumed to II(' first onh-r."·" tllO' "1lIJ:.... 4-1. HI"(. t he fr. A ~mph it"llml't1\(1( 1 of l'xamining dIe kinetics of absorption fR)IIl plasm a data follos\i ll ~ t"tr.when plotted st' lIl ilo~~aritl IlJlkal ly.. 'lilY~ ilnd ll'(lul. . ..i. n.. then the equations developed in C ha p . 0 D ~ ~ 80 60 Zero Order '" s 0 ~ " .1..u.~ E 40 20 0 ·E ~ 10 5 FirstOrder First Order ... 8emilogarithmic Plot u 100 100 " .illl· rt'il~ill)!..K'tioll al rail:' tucreases wit h n uu-. l.1an'. 11 dmg.OWTE ~ 4 Souu-tinu-s. nt 4.v.in a S('1l1 ilng. tln..". ." .arit lunk 1'101 of till' umou rt' maini llg tn II(' abso rll("(l ( Fi ~.li~llt lillt·..t'rn-on. 16) that at any ti me dA d' R of ate <lAo d' R of ate I·A R of ole change of o b$Orption elimination drug in body . a plol of amount rt'mai n i n~ 10 beuhsorla-d ag. 1" 'rn'Tll n '".wa'K'u!. 2..ainst tilllt' ~id ds it st r.1 ~ '.~ '" ~ ~ E o: ~ ~ c... 6 (C onstant. 3 Ihal tht· fml'liona l run. 'mik'l{>Ili thmk I. b c a use the rune is constant hut tilt" amou nt rt"'lIlain i ll ~ de-creases ... f " .. 4--1A).Io'r and li"t-<""Io'r al"" 'l l(inn I'I'" . " " ~ II: Time Il " Time t"lII:.. 111(' absorption kinet ics an' tiu-u ('<llll'li u'm onler. 111l' rise awl fall of till' dOl~ couceutrutiou in plusma art' be s t understood by n'lIlt'III I I('ri n~ (C hap. . If ahs(lllltion is z eroorder.sloll(' of wlitch is tilt' m il' of ubsorptlou ( Fi~. is ahso rll("(l al t"s<..1 H.lf lld ministm tion is ~wn in Appl·mlix (-C. p .. D iO' t'!Il.. N ' tmtt"(l ill Fi ~ ... Regular Plot u B. 111is is n ·8('(1("(1 in an l·s"t'r ..

"!./i mi llllt iml l ....I .. i" .lfJ "'I"" "" \lIlll(iU II.. .u rplioll.. ("I~~J I '.ulm illisi ml iull uf till' sallll' do.1 . it may III. l"l)lIlplt'h'IIt~ .... E .g tilllt. S I)..' absorb ed. ur.11 a maximum. tilt' di ITl'rt'IIl'(. zem.• ....1a' all ur.. C..i.t)alt. "..(II.lifin l frum ... S<...I. '-\' I" rin (6.' llitrtk111arly important Wt.C .() illllll.. rt'sllI. 1w •• 'Ol .of ah.'!. \c.ma ronce-ntration t'X('t't'lls that f(JII( J\\i ll~ L\"... A Ilw lhlll.l. r an.uus at lilt' nhso rp tion silt' alltl <. 1. 1'. h (J\\ '( '\'{'f.. is rt'adll'll wllt"n tilt' mt(' o f t'lim inalioll matcht'li tilt' ran . E\"('l1tually..Il"lT...hnllid not Ill.ly fol\(l\\i lll' rlu.Ki tl-Iahi ll' d n 'g or pn:"' l..4-2. j ancl9.i .tio mII rnlo1I. r..1 follc I\\ill~ in~I..' see-n ..'ll aftt-r i. always IC I\\'t'r folle l\\i n ~ ('\tm\" il"!11Iar ad ministral io ll t' than lilt' initial value fn lln\\i ll~ all ('lillal is.' o r to swc... at Ihe Ilt. . ito.. Suhst.).' .. ·nlr. The-n-efter.!: A. Initially..... Blo(l w iltJlJilit y aud (In '(1 an.h.t:lim's...' al<. tl u. S.F rom a fl"w minutes 10 many hours..-\.... \ \ 1lt'1l tilt' rate of abso rp tion i. IllIls ' · p rtJlt '(1iug an . u llcl lhe ()I'ak tune.' auywln-n.JIls(' is desirl'll.()f]ltinll III.:.('<IlIW o f tln.tilahility is IfM'. 111 dday hl'lwl't'u drug administ ration alltl lt. ....hOlly. l i. In Iht' Iomu-r (' ''-'it' .'usSI'tllllon' fully in Chaps.1 tabh-rs..I""'1>1io" ..Lq>tI'tI...uq llinn dt'1·n'il<'(~ .m •.1 Is<'( 'l1 in Appt'nclh I. CUII''l'( plt'lIl l~'."1 .-rilti/: {If II""I". . . I M~ Il.ma ('tm('(·lllratimH irnt' ( 'U '" I · is culIt'tl tln... litis dt ·· scription ma~' b mislt'ad ing. 1s l..p lil. tLI.. (OJ" n ... ..ln" I.::> E ~ '" 0..... its ra te o f r-luntuatfon tncrc.l" d Ol~ is ahsorht'll..' lIl ili n i n~ III Ill..I~ l l .. tilt' pLt.l..CHAPIfI! 4 when.g of absorption.!y.. 'U''7...g la. lilt.. lilt' c1mg concvntr ation llIay e remain IClwI'r thau tltal Uh M l. Lu n. rate of ah~)'11tiul\ is mamual an d rail' o f elim ina tiuu i..t~ .... ~I " 1\. ( ~ I . I I.lr~k. ltlll~ il" tht' rate of OI!JSC IIVlitJIl C ('t'l'(L thut of t'li millatioll lht' plasma concentr atkm cont inues to nw.lpitl il" \\i I1l UIl("Ilillt'tl lahlds. a tum.1Iert'a<. .5.] .. ('IlIt' ri('-{'tlitlt'1l pmdllt1 5..' 11<...\tri(' Irri tntiuu hy a dnl~.'}IIt·t' and the dl'('l i n i u ~ p \ ortkm..· . Ilt. Il. CI('arly. 111t (. ¢nnin.Jrtanl f.A" is 11M amoun t of dm~ .. Ht. n lllirihuting 10 11ll' lag lilll<' an:' lhl' ddil~' ill ('mpt)ing Ihe product from the sto mac h am i tllt' lillll' taken : for IIU' pmlt '(1ivt' ("llilt i ll~ to e1issu!. Ihe t..1. ml' ""ti"" . .'qu e ntly.(llllt' lms been t'l im illalt'l l. till' ris i ll~ portioll of lilt' pl'l. holus (lelSt'.m nlinlla ll'ntl)' of d m~ iutn tilt' boc..' ItT ) ..jni.l fur esli lllali n~ tl~ tit lll' is c1iS<.·ak l"..II rln' ah~)'11ti ull ~ il l' n. ti lt' ("l)1l('t'ntmliou is theu .1t1...('(1 wllt'll a p n )lllpt alld p n 'tlid 'lhlt. ..()'1Jtio n is of primary im po rtan('t' in t1lt'mpt'lIli(· . .1 is des ln-d. di N' . " . ill ti lt" hudy illllllt'1lialt. udnuuistration al all ttuu -s. of ab<.l' Ix..tt10N .v.~ ..ma concent runon i. ran III..\ .all. - 6 4 . " ' '''' '''11111 >11ca. l ic lll (If t't\It' n c-(. u-..Il. Also..')..lI and n:·tl"l~· lilt" ililw r ('tmh-nls into tilt' inlt'sthml llu ick Olll't' ah<. Fn-queutly._ '" ..g tunes have 111. As (liS(. wi th al l dm~ al the ahS()'11Iioll silt' and nOll(' in Iln.rjns..'t lilli n~ is resistaut to till:" ~'l\l ril' envm uuueut ."·I. .v..c!US( ' i.. in..u f ubsor ptfon and '1I. p"' n n i" it ll l ..:\ 17U-... .5 j.... ". As \\i ll hI.ea-s. lIIay l' ' III. 111 pe-ak pla. whilt' ti lt' entin.t'li a mpid o ust'! of t·lTt'(.tim l ...'11 nIN'n'!. .. ~ 2 0 0 20 40 60 Minutes 80 100 120 t"iJl:.. ..'ak lilllP ~ ltllt' d m~ n-m.. If nwt'\"('r. The b .of ah<.''10 "'It) w. ·"' l A {:.·ll till ~ ~a..l ltl-w.lua conceutra uon dl. lhe mil' of elhntnatton e:\('t'1 thl' rats.. til II. time.5..! all". IWI'l'n lilt' I\\'U nm-s diminid lt's.. ~n'n hy kn-Au." " f .'1..' all ..Lv. 1\1j2 . of Re L.iluations. Fal"tor<..nl r.. ~ 0 0 ~ 10 8 - " ~ ~ '.. if biclil\-. <i "-'1lirtn In nl<U' f"llc.Imini'kn'ti ll.. lUlIl ..' hl . J 1 m.. absorption IIl'CU O h~' a first-onk-r p R ll't' S" ..

~..·di 'l<· Il( ..r 1'0" o( II.. lilli""" I. .0.."Mli r>l( li"." (cul.'n"oat.ollllin n"'n l " 'MI . II'r pnll~.. I." "" 1"" 1..'f' """"" )' In C 'l _ A ""... h".i l' .. is proportional to the-t otal urea lImlt'r the plasma couceut ratiou-time curve (r\ Ce ) irn'sl)("(1in' of its shape. I''f' 11m." ('hmll Ii.. hioa\1lilahi 1i I~' llIa~' l lt.l"-' in phlsllla coucemrauon ut all tunes ...0 .I... F .. 4--3 tnvolvtug only a dlal\~t' in tilt' '00 Case A CaseS CaseC 300 100 Absorption Elimination o ..] o( I.... k.""' '' Indit m · li nlt' ('\/1'\'0'.1." r. I.plots of Fig:....' h".sin~ tilt' dost· produce-s a p ro- p rtional ill(:n:'...1..... or tI..'ftt" ri" ht l .. l... (It""..1.. ch-arance.."t'au't' II inl' V .t .. hitl\(n liLJ.f r h". Clearance ' AUC 01 hul tl....apI" l ...Clearance ' AUC Amount T amounl otal absorbed elimina ted Thus.i.] or th.. tI ".. ~aj>l" I .I.tl."t1$ a1""orpt"... a ''' '! . 1' 1 1 ' 1"' ..w.. Ii''''.ilily i$ 1. . and un-a... F.'r t ]. A ....il.. In CoIL'" C (Ihin l ".. f.ok l'u"TllI dro it l~"'I<Tfl..E XTiAVASCl.-'.0""""" .. t.It' .so .· I.... i"" lio.. '''I'''''' II.. ll!1l·h"n!:.J..·1< lmd io . liIl n\\ill~ tlo.. tla-n.I.· ra..·Ii.·di. "'-1"llIl . pt. .u.·1< li'''' l r. 11 K" r.'nli.( 'lJlilo~~arit l\lll il. (' ". ." In all II.>r pl.•-r .' ... Dose .." tI.. .. h"n (I. nf dniK (!llrinlt tht' .• r"l(' o( d imi... lr"or tI..Ii"'i.......h".H ·C...t' lul.lmlt Jo.. c.Loo. · " 1 of ah" ''1" '''lIl....' tilt' tlm 't' situations dl'pi(1("t) in tilt' o...In ti( in pt.on'" .''1" ioll' II.oll' 1lI. n 'maim unchauo gcd.inatio". n I. at til<' a1"""llCi"" . " ..lioll is .. TIll" value of ' "". . .I. i ll(:n·a.or pit" ... !t""...'. """..o1o"" l'liou (IoLoo.1.!....AR OOSE " 2 TIl(' h iua\Oiilahilil)'. 3 th at : T01 a mount eliminaled . f .fI.Wi." inat io •. 8 '2 16 t "i l(... T lns must la. Changing Absorption Kinetks A!tt' ml iolls in t' illlt' r 'lhS()'lllion or di spositioll produce changes in 11l' ti me profiles of tl u1 amou nl ill IllI' h(ltly am i tilt' pl. Changing Dose Unless ah"-''llt ion half·lift' or h io<l\'ailahility is altered.. hilt C"". d.. ~ TO 'a.f .1'''''''1:: (fn nn \o.. ....-s.ll a mollnl t·!illlinatt'ti is tilt' <\111011111 ah so r])('(I. al.....· .. ".''' '' ~ I".. increases p roportionally with dust·.0 (~..IIi.. (... " "' l(Tli'n... on . ..l-sma co nce ntration. inati.. I•......."t" ~. den-mum-d. Ilr tI. tl.." ". ." . ~"". 8 Hours '2 o .....h" ~· j.' 1 ~pl" ) an ' itl. ..t..o1""'1" i.t . m~r.."..I K (hoUom I.. He eall From C hap .. 8 '2 o . ).1 n M. Thi s poinl is iUmt rolh"tI I..:..+.or · "."n l l~-.. ~1..><1 (.1. Dust" tllt' rt'fo1l': 3 F ....· inh V .

\ tt7'.. body -I A~" ' In be absorbed 1 0 5 A(1.ahM. htt le is in rlu. tilt' f(JIl(J\\1 n~ approximancu (.mi later ht'<.. «leorptjon is stillt·s. ahsurp tiull llalf. )(' Distinguishing Absorption From Disposition Rate-Limited Elimination . For ('xamplt'. al tht· peak. ) ( "lUI 1)(' written I·A Role of eliminotion - ia ' Aa Role of a bsorpl ion thai is. and voluun. . tln. All other fat1nr.t' C prevails ( Fi ~.phase .t.ll"t. T ilt· half-l ift. d t ' llnU J('( ' .Umited Uiminatio" Occasionally.'\ "(·r. Absorp tion Influe nces lhl' kinl'ties uf <In lg in the IKKly: hu t what of the A(/C? BI"laIlM' ' bioilvailabilil)' and clea rance . and Cl<. A . II lt 'a ni ll ~ of Ilalf-lill· del('mlillt't ! fmlll the t11·diIW pha". amount in till' Iltltly (am i p lasma ('()m'('lltmlifln ) du rinp. 1> 1I ri ll ~ W tht· rtw 10 llll" peek. IK'(1.. TIlt' pe ak occ urs lan-r and is lo"'. is e limi na ted a'i fast .hm. In f. remaining mount a .lilil itill ~ stt'P. till" C is IllW 1)("( N .e re hdd constant. A VC must 1 the same fur Cases A. fKlRAVASCUAR 005£ CHAPTER 4 ah sorptio n half.. · In C. ll- lilill II lay Ilc. of dechnc o f d nlg ill tilt' hotly lIO corre s ponds to tilt' ahMlrptioll half-lift'.hudy to reach · the value at wluch rate-of clumuatloumatche s rate of absorption.' fo llowi ll~ t'\tr. .peak tune.is. til(' elnnmanou half-life. Even so. in con trast In tilt' pn.i\'a\('lllar adminh lralion . thercfun-.. T Ilt' half-lift' es timated from tht' dechue phase..of distribution anti lu-uce elimination half-Iifd remain co nstan t..\ 11 1.VJ. c'sl'rd '\t'(1in ill!l"llrdi ng tilt. A hut still shortr-r than t'li lllillalioll half-lift" TIll' Ix·a!. tt. ubsorpttou is so slow that much of 111(" d m~ remains to lx.('f l h i lit. Altsorpliol Rat.t' B.L'tL' A. absorpnou half· lift· is much shorter than r-lhnillation half·lift..t. d ll ri ll~ the decline pbaw. . Ilnwt.llfe.3. Under t111'SC circumstances. e-quals lilt' rate of abso rption. ruc st of tilt' d m ~ hil~ leeu < \(' ahsu rbt'( ) am l litt lC· )la. d isjx)Silion remains till' rate. 11. the !iIIit' fur this to occu r is the absc rp tkm half-Iifl'. B.( th an elim inalion half-lift·. . ab sorpuon h:M-lift· is 11111<:1.\'OfJJtiorl ~~ fllJU: tlw ratelimit/'l l! slt?J. In this ("" 1. 4-3). d ispm il io ll 1-:1'lIt'mlly is m lt · · li lllit i ll~.I)(KI)'.l by that time. it f" lInw. In Ca<. 3 tha t Iht.rflt'(l well Ix-yond tlu.(I) . am i C . is <Iirt"{1ly proportional to tilt' amount remaiuin~ I" lx' ahsorbed. lilt.. wln-n amount wmaining to lx' ahsorl a-d falls hy cue..'atlM it takes IOIl ~l"r for til!" amount iu tlu. Il o". milwd primarily by tilt' t1isl)()Sitioll uf til(" drug.:tIIM ' les s dm~ has lx-eu ahsorlx"i.(. hy the !iIIit' the pt·ak is reached. IO Il ~(.~JJo~itlon b 11ll' m tl'·/imitill1!.<.s 111:" '11 eltnuuan-d. OmM'fIIll'nlly. from ECI. N than in till' two p n '\1ous l'lN·S.LS it is ahsurllt'(1. T Ill' d m~ is either al till' abso rption site o r has b en 1 e ·!imin:I!<'(!. dt"l.. .\siun Sll~t"lil s tl llIl e d.(lnling::ly. tht' pr('('I"tlilll-: d i<. (hio' l\1Iil<lhilit)'.l· d m p. ( :o llfu\ inn is a\~lidt'tl if lhe d n lg is .0 111-:1. T he n-after. and lilt· tcrmtnalhalf-life remains till' elimi nation half-life .of d nl~ in tllC' hotly h den-r. (II..dr-cltm. that is. ra te o f eliruiuation increases ami t'\'t'n lllall~'.-' 'lIlially complonbefo re t1 lt~ majo rity of d m ~ has IIt'("n ehminated .'u.( most ccnunou sltuat km.\"(·r.lift· is 10l 1~t"r than i ll Ca.half MJ docs amount in IXKly.'\10 IlS situations. since the rate of elnninatiou ('sM'lItiall)' matches Ihe rate of absorpnou .

Il l1l~ P. " ' ! .life .. tl p1 rna t'f"lO'ntr.. T akin1/: tiM' .. an. C. I> F . ~ ~E u- f"ri"" or or h .. hut Il1IM IIlIl1.llw (Fi~.k-n on lU I " ln l>l~' _t" m.. I'. li n " " "III ti.. ' '"''.1 (nUll \\'..'(I.!: tI ".Iy. nM'r " .. \\'ilh a 10 1-"11/.M.tlM·.... . ~ . I'. . I.( I mWl • .·_ hllllt. ~ ~ ~ E ~ 0.... " . the ab sorption kiuet fcs of lilt' t1nl ~.00....1 r~>i.. . (0) ~ull .. 'I"" 11"mll.. . .) ~ '" ~ ~ or ..._"1 to an "T"i. II ~ J! 0.. tiN .k".t ratif". enliJt. th.11) 111ne ..'lilll' pl... hy fonllllialion of a sparingl)' solnhle salt (F ig."...· w~ II.• l. 1 -niM llin in oil (P· I..... t "''1>1..Iml"i...(11lllt' mk·limitin j!...... e h" n. ( AP.... . ~ 4 Hours 8 12 HI!:. intr..." hlliutic b Kt'-TT1 . tI. I..·.Jf·lif.1... n-main constan t..1 f ru m M""..Ml IIniel un hi""""... ai. I~~.... but bi{lil\1Iilahil ity n -mnins constan t. rio.3 tl. "ith Itw Il&mt' " >1"" . l" fI" of.....mmn..-.v.. .ss c. t:----..· n t " I '( oi" n.Iif· rod.. dc't..· u c 0 U ~ ".-') 1.1 I. dispnsitioJl rute-linuts theophylline eliminauon.. .1111: i.st'...' wr ..).·...1ire a......-1. . ishi nF.".Ii "'.. .. il l. n Tll..r. dusa~c' forms of Illany <Inl~ do IIOt exi st \ fur eliuical IISl' . 1 raI e..." " tha" t... "'ith .h it.. III pml1k'-'.· lh''''l.> 6 1"...d . {It·di n.475--4'jll.yo I_I ~ ..t~ th'l"lSilk'" f... I.. Iilin'" _ i\ IKC oq>tlo n .Iia"·~· li>llo.....h yili"t. 19. FIMMI nnd wate-r inHuc'nl't' tilt ' oral ah"': lIv tion kinetics of thc'tlp hyllinl' hut nul t "c~ ha lflife elf tht.U'11.'''' "fIo....ltJ.iMllin (. 111 2lJ mL of .h""'l'h. 1 .... <If ". fur penicilhn.·.I.1>11.5. ' "' "" " "'Ilty .l (el. i". 1'f'fK'M In roll". ·r .. ..) ahsOIVlioll eanlk. 4-4 )..1'.. 1 ' ''''' ' "'''' "".lf·lif..~ c 8 6 m. t h'.d . "" Iio-It. ( Mod ili. .unin]( 1...G . 'M . -1 ~5 ) ...A . ~ ..1 tI "..I..IIIl\\·I·"{·r. " .. .n-f".. tilt' I\ve must illl·Wit. This is most n'adily accoruphdn-d hy ~h i ll ~ the t1mJ{ t'itlll'T in diffen'llt do sa!?:t' fo rm s or hy d iITen'nt mutt's.A ... Ii...I.. al~l ~\"en intnl\"{'llollsly. t--S .5 0. nf a!>.....II rn oil. I'h" rU l..lsma concentration-time profile of a d rug when till' ah "':Jlvtiul\ lifil'iltinns ill d islx"..i... """. . ..rl'li"l1.M...... 1 h...~ E J ~ c... " 0.'!." r-....I n'''''''''n ""'IOCKt<'anll.·n tI.Jlh.· .. \\ith a \"('l)' sho rt d iminalinnllillf. "'..: o"tli"" . '.of 111... +-4." (1.5 f.k.1 hill:h {1lrhnhy.. 4-6...tl.f 1I"''1>1.· ...111 "'I: §.d... ( " . Sf) mu st IXlth tilt' tirue itntl magllitll<ll' of tlu.nd in " il o .l ... J)iotint1k. ..3 . 'l>l l~ .. m. ... Iminio· h. G . .. I (0).. ' .lwak coucentranou.1 ."..f Fu lld.0 "M )..1 intTII. To i11l1stmte thi s po int ...'''' 1'1' . trl tI. In contrust. <IKIngiag Dispodtiol KiM'ks \ \1Iat happe ns to tilt' pl... "" ' 1'1 ' di. It'n niruoJ h. .. lal.o-..l\l l. .l Trudo!a. 1.llO T" ... li e n ' then.jun" ~· n "11 ' c<M 'I.It· by K*'i"!t l"". uf 1"'"i.~""...tnun " . .i nll: .. Distin"... Tho· .1 in "'..3 0 .w. 1".-li miu "li."'.. t'ltIl '''lly t.. i.ilion 11l1.1- c 5 1 _ ~ e 8 c 0 0 P·I..tantLordiD.Q1 0 6 12 Hours 18 24 ' ~'... \\"....) .."."n) ".. D' ''' 1'il '' rlifT..l<1'. Intrur nuscular (LIII.. " f "..... SprinKfir1t1.1Ir? \ \1 lt'1l d e arallC'(-' is rekim'tit.rn.k r ....lIill G 1 ..M.. ( I mWI..Larl" to I 'u iI" lni<llIaI un dltT. . " 1 .. . 11\{'w events an' depicted in Fig. .."ttI. Th. 1illlit.. tltio ."". e ..>1""11 ill 4 2 e s 0 51111 "..1 ' "nIl I'n ... lIi... "' '' li<:illin c: (3 1fW\l() ..... ht'l W '1\ ah sorptioll ami d isposition rate -limitation s is n l'C aeh il'wtl by altt'rillF. l'ulisitiN data fur t1wuphylline ami pC'nidllill (...CHAP1H A ... C h n.

!' rnhl.. 10 5 2 ... 1II( htlwt '\I 'r .. rate..1 .I II.-• ..mplio n: the. " . < " 0 =E 0 _ ~ ~ 1:'''1. tl. ' C ) (..· nor" "'1 .l tl.hl"t'li foun d to IN....· I:"'~r. u ~ ~ - l li...a1f·li f(..-S <111I1 dilllimition 1 ' " ('('n '... ·..' rn. p.of dilllillalioll ("tillais 11. It appli.· ..... r . I..1 I" tl.d l a l\~(...<lI<.' 1I<. "f tI.. at ..· ) (.. Til(' s h.• n·II 1..(· rate o f ah\l)'l)liuli . · .· ..'. .1"(lmt. \\ PreetKting Changes in Peak Qll alil"lin..lt.'s as wt-ll 10 C ...( . " f ' I"..· C...('!illl ill.I'l'SS ((.( plills tlus mit' u f all .h".../.llioll P".-Mall'" ". ml n~ 11>I.. .·I"""..11".l\"ailahilily and ('(1'011'..!' I " '" 1 '11" 11I l:'''l'h l..1 .("lel.('fl1l ./' .di" .· wit l..1." E ~ 1"....l-\('<...·... . ~ j" . I . li lt' amount uf t1 m~ in lilt" 1'N'Nly. am l t...l. tilt ' g rt'... hl:h' l ~ ..lSt't1.. u b r):t. 1111' fasn-r tln. An t_ .l'i litalt' t h is pn'll idiulI .· 1<". 1"'1 .1' . Jy..t Ii"."I.. As SI.(If di st rihulilm b n 'sl'NlI\sihl(' fur a IUllg(' r (.~ .·I""i"...-. I.....\('nls a n' d in-I'n 'nl wln-n an illl' I'('.. " ... r'l" '''( . I.· . IWIll.. . ... u IIII'mlll)' aid h. 1l 1\(11"])tion iUl'rt' . 1 .Ihl' 111'\\' poi nt of inlt' N'('tiflu iml it'a!t's t hat Iw ak anmuut is illl·n "lSl. ·1-'j .lslt' r III(' ahSl:I'l)liu lJ p n ll' '<..I-\( 'l! volunu..(1. " 11 "..·" . If t'l illlill<ll ion rat(' coustaut is iUIT( '.'''." lo".. ."1.). · 01..111 carln-r lillit' .• I" ·. . . ' h...o f IIJ(' lIw tl uMI ( Fi~.' .I<-.. Ih.11..11 \ l" I... ).'r ...uue if h iu.. \\'itl.· Mo' " ".·\lr..l""..·n·.\1J(1 111t' rou ve-rw-. II.s ill C".... 1000 500 - Absorption §... Tlt l' f.constant is illl·n·.· in "!... " ' ''' " I. T Ilt' gr<lph is dl'si~IJ('t1 for pn"( lit1 il\~ d l<tl l ~I'S in and IJot'.l.I. h.. •rn .--Ii) is silllpl("..Lsllrt"t1 hy ah "'ll'lltion ran.ubsorption run. . L '''' '''' ll l r~ · 'M'" . .1 " "l:I. ~ Ic " " 1:'-"1".· ..tt u lIl l::r." .lIM{.n n AV ASCULAl1 rose 0 ~ CHAPTH <l •.\ ..1"'1:: h.(' p l...1' \'UIIlTlIt' tlf distnbutton. 1 "...".(I\\11 ill Fig. "~1 1....l~ .. 1111' peak IJ('('11rs late-r ancl i~ 10w('I'.n'nl..llln' und..I.. ...· . d ~Ul~" ill "I> ...0: . (..".·".a...'1.' rutr... h ut a t a Illw('r a mount... 11.'('!im ' uf tilt' ('Iillli llalioll lim '.s (ant'.ah-r is till' slop" of till' ah\ll'l)tin u lim' ....I'n ' .~l.. \\ i lb 11 1I' ('\u 'ptioll of \\"111'11 \ul llllll' o f di st ribution is aln-n-d...·. ·... plaouu 1'lllll" lIlralioll ..1111" a n ' 1 ·ha ngl.MT" n'''! h.. 11. 'loU"'~'!" """'I.1 j.. \ \ '.... · ..Ik a mount in 1111' bo... ... ...is 10 1'1' tlu-u ilTltI so is ti lt.( tl.." .L". tilt' IlI'W IMlinl uf illh'rsl '(i ioll (J('l'u r.Iilllinalioll l...II" .diffu-ult 10 pn-du-t whr-n ab sorpnon or d ispositioll is nhr-n-d.·. 'IIln.· ... 11.. .("(lIIsIOlIlI). Li'".. tin 1. T o f. Fill:_4-fi.. I'O"'.. '. tl.. ".I.. If a h\lI'l)lioll raft.·rt·...n .n"".'10" h UH" h . in (... 100 ~ ~ 200 '" '" 50 20 10 0 4 / ' / Elimination 8 Hours 12 n"t lm ·lio u ill dl'ilf. " ~ I ' M1 " " .1 1" .. 1 Ii'.. ••".. I.Iim iualillu ra n.f" ·r ..10·· .coustaut .... tI.o f eli nunution ((.1( 1 p"... "' '" 8-a.... ..1. II... ""!.. . I" ..' ahsorlN.It<.I.' " 1.· . I. I.('fo n ' 11.10· (.. am i lI lt' ptl\lIIa l'lIll" lIl ra tillll 1I1mt Ill' gn'alt' r pri o r 10 till' li lllt' wheu th. a g n-a h' r a mo u nt of t1 nlg IIHlst hi' a h\ll rlll "ti.l\l '(1. """..." '''1".l li UH" '1( ' .111 '''.1 und thut it lll'('ur.I.-) . ' r.·". ah"''l'Ii'' '' r.' t.-. at all earln-r t ime-..' I. T Il<' 1."t1 (... f 10.I'IoI. 11I0 1'(' d m~ IIIU\I IN... .stc prtnciplr.10 · (" F..1Ii".. Um ll' r 11ll'\(' r-i rcumv tances tilt ' t\ UC is til l' s. tIll' sh"('I)«'1' is till' t1..lI1 t)...(lIIl"('lll ra tioll n-acin-s a vulue al which Iht .". 1".... ('!illlinal ilm run.."-.on-.. .. 1 Io:r"1'.f " I"" ......

C l ion ral e:' co nsta nt (colored dashed line and poi nt Bl and an Incn-. m rpt lo n or di~i1iun " . " " . . '11: 4-8.... Me mu ry aid to .I~ i.I. II. lra lion wi th aheratlo n in druJl: . 46:154-155. Spt"<.... ' ......"'· "I" ..0.i"I:'" .1 t _ . tlf . and the cnuus e-xplained under Ch'UlWI\~ Dhpusitinl\ Kinet ics .t p l nllK""tr. a h..Jic. li"" .\ f\>. .{ li".·.... h"tt"". ·.. ...~' 11\~ly. T. With "" d.n... (... .lr..H .... .. . 01<..I. .-ion rat"..Lt.II"I..' "f o -li. " I.'\I r..hoorpuon or pm iU n....· . 1(.I. nd point C) .11 1.(..u· . ) duo vnlunu.· ill tlo. •" t. ".. • nd Tour..lI......·!im j" .. . b.ips for t'stiIl l<lti ll~ tln.fuM .' n d lil m ..lImi l1. .'r .m I(r"I". " .fi"'I"..I't'l....n'" .. tiYr pt'u 11m... i. anU Ih<.. ...) n .. Pharm .l ....· ill . n-p... .on<1 ...es in Fi~.i ll~ t'xtm\ll...10..\ .."" . "foid. 11. 10 a..1... " . Am."'" ..100 ~ a: / / Elimination ~ 200 50 20 10 r 0 4 Hours .t\ lIIa conceutratkm -tun e (·U . .· S.. l ....I. 1000 500 _ Absorption '~'''''I:'. o ea. (A) with ."\.dio".. ." ...I(·l i(....'Il1'1·.nM . ohtaillt'(l ." (.ullk" I".i.. ..." '1 .·. ... I ">I""... "·fj"...m lin..o...I.1cI i'K.I••l". i ". .1 ..>I lill. ..lr...limlnaU..· ... tI(U.... ' ar Il.. " " •...o f distrihut ion v....tial~' ..11" "'I' j(ml>l.. np:l'l in pt'a k 8 12 B . " _7.. I-l K. ASSESSMENT Of PHARMACOKINETIC PARAMETERS lI ow sonu.I' " ....· "IM.. ( Modi· fl.(' in pea k concentration . "1 .-I..u... 1. . 1~2.. tl". wle-u absorptio ll am i dispos uson are fin t·o rtlN an' wn -n 11(1 in :\ ppt'lltli\ ). A Iim... ""..d rrnm 0 1 S.·]i"'...ifil· rt'l aliu llst.. -." 1 I n ...paralllt"h-r vuhu-s art · t'stimalt'tl follo".oIic.-C. " " f •..tll... "" a pprt'('iatt'(l hy {"Iln si dt' ri ll~ ho tll tllt' pl. ftl'rnlravalMIla r ad m lni l tnatlon o f .. II.pbon a nd .. 4--9. shown. nlinp:the . .· 1 'oIL pI. n.. .ur<! ebmi.CMAP 1E ~ A . n.' .l.1 [illl ' ..m.. .~ .. J. nd prak a moun l in the body... p..tiw' ["'a le amount art' tndicalNl by lhoe Inlerwctlon of the ahwrp hon and .L".... i.111M'S a d('('n ' .mory aiJ ....ti . Ii "".·I... > I". 1 1 .' . ..· .·at.. .1til 1 ...· .. I..ll .red.....J. u du.. 1 ...I1......i.. Sf'lt duo nKM In pralc ti me and pt'aIc COlKTn- Time !IIe l'l'il'" i ll \"(' I"!\(' .l IUN'.1lo nJ (OT a n IIK Tt'aord a hso rp- .. .1I'l ril. l .· III ... .0 IrinKJe . ..· '. ·n·I ~· n-..·... .N .h..".... ...: A m....unlU'l n ' (col· a c red dolted lille'. 01"... olilr ad ministra tion ran lit...I"n'd ISo .' -'llut's of C..l<. .l.Iopo-...lIiI.1 (I.·"tr"'Ii. III . .lllio n rale conttanll.. "f .. It... tI.t.

1/.t..1". \ 51"'" "" . SOO _ .\.·li'......Wl... . f .i"'" .J I~ (0.1<""1:- 1..0 0.( SOl) mv.Il. 6 E. ·0) h.e. 11... ~ 7 8 Fo r ('xa rnpll'. app m priatt'iy SlJ ltstit ut i ll~ till' an-a 1II('.f. . and u ra l adm inist rat ions . inopll<" lilA .M .1 0 2 Hours 4 6 y." il . " .w.mld itin ll"l tnformatton P10sma Data AIon... ' oI!t".m .mJ Io·1 ...i nh.-' l... ..U...' r"""'''-~ II."" H"r...I. extravascular adminis tration is d i\itlt'1l by ti lt' are a fnlllJ\\ill~ <Il l l..-...m . and in Tahh. S(' F.I" eon InIlO. ]im ih " l: ill ""d. ~ _ . Sup plt'lIlt'ntal dill•• [mtn L\'..ttI 0Ith It)' Dlfte_.. il..l . ti .5 0 00 0 0 0 0 0 In.1N( AAlOJll E lC tn1DLNC ~O l""!ll Intromuscular 0 01 190 185 193 152 147 70 r(lllm\in~ i... 1 " .i1l1h ilit. ~ .· t1nlj( i. hi .'"<1 ..0 Fl~ . "-"..1. .. .....t\" (·l\ou s (i. i n.I~· . .Ii..M. ~ .'·. . Clearance ' AUC.nv.1 " 1 "....... ad lllilli"tmtioll allow ('a l('u lal iclll nf hiu. S . ap pmprialt'ly tllrrt ·<:ti n~ for t1o<..· ". It·•• loi.l m\·'l\t'u la r (I'. is .l\ fullows : In tr.'. of a dnl ~. i.2 0..l' urt'lIlt'n b ill Tahl(· -1-. tln.· '<a"'" ..o..I.-enou~ '.. 0..v. o..... l'\A.w hlvll 1..IoI.4 R 2. D.. n il" tol ot! Ace fullo\.. . holliS. n ' fn .lln '• . = Clearance ' A UCj ~ .1 illto ECJ .Sl: ..) (1 0<.o.wailah ility.I.) ill....10.('. &tI. ~ . tI.m'h' .. Dose.-I..l'" !'WJ~( ~().d .' ''' i. ...42 CHAPTE ..· 01"...A> """ 76 74 35 DECAT PI-t...' newl.u h. A l'. 111(' h'l\ is fur tlais cal culat ion. . "'K IIIr.(' Do~.1 . Cl. ~9 . Hinn n.. whk-h ass tlllWS that d n lnlllCf' rrm atnx olllMtm t .. ...

l\'ail ah lc·. alt holl ~h a Ilalf·lift· cau be .cu rve.... If on l)" two oral doses had · I ~ '(' II ('fllllpart. COIISla ll(")' n f clearance is tilt' only req uire ment.. b olus dose or a constant-rate is .v.' 1I0h'i.1I"{1 into 11111Sd t.v.same answer is to .nv.l\"ailahility.ng allY of Ihe fon.tIly. I .lmilabilit> o f till' oral doS(' is the n -16%.I1~ euher an i.Ilt's tha t the. In 111l' exampleoonsklc red .ca nnot J)f. solu. As with th e calcula tfou of hi().l w hen the re art' 110 i.(. \\. sUIIll'd to I)f. irres pec t ive of mule of admuust ruhon.. A'II alll'nlalin ' method of ('stilllatill~ bioavailabthty. Otht'r Pllllnllll('Okint'lic Pa ramt'l e n .·11 only extravascular da ta. hio. . the vahn.1 1tilah ility is det emuued hy ccmp an ng different dosage fon ns . Ihey nmy havebe. amoun t \ l'1iminah 'i. Converse-ly. III contrast. whe-ther s uhsorptiou or d isposition is nue-ltnunng. TIlt' area Iw)'oud ' n_ rt' f1 I'l1: S the amounl n '1l1ainillV.' assfgncd to t'i tllt' r aleorp non o r ehuunation. diet. s T hus . <'ri l )f.' h<l\i llp. ut hility limitations.llIoul kll(J\\. lll·til. d t'am lll'(' is . Ba. till' hiV. doso is 97'l .\. am i polt'lltial hazards art' major n-asons for the leek of an i. is. Dose" " Amou nl = Clearance ' AUC" Totolo mounl 9 absorbed ellmlnoted Fe ' Dose e s Clecrcoce . o r tliffl'n'llt condutons (e .g. Clearance can lx. Il ~ hioa\1Iilahil ity. AUCe 10 Relotive _ bioovoilobility Fe fA • (AUC6XDoseB) AUCB Dose6 11 TIll' n ·f('n 'II('l' d nsap. Cond sick-r: Art'a can be (1Ik'lIlah'll without kn(J\\.v. it is sOllll' tiTnes diffi('ult to C'stimah' pl mrn ml"lJl."'lI to 11)(' c1t'l~dY phase. for e xample. difh-reut routes ' of admillistrati oll.. Hdati\"l' hi().( ~"(' FiR.l' fnn n d lO'i('lI is uSllall>' th e om' with the highest hioavai lahil it> th ai ·. di ~·a. only -16% is btoavailable w hen drug ts ~'1. hitl(lt"fli!"I.<1 CIlI till' n· lati ollsbip hl·tW{"'l·n an -a and amou nt dimill.. w htch ~vt's the. F r acti o n Eli m ina ted . tilt' on. Gh 1.bioavaila hility of tilt' LIlI ..\. It should I)f. n-latlve hio.. dose . .! that all th e p rt'l'l. ·11 e-qually. 7.lkill ~ the ~1'1U' rall'l'it· : F . . 6 1.e state ].l. .. is abs o ed s~~tt' lIlitM. th.. til I ~ · t'1illlinah'i. rat e of ah sorpt jon.intl it-.. p rep aration. because absorption is essentially fin ished . u r slla p(' of rlu. infus ion (C hap .lll'st un-a-t o -dose reno. n ·f1t'l1:s th . 4-10). Indeed ."( 1:ly into Ell.' constant.'1l rb ondlv in so ilitioll. slahility...·nt c"{l in C ha p . 3.. Virt ually all dm ~ illjP<.. Cost.1 ("lmfi c'ntly from ohse-'rvatiolls follcJ\\inv.<l i ll~ n-lanonshtps hold. ullx-it poorl y. tln.lh "{! < pn 'S!..pamnll' tt'r!i.l up to that time. Rl'1 it t. (lila.-goi n~ pa ramete rs. Similarly...fo r clearance di l1. t n.\"01 \ 11111(' o f distribution dt'M I" ca nnot I ~ · calculated.1 (or pb. it approxtman-s amo unt n 'mailling 10 be uhso rbe d if absorption is rdh'-Iimit i n~.es tunan-d fmm bloo. 1. 110 phannal'flkillt1ic parameter i l" 1Il J~ ' dl'l e n ninc.sllla ) data foll()\'.il ity is dl'l enllille. but cleara nce ca nnot. only a stngle oral dose. UC lip In a given tune. \ \'ithou l kIlO\ .. Th e latter an-a n'p rt'M'lIls dmg ill the hlld y if ab s orpno n is filst compared to r-liminution. th is is the i. subs titute tilt' vahu.m .

lII... in till' I' \iullplt.'('sst's.. ahst lT)ll ioll o f lll. route of ad minist ra tio n to arTt'(.· "I" ".of t1mK is constant . or sllll(.1111 <It'IIl..ah st lrp tioll 'S " kiuelit..".I. 1-. dat a in Tahlt...· . thco n-tunllv. Failure o f food.lIlKt· o f likt'!)"ahso rp tioll llillf-livt's W..lh l!' (1" = I ) F rom i.i: til p mdll('t' a uriru.h.-.1 Lznun.! .in. 1Il ~.d. and. ..' (:ak11Iah 'tl k lJ(.H dllst' p!.alllo uul a IlMIT IJt"t!. In l' r.• tim."{' by tht. mi t' u f d m K l'xc n 'titJII is I' ml'urt ion a l 10 its pt L llla concentration.. a nu-thodmust tllt'n 'fn n ' 1M dt. uhlaillt"{l hy t1i..· l<Jlal ...<lita ( <III hl' Ilst'(l to r-stima te.hiom 1lila hililY. 3 ).lh' t hr-se two p n l(.. fo r t. T \\11 n .) to tilt' totul .1("''t' t' il:. . in Fi~.xalllp lt-. Cumulative uri ne.a t Il'lL till' I'limi na tio ll halfst lift· of most drugs. 1at I .lIIy \\"t'II-a llsm IJt"t1 t1 n lJ.LSUn 'llIt'lits uf llhso rp liOlI ktrwt tcs an' illlpos sihlt.lal in ·I>' sim plt.11I fm lll C ha p .:t~lm ·Il. ult i".'uta nt't ills silt'S.. II.is a su ffid l"lll hod y o f dat a to determuu.!i hil l is tmpracnca l bl'l. 3 Ihat fr is lilt..lliflll ls an' dtscusscd ill Appl.1: Iht· lNlIlillil1hillf-lift' indicatethut th is must ht ' tilt' r-lhmnation halflift". ..· I 'i~ ""'1 .mll st l fn 'tlllt 'llt ly..f tl ..\ I-G Urine Dot." ...li< .. tl u-n.. ll(.Lsma is l ilt· sitt' (If n u-asun-rueut fo r b oth ilhst lT))tioli a nd di spos itio ll. The lIlt'I IIIM I n -qum-s Iha t the." " . To calculate til(' kim-tics of absorpnon.. h' II...\ ["C "p t...CHAPTH 4 Fort unat e ly.s ampk.... Ir.i ons!y. usllally I or 2 hr a ftN drug administratinn. dosa~t" form .tl1:'k t " dllnll~ l ilt' firs t t'tl llt'l 1: io ll o f urme-. 69..· 'nl. am lt lw vulunn. ." c. a r.o f d ist rih ution t".....o f fr remains constan t. ~ E 4 u c " 2 0 o o 3 6 Hours 9 12 . 4-7.lva il. in t his t' LSI' :J Oll L. ami IIndt' r Ihl 'st' circum stances .~ c .....(1..llm's wt' n ' t'Sl imalt'l l 1 imlin'(.· . Ih·m"{·.\111 1IIIlt' of dhi rih utitlll.1 ). ( 501l 1ll ~) hy Aue (7. a d nl~ is "ftt'l\ fully bin. 11. is \irtllillly fiuislll..i din~ dost..t . Consider. t'!t·a r.) min ) ~\'t 'S tlu. n·I••t.. AIoM G in'lI o nl)" uri ne data. -I-I. h . C k -arane-." . \ " 1"""""" tl.. 'n B / C _ 6 . Uriuurv t'wn'!ioll ra te data an' the-n ofh-n of lillI e USt' ill t'sl ima l illl-: a hStlll'lio n kim· lit'S. (' lIl pt~i ll ~ o f tilt' hladd t' r and a ll inahility o f it sllhjl'l.".1:inn Inn-nul is Ilt't't lt'l] 10 d larat1:e ri v:e.·~.Ir. just tilt' i. t·C .I1ISt· uf ill('O lllplt'tt. If ' \ n-unl c k-anmrx.IItIi. mho of lilt' Intal amount t'X{·n·!t'(I Ill\('ha ngt'll ('\1'..t ht' t·limina tioll Illllf·l ift' is known.· . Dtn -ct I1lt'.lllt"{· can II(.lII. . IIlt'tll1M for ad lit'\l nK this Sl·llilr.. 10. m-i tln-r ch-umnce nor \Ullllll(' of drstnbunon l '1lI1 1M calc ulated."' t . Di \ldi ll~ dt'amll<.·li ". Also . TI lt' v. Pn. el im inat io n mit ' cous taut ( U. excn-tiou mit' dat a can II(...'l.' rrea ted in 1I IlIl11111t'r sim ilar III Iha! fOT pl.1II lx' t"sli malt'tl tlIwt... n 'Wi".vulur.uuur dat a.hr/L) . ... is 1..i st'(! to ' Sl'!l. A shurter t'()IlI'l..LS II\lokt l.·l""inat... :I)· fn nn ptLSlllll t'tlllt'(·nt mtio ll·tilllt' data.\i ll~ an-a (Efl..1I 1 ~."."" .... RI'(.

v.hioavuilahility of .' hh)('fillh a l('nt if till' l..\l'h is idt 'nti l".l\1ulahilily ..11(''''.. til(' ('stimatl' of n 'nal ch-arunce From combhu-d pl.L"l'ular udmitu strunon is us a ccu rateas that obla illl..elf• Amount absorbed Ictcl amount elimina ted t.can 1 IMrtit'lIlarly useful for t'sti lll at i n~ hill. n~ i.\rkd ill~ of till' new pmtlm1 if it shows hioequb'ulence. SHeil laws allow n1.dala alom. TIlt' app" ).. 111t' majo r proble-u ln-n.. Iht· rat io is rlu. hut lIot the. (~) •. • Dose..ah. whit·h is a dtrect t'l1 m('. :\o!it" that .(! fnll(}\\.-•. .o rlx-d drug h.("I1('u mulatin' mnouut (. lit· d nl K' 0 .52 l ll~ ) X IOU].' no kllowlt"lI~(· nf hi().L sun's used to .mda!! ' th at nt 'W tlnlg: product s ht· Slife and (·IT('l.l\ Un' of am ount ah. Two p mtlul'lS an.In1g: lilt' Sl IIl1\ ' Illolar tlo.'lin'.(' till' mHo ~W!i tln..availahility wllt'll thl' {rae)(' lion t'\ (·n·!t'1.. dose.dll's I..• and is of sim ilar fonllulat ion to mn. = Ae.'au t t1ilT('n 'IlI" s ill l'itll('r tllt'mp('util' or ad w·rst· (·IT(''l. h.v.m. dmg: . Sinn.l\lIl<l dala.lr.IWS lIl. Undt 'r this condition.llludl'Ul!!t'l l appm.. Ae"" s Dose. Urun.. 3 ).lul1 of..l~ .is in ('lISllri U ~ l.1Ilg:1· UILI' p mtlu l·t fo r tilt' other. ug: t·:l.(' dinim lly n-h. ' total d l'a roUll"l') alT :\ t·C. C.t. fm m thl ' ('l1 l1 lllb lin' urinm) r-rcrr-tion (Lata in Tablt· 4-1 .lSSl'SS dilll'n'n(. 15 mwl . thi s \ -al i li' is th(' S<Ullt' .(C hap .(lmpldt' urme colh-cnon until \irtually all tlu..CHAJ'T£ ~ 4 os Fe _ Aex F · Dose 12 T1lt'II. alld t. If a IlI'W pmt..u Inunivt rollion.m ht"ll... it is .... \\1w TI Dose 8 is ~\"t' ll int ravenously..'ls. BIOIQUIVAIINCI 1.aln-adv sIJO\\1l to 1)(' S<lf(' and ('lTt'l'liH'. changes in n-nal d('amll t" (aml llt'lI(.. dos(' is almost l''UlIlp l(·ft'ly hioa\~lilahlt· : til(' mm'Sp0ll(lill~ value for the ora l dU M' is only 4fill ((70 f'tasma and Urine Dota T Ill' n 'nal dt·.IPlmn 'nl that til(' t. Fs g (A A) . For example. m{"l'ntr" tion-lillll' pmrilt's an' so similar that t1ll'y an ' llnlikt'ly to pmtlul.tioof till' dO<. 111(' majo r ronceru is ...\" ailability is n-qui n-d.1.Jfe 13 14 Fe ' Doses = A• •.L~ lx-en excn-tcd.lllo thai taken fur an i.II1(..lm\·..amount (·u ·n '!t"ll.• similar ('ffieat)' am i safdy.(· u f a d m g: r-an 1)(· es tilllit!("(1 when bolh plasma an d urine da ta exist.1llSiclt' n'll 10 Ill.:lOl'n '!l"ll um:lmuK("I1is 111t'n·fnn· tilt' ralio uf tilt' hio<l\'ailahiIHil's..(·. tilt' ahi l it~' of a p"li( 'nl 10 \ (·\t·1l.t~ l'X pt't11"l1ifJe is con stant. that l'sti nmlt"ll From pl. The common 1I\('.l t.·IL·/tclw bilitlj ..'s in ab\U111lion art' AVe . Ilsing: lilt' SUhSt'ripts :\ and B to d('noll' IWII treatments.(·-lIonnalir.n-lative biu.l~lI1a and umndala fol1()\\. i.. <.. 1111' ".. il follows thai F.

\\11 a rt' tilt' assumptions lIIat!" ill ) u u r t. F irsl d mw fi\"(" pairs o f 1'lln.. li lt' s!IJ\\'l'r tlu.llIlitlt' lut ravr-uonslv am i omllv as conventional a nd slo n-h-asetable-ts. 111t'1I the.kill t'l i("S (If prollt' t"1till.Int! a ll n tllt'r IMmll ll'h ' n. ktl .t""'. . STUDT PRDllfMS (Answers to Study Prob lems ore in Appe ndix II . of tilt' p!.. ptl\lII<t u..\ UC is p m)'nrt itllla l to tilt' amount of t1 n l~ abso rbed.. 19 • .urn-rcul to ubt aiu u ~Otl( l {'stima h' of tilt" t. e lin. D o(. ('s lima!t· is Iilllih. 2.'":-114-12. \\"l(. Fur a ~\l' 1I dnl~ in a sllbjt"t'I.· va l')' much . Juhnsso ll. til(> vahn. ma concentration afk r a s i n~lt· oral d n.. in l'\ltlua ling tlifTt' n 'lI1 dosagt' forms n f p n ){ 'ltinm nid t'.lir nf tht'S(' ' e lln. lvlliiahilily t'tlltst'" the pe ak ti me In sllOrtt'll. d . st.is a lk n't!." a rt" ('slimill("(l [mm till' I li~lu 'sl ('UlIt'\'utm!iull measured and rlu.' lr.1~' nul lx.. that is lint t'OITt't1.lUW uf assay variability.. tlmw mll ltlll'r ('un·t' (Ill ('. l . C. O ther manuflu-tun-rs lIlay tlu-u wis h to ma rket tln.fouml in lh is siudy wa'~ 2. \ '.'S i(lt'l1lil 'al ln 1110S(' ill Fi ~.101>Otl 1 f Ol m. till' (·!T('(. . or wln-n tilt· sitt. thl' iK't. 11 1t li.\ l:C and ('u lIlu lat i\'{' u rine {'u'n. lil lt cluntnatlon. -I-II . ami C /.0 0' FOIm.1011 '2 0'l cos '" 500 -o: ("'9"'/1) IWOJ'{I t . For Iht. tilt' t!uS!' "t!mi nislt'n'tl . lilt' h i ~l 1t' r is lilt' peak pl. of Iht' stateme nts b elow tl mt an' corn-et (see..')). Pharwmacol. (:ralTlIl'r d al.J hy silln plt·s II(' i ll~ o hla illt"tl o nly at d iM-'n'h..l('h p..~ till' uri ne. a nti Sji~n' n .Il('t 'I ('still ~ usually urtses when a pa l(' l\! (Ill an Innovator's dnlJ' ex pi re-s.. T. I. 4--."1l1 l1 ula lin"amount t' wn·lt'd at in fillilt' ti llll' ? c. Furt hermore .(1IlIt"t1I'11 o\'('r a Inug {'lICmgh tinu. :\ fiN a siug!t' oral close..tl ' lkind i(' !l."1tl(11Ia linlls? .'t' trt'atlllt'nls ? :1.. m lT r.-. ( a"ll lll~ f". dlll'O(' 1I 1ll.tlh'ml io llS in phann. lIg . wh en a foruurlation is d mll~t'1 l. eccn .a ~ull(l "·(In·· v-nta tiou of II\(" act ual value...l('l.data.1 h . a .t ' fnll()\\. T Ill' half..2 .UIIIlUg III(' tltn...sam!' formulanou of tilt ' dnl ~. s b.. Formulations thut are hio('(llIi\'a lt'1I1 wuh that of ti lt" innovator a nd ht'ari ll~ till' 1!( 'II t' rit' name o f till' ( I nI~ an' ( -. -I-I I a n ' ('unt's of plasrua t'llllt'(' niraliou ami 01111011111 ill f ill" hl " ly \\i t h li llll' flJlIU\\ill~ till' oml ill~t'sli{) 1\ of a si ll~l t' tlOst· of a d nl~. As till' plasma coucontratiou-time curve is fluitt· flat near thept·ak a ll tl h t"('. 11 1t'r.7 1tr.times.linn' uf its occurrence .: I'ha r m. All utllt'r paramdt. uhla iTlt'11 the fnlt()\\.ahsorpl iull p n l(' '''''s .1111'( 1 ~l'/lI'ric products." ain am itl. III 1'. J. E ~ l i llmh' " olh hioi. C HA PTU 4 In p ml"liet·.IIItt"lt"rs..lali\"(' hioa ntilability of Iomudatton 2 ..«:t HlO 10-48 "'I to-gl 13 1 200 10 0 332 586 554 1000 1000 Irom hnth <llId urim.~"4-2.l ift. I )" pil1''t1 in Fi~ .rs n ' ma ini llg tllw hallgt't l. n r mere.t11rVt' n-th-cts «leorpnou .a l\~t"l.t\1tilahility a m i rt. nillt '(llI j val (.) I dt 'lI ti ~v t'"el. ) n ' ma in \l llel.lf. c.'» ). l.3 .. one. of prtxunuunide.LSIIl'1t'llllt"lltralinll \l 'rsliS tum..tion {la ta H ste-d in Tahlt' -1.. Bil)l"(iuiva lt'll t'(. tl"slin~ is also rfomu-d dllrill~ the t'(IIIN' of d t"\t'!"pIlIt'1l1 n f new drugs. If kll < < lc . 1II 1 illt'n 'lL in hin.ll·~" o f tln.!c' wb y it is no l or su pp ly a llualifit'a!inll..1 of t·ad l n f Il.terminal slo pt.. ( .!l'11 lW>t'. r". / . I1~ ..n r I1 wlllOtl of tuaunfact un."s tha I show.. um l I . (( . S(' e. ..of t..Fi~..s n-nal dt'amnt'(' (If p n ll.

. k Increav . k d t'('T!.7 Time Time a. in pa tit'llh \\1111 ('nd -staj.. k <!l.... T..1\\1Li ti ll~ (~.c. Table 4-1 Ih ts Ih t..v... lowt't1 tht' lahlt'! wh ilt' sta lld i n~.it'>t't ! hv same Iactor r-... j.W ..1H.".(t' ph sllla ao-cuutncphen dat a obtatncd ove r 6 lrr a ftl' r s.. )'.nu-an wt"ighl uf ti ll:' pa tie uts wa.. ' ''''''' .1: s who swuly.. .lJ. C l..a NTV.. I.dhy ~1I 1l(' (idor d . _ . M .l\'ailOlhility of ('l)1 hropclic'li n aflN s.(1.<1protein ( ~ I.( 'H' . .li 'K· I·llt l. = 34 . Kumpf d al.000 W lllold used tn lncreaw n -d blo od {'('II Ionnation. II nw dn '..-. III both ~rnll p~ tilt' ta bid was ta ken with a snffid t'llt \~ )l tl llw o f wa ter to past" swalltl\\i ll ~.:L"io ns .lR. do. .." I>oc<j ~ wa> "' '''' ~~ <><h.l S d t..(lyl'()sylatt.::I _ ~ 0 f~ ><'* H C ~ "'" t~ 8 .... 67 16...c. M_..1 '-- I"'!ravenous Scbcccrecos '--.1 a single' tahld ('(m ia illilll?: acetaminopla-n ( 5()(). . ck-cn-a sed.at iou swalloWt. m lluwi llJ.la) l..I I S el DI _ _ a.". AU~ Maxi• • • PI. mcn-av-d. col _~ ~"""""""I'QhfI<O>"'" ~nglo _ . Tahl(· 4--.If·I'" ef 'onowl I.. . CeIK Iryth p. t ra nsit IIf 1 lilt' ta bid W .NoP-.t while I)i ll ~ t1l 1\\ 1: in III of these subjects. A _..( nil st'Il.l: 'I"\'alioll? ... h . «c 3010 1372 ( U • COt<EN1lA10'1 .t'.st' r\"t"(! wus uun-h Iuw('r after tlw s. Dd l'0I 1ine tilt' d l'arann ' am i vclunu.. o f 20 pati ents .ll1Ikillt'ti<-'S o f reeombinaut human (·1')1h m plli{'l in .\c'{·!... 60 kg:.lrah' O(' .· patk-uts..5.1. I. h. "'"""'" 4 17 40 .. 5ctooooalo .•• olld •.) ad min istration s of -10 Illl il!>/l.( tilt" tahlt'!. CI.l'it 'i! hv ~l1l1t' factor -I.(l' n -nal d i ~·il'it· after s i ll~lt· i.. l S \i. Calt-ulaft· tilt' hill..It•• 4-3.5 C .. ..'>t'd . J tll(' lahlt..rm. v i1wrt'a." l" plaill lhis " h >. an d subcutaneous (s. Clnunn-r uud Holx-rts ( W ~51 stud ic'(l lllt' t'fft '1. F dl'('n '. rn ( 'o ll l '(' ni m tillll o h. ... 0 1 )QJ-)Q8 1991 a. Ead."nil lllplwlJ. a j... T Ilt" fin-t t ari J I sllhjt'(:b swa l1ow(.a.. Tlu. ~S!~"TO-' _ ••1HI ' . it ent er ed the stomach imllll'(liatdy. lI ow lIl i ~hl }UU exphdu }ullr answer? C Tln.c.I .o f distribntjon of this d r ug.slIaIi7J'(1 hy lluorosco p In th e ot he r 9 sllbje<..!lON """"" 5 mm b 17.. atl minisl mli o ll in tl.1 lists lilt' saltent fi lld in~ o f ( t ht"w studn-s.. stm li("(1 till' ph . . CO'-.dt·ri7.l'>("(l h.. m~) and b um sulfan-.c. _ " " (> "".. . . a\"t'r. 't of del ayt't) (o soplmgt·al trans it O il tluabsor pt iou of . Incn-ased c.muxin.

•• T..adnnmstration of ". Clin. M_. IU (illte m alio llal u llits ) of bios~l lt ht't i t' hu man ~n)\'1 h hormone.wI..lectI_ .. S.· CHAPTU 4 10 o o 2. T ah le 4-5 (:1 lists till' meun seru m rmrcentrutlons ill I I subjects ohserved dunug the first 12 h r a fle r thr. 1.It'..1in!l site Oil III(' absOIvtioli of lm mun ~n)\'1 h hormone.. Sharp . Do tilt" fimliuj. Endocnnol.ft'ad lillg tilt' S~1i h' lll i<: ctreulu tion. T"t' dearmlt't' o f gnJ\\1h honnouc hits been rt1x lr1t'tl in the literatun.• S ilhthya lliUllhiln. 1io . d im'? Brit·lI).1 03 I 1 28 32 39 31 18 17 "-...E il'-1 "'C!lCNSllf 0 1 4 ~ 6 J 8 SoIR\..-line ill pb.n-comna-ndatton for rlu.e.latiw to ahd olllt"n ). a hscl'lltioll til" di sposi tion ....4-5.( .. D .dt '1. Is there informat ion ill l"t'Sl. 0 10. 07 n. \l allYp n ueiu..• J . n "9 h AIHI.• and Joh n.A. Q 1w... o f thi s sludy affect rs th r.dmg fnlll)\\i llg alxlominal s.~d.c.. inj' 't. V._ J _ o-wth M_ _ " . .. 10 II 12 12 11 <2 <2 34 10 55 27 92 27 84 37 75 28 74 28 " 31 24 19 20 14 8 10 23 20 a. c. ~ CJC f-'d~~ _ ..5 28 22 17 29 15 18 15 075 ~ ~ _ ~-. illjl"<. 10 SUAAt's l wln-thr-r ab sorpnon or d ispositio n of gn )\\1h ho m lollt' rute-linuts tilt' terminal de.. 10 85 240 300 o-(I .1t'(I..~ .. H~Jl ) examined the l' lTt" of s.. a~t·al t ransit havl' 0 11 the slx"{'(1 a nd extent ( If ahsorp tiou of <lct·ta m illoplwll? h . 1111.ml of Ihe alxlonn-n. Kin 'lI sllIK'uliUlI'llllslynr intramuscula rly a n ' partially d{'g mdt 'tl wi thin ..ton s.sma dnl~ ('1 11\ l't'nl ralion? c.5:40H.('ss..: 111l" d Tt'(:t o f SlIht'ula lU'()IJS injec t ion sitt' o n ah smp tio ll of hu man ~rn\\1 h hormone: Ab domen \. into 11 Iifted fnld of skin Oil tilt' an terior t " i~I I am i a Il)\n 'r lluadr.1: do('~ dd ay('(I l's()pl. . .'!l<U s 'dte IK'<.li S(> of this d m~? fl.10 a\"{'m~(' about . T Ill' t1 nl~ wa.. n.. Anyanku . Illt· lylIlp ha lit· syste lll bcfon.. 120 150 180 210 3. II. ~lt'am"(l From graphical llllalysis. Bt·sllyah d ul. "'9Jl .w. \ \ 1M! pn ll.H 2.c_ _ "l:>.. ( Bt'shya h... 12 . Al't·tam illoplwlI is !I st'(l for tilt" n-ltef uf p ain.11.. CONCf"ITlA l1ONl"""""""..' data... 011 Sl. 4 IV I. .-_""'--""""" n. inject ion inlo lilt' Illigli (ft."I. illjt"( ll. C a lt11la te tilt' n-lanvt' hioavu i1ilbility of lilt' dmg aftt'r Sot' . \ \ "hat d Tt'(.•• c..5 I Jh r.(' fSUS t hi~lJ . Houghly es tima te tilt' hioil\1ub hility o f tln. d iM-·nss. ston . rate-limits tlu. h __ e.1 o 01 19 20 40 00 Q() 30 50 50 58 03 47 4. P.l7n_ a .

.'5) measured plasma phcnytom coucentruttous ufh-r tilt.. art' lislt'(l ill Tahl" -t. " ' ...t' data obtahu-d ill 12 Sllhjl'<.4-7."Io:G:o. From a sl'lIIilogarillullk plol of 111l' p lasma concentrations..!. ( .. I Tln..olllplt...ltl...(1. eon rm G<. O"d .011 orul administrutiou ill this ind hidllal? II.. 0 . . . " " " " OJ' 0 " 0. 0$ 007 I 1 0-1 a". T. \ \ '.Pooo- .5 g: o f a mk'rtllliz("l.l"' M >u.f ~. ...4-a. . Cak'ulah ' till' ora l hit).rist'o ful\i n in man . datu... . on anotln-r occ asion intr.JP F~.o f till' i. ( 19• . 8 272.1IOm rt"( '('i\'('{llxJth trcat nn-uts.:1 \'(·r.t\'('nously. S.0 QO 82 7 Q 66 6 2 46 32 23 1 2 3. s a " " " " 0"88 oa " " n. Epstein. JO 3J 38 . (Howbud .our. {. 1 4 I 3 0 2 3 1. . i.<J~~ '0--0"'\l/l e ~ 0 .276 IQ83 ·~""""P'><I". " " 0 4 OQS r ""'"" 0 OQ8 000 0 80 •8 035 . lx-low.ltl. 1968 ) ga\'t· grtscofulvtu om lly. estimate till' ehmtnanon hal f-lift· of I' E~ l:\ in lilt· subje-ct .UlluSt.1 d mg: fo rmulation and . DG 1liod"-.. . e. 0... each o f \.<J~tp[ lMIa1w<:o'Qlatd-.It•• 4-4.II_I. and oral administration.dt'amm'(' and VO ! U Il l(' o f di slrihutioll of P E ~ I A .SS of ahStlrptio n? 9 .. ]lX) 1Il~.cn-_ a .. PI••_ TWf(lY] III' at HMA (mg/ll to .sllhjt"( art' W\'('l1 in 1 T able -t-.. Halt· tlf ahslIIvl ioll of griSt"llfuhin with tiuu.<"'.'50 lll ~) ..lSSl'SS the potential use of PEM:\. ('st imalt' Ilu. " .ma concentra tkm-tlnu. s...(' .CHAPT 4 H 4' ...·lIlarly (5(X 111~) and inlmn 'llollsly (2. Sci. II. T I](' ph.l~.l [n un tl ll' St.'. . " I'l..anlit'p ilt'plk (In l!!: prtnudom-.. Cal{'nlah' tilt' total Av e f()lIo\\ill ~ i. and oral adnunistrut lon of :Jon Ill)'!. F ro m tlu. and R i {'~t'lman ..I)?.. l\usl l'llhalldt 'r r-t al.. c.data ohtaim-d in mn .~ He ~ oo. ~ I A ) is Ont' of til(' majo r me-tabolite-s of t ln. As part o f il p r ogr am to . ~ 1$ J2 F'Iom'la conc enlrahon 14 7 . Table 4-6 b"l ow lists till' resultan t plasma concentration s in om' suhjt"(1.ltl~ eo.l\" ailahility o f lIlt' dm)?. doSt" wa.I.. IB u~'>O. Also .""".n-ual dt'ar.s recovered i llllri1lt' u n ('h'Ul~t..~ Conce<>MO'oOf'l "'"" 1~IrO"'lI1(:uIoI~M~ Img/lf ""'W«to<l.. 0 " Img/tt 00' o '" '" 'OJ " " 000 I OS 090 0 85 080 050 Frmn appmpriatt' plots and cak'ulations. what can lit.. ~ I .c tI••• f.O"d~~oIo""""..s' .i.. Umdam l ("/ til.!t·!lt.trwtt•• at 16 24 500 48 on ...1S..v.' data with n 'slx'{1 10 : a.. Phu rm. T... o c! O"d ~<""" 12 6 24 11. F'Ion-o<cI ~w ..57:WH-9S9.mdlltlt"l.. J.lIll. ad lIl illi ~t ration of St lllium pl J('I\~1 n in inl r. I'l ll 'Il~ I t'lhyllll alllll id(' ( I' F..8 4 2 4 6 8 1 5 8 5. 1075 0.~""~ Conce<l"'O'""" 11'01 0 .. Cak-ulatt' tlu. • e • n " " .1MI"1 Pb"""~". o 3. we .v.. 4 6 10 I... ce 08 oa "" JQ H . III volunte-ers.. as an autk-pileptic tim!!: ilst'lL its phannacokine-ncs wert ' stud ied foll(l\\i n~ L\'.: Ahsorption kinetics o f " ). d .v..3 C"" Pto- """'010 ..

is Iht' j. h .. was ahsur l..curuulatm.lIIN't IIlt'nl absorption 1.l.lII.absorpnou dat a an' shown in T ahle -1-9 .a.'" " 23 40 80 Q() . P... udnuuisfr ation.first hour . Estimale tl.~ much slmn-r..1% of till' do St.~ Iilll itin ~ Ilu.m..l~lIIa pllt'II~1oill l'()lIl'('lItmt ion fol lo\\i ll~ i. ~. couuueut 0 11 lilt' pml''S.loble dfug c bscebed h-oml...l<.'ll tilt' p lasma conccntranon-tunc dat a and found that.ltle 4-9. after absor p tion wa.cenl <:J bioa.t'(1u n an-a compart aila ~T1 S .. und rln-n -. From an apprupriah' plot of till' data.t' hiflil\" bilil)"o f plll'll )'to in From till' i. c. T Ilt' authors analyt. Arte r th e rapid ahsorptioll in tilt' first hour .m.'(1wi thin tln. folJ( "'i ll~ LIIl . 2..dechue of Iht' p l .o. Tln. administratkur.-tter charact e rized by a zcro-onk-r or a first-order pn K:t'ss? . site h.

Section II THERAPEUTIC REG I MENS .

.

..a therapeutic object ive . A t1w mpt 'lIlil' dnsagl' n -wnwn is I)'.1-\ OI"(' U fS in some lllllillint ic am i anticance r cln-ruotberapu-s.. In this section . list !he 10 nge of plasma cceceoscucos ossocc'ed with lheroJ:')' fa cny ollhe drugs given in Tobie 5-2 4 Deccss bliefly situations in which poor plasma drug ccoceoececo-resccese relatioru. 1l<:1.lIlS fur thi s approach incl ude tilt' dt.' .'ing treated. In ot her situations.h. rhetopeulK: ccoceoncnce range. .p irin 10 er In'al uu 11l'(. fuudauu-ntal aSI)('(.. A thinl n )lJsit!emt inn is that o f tilt' clin ical state o f th e !). Tlw fR't"II'III'y am i duration S ry with the l'tllld ilio n ' ll Ilt. o f tilt' latter . that is. til(' c d onunuous is . ami subst'( )III·ntly. and IS(' s. An exampl e o f tilt' for m is the list" o f a. A fourth eatt~of)' includes all otlu-r Factors sllt'h us gt'lwtk differences . Define the terms: graded response.Igl" n"¢llwns in illtlisiduall). infus ion of le-pann to maintain a tIl'siR't1 dt ogn't' o f a nt i t't "'I~ ll at ion is all ('x3mp lt. Anotlll't l'u llsit!e t'a tion is 111\ 1 \' th e hody act s Ull the drug and its dOs.']uPIIlt..' d ntJ!: an ti llit' 1U't't1 to produce hi~h concentratio ns fO f sho rt pe-riods of nme.. t Illations ill Ihl' plasma conccntranon.. uf course.in~ larv.iullal dose 10 co ntinuous and constant inp ut.admi ni stmti o n. flx'us is turned tow ard th e l'st ahlish lllt"nt o f dOS.'tit'n ls .t1 it'lll and his or her tnl al tllt' mpt'u tit' rt~ lllt'n . t'xtl' mling fro m a sinWt' occa-."1 · of tolerance to th t.I~t' fo nu . tolerance . 2.lft't)' of the dmg.. One co nsiderano n includes t!lC fadon. Explain why elfecr [desired cenh'allOf'l thon with Of roxie) 01 a drug is often bettef cceeoed with plo~ con- dose. ill St'(1 ioll Four.1.' IIlIl'ry. tlu als \'a l)' in thei r n-spm lst·s 10 drugs . ad li('\'t"t! by S1lriOUS modaltnes of d mv. !tt ' il'it.ri llll' 1IS art' nln'n... lnn-rrelan-d alltl in terdept'nl!t·lI1... mai n- . II gi\"(' 1\ d l'\('. thai fd att' to both dlil'at" . All of tilt'S(' dt'll' n ninanh an' . It is realrzed.ah'tll)' ill dlscn-te doses . and d nlg tutcn«. all-or-none response.ps ore likely to occur 5. Ihe essence of pharmacckmcncs .1:itllls.l imlly de riw d Irorn tilt" kind s of information shown s in Tahk.'>.I' L 5 THERAPEUTIC RESPONSE AND TOX ICITY OBJl(TIVIS The reode WIll be able k) : 1.1 pri marily from the {Xlint of view of tR 'nti ng a path-nt p opulation \\.\"(. IIf ('. Sonw d n 'h 1II't'.I-'\('. hplain bfiefly why modality of odmini. its phannal'U ' tlplamks and tU\k(llo~~)'. dru gs an' admtnisleR'll rt'IIt. and tolerance .1.siu llal lwmLl ll'. tl. admintste-n-d R']ati\.. 3. TIlls objt'cti\'{' 1I 1i1)' lit. ~I o n' commonly..-a... lgl· n~ lIlt'llS an ' ( !t'S i ~ l t-d to produe. that iml i\.( J11I'M..t.1S o f dusll~l' rt.'Iy infR'tl'lt'utl)" prtX lll<. TI l(> rational d(osign of SOI[ I' a nd (·flkliLiolis d O'i<tg l ' nW"It'IIS is 1I0W examtned. Ulilily CUM!.wo rion of a given doily dose con affect therapeutIC outcome.

clorS Age. sto lnfo n uunon rdalin~ conceutrunou 10 rt'Slltlll'it' is oht . lI oWt'\"(" ..'usst't l ill lilt" subsequent h-\u chapters of Ihis seceton. it would S('{' 1Il to he must appmpriah' III apr l>' phar macokim-ti c principles to the desi). mien.1of dmg in tilt' b odv und ist. unfortunatr-lv. in iM. nrgallisllls.l-ss('s"'t't:) hy tln.pll(·S.. !lt' n ' a"ulil Ih.. !lIml releva nt to human dmg: Ilw mp>.:l~t.1(1. however.elohon!>h t~ Ab>o<""". III Illis ehapn-r. attempts an' 111.L lie h luod p ress urt' hy 30 IIUIl I lg. /II l:itm cxp -rtnu-n ts.:(' much of tjn. wh id l indmk' studn-s o f the act ion of dmgs Oil ('Il7.'I\\'("'t'1I in t:it m t'\pt'rillwlltation and hu man tnves tiJ. rt" lIlt'll and _ 'it'I"\'('S as a useful !lIt'1II1 S of (. lIlany of lilt" comple-x Inte-rn-lationships that ('xisl in 1:1. t:tin Evuh-nce. A(:(:(J nlill ~ly. with all that it connotes. mali! III is 01'11'11 uh la inah lt. 111 d uS(' 'I(Jm iuis ll'rt'tl. TIl(' last \('\-. tlu. An.JI of dosa gt· regtmeus. ""'" To.:C n... \1uiOIlS r-k-ment s of tilt' l"tlll<.ll m exp erinwnts.~tenee 01 orner d. ~i\'t' n ph annat1lkirwt ic da ta l f(JlI O\\in~ a si ll~l t' d"o.t'xisls tim! n 'sptllls(' is often la-tter co m-lau-dwith plasma concentranou than \\...on Dosage fo.ullt"'t l at Ihn-e h-vels: 1'1 r..therapeutic and to xic n 'slxlIN'S p"-)(III('('(I. Studies ill animals introduce b h lilt' variahh.seose $JOIe~ ~~e 01 reg'men Complianc 01 potoenl e Nv"h. lilt" value of a d()~g(' rt '~IIl('n ruu st 1 .. onl>' Iimilt "f.rt'spOll'it' rt·laliullShip an.:ap h..lIlM' Illay ht.ti me.'iM' 'L~ a l"I\\"t' ring of tln. and ot Thercpecnc W Indow Sod.-WIllI'IiS.. are t1t'st n ~l 'tl. to minimize uudesirable and toxic effect s am i pn-veut ine fTt" " therapy..1 is II. Prilld pll's fur att ai ning and lIlilinl ainin~ a therapeutic It.('Xplcn-d. nature of the dmJ.-m T oe-crce-deperoeoce I't>ormocogeneliu-odl<)$Y"C'osy [)-ug Inlefoct>on~ COO' .pIe d"J9 lhe<opy R ou1te 01 odm iniSIIOf.:alioll.\"(..di . st' l"\"(' this purpose Ix-st . weoghl Cood "l()ll be.('. Plumnucokiue-tlcs fa)(· dlila h-s til t' achievemeut of an appropriate dos..J.I. In all cases .. ami isolat r-d tiseues ami organs."t'lIlrution..plusma conceutrunon O f amount of drug i ll tilt' hod): fllll()\\ill~ any dmill ~ sd ll' lI11' can IH.'9 lleoted h.:.. Ultillllltdy.. and ill\"t's tig:atiolls in hiuuun volun teers and pal it'nls.1 lnfor. Di~lIlburlQ/'l MeIoOOIism EJ«:rehon Dosage Regimen Sl A't QI PArtNl O IH( ~ l.ding tht' va riah ]"s .. 11111s.. imal Silltli('s hritlJ.vllluat i ll ~ t'xbti ll~ t!USilJ.rt·(-'l 'ptor tntemcncn. receptors.Jy Coeceeeceoo-se scoese . RESPONSE AND CONCENTRATION Ih 'sp.' estimated. nntmal st ndu-s .54 THERAPWTIC R E5PONSE AND TOX!C1fV tenance of a "-·b lively constaut concent rution of dmg is 1ll"('1lt"(1. as n lWlt' ax a g"'lwml fl't'hug of Imp r ove-uu-nt or 'L~ p rt"'t..but.

e..the chmcal I'ntllx)int is all-or-uone..m a ('t..L 1.d .M. 111i:'i is iIlust Tilh "ll in F ig. TIlt" 1ll'ljOril)' o f d n lgs list'll c1inlt...llt1: 1Of gradt"ll..... till' fl"t'1. l ll ... n ...II"lt·k t.'s po llo. 5. \\'1·11 .)1111Iliil either ts or is nnt sUp p u 's"l'(I... the. 5-2 II p lot of fn"(llU'"l'''' of ti lt' supp n-ssion of ventricular errhyt hmias us II Function o f the plasma comvntrauon o f till' untiarrhyt hmie il~t'll l pn:lt'~ti n.: function.. ~1. ". s (' of most gra ded ft'Jij'ltlllSl' curv e-s.1 tlu -rapcutie a~l'lIt a nd for dt'tl'rlll ini ll~ .of a )...II.. . a 1i".(lIltl.1 of alltihHlt·rknsi\ 't. 111 plot is dmmt'!t'ristk . elm. PI..mdr d ..5 0 2 4 6 B 10 12 Plasma Terbutaline Concentration (JJ.t! high concent rations 'In" a ppan'IlL Unlike a gr a ded n·spoIlSl~ .."\1J uatin~ tilt" p lmnll"nlln¢ c lipt '1.4'.rtt'lIsh"t' a~t' ll t s is it ~radt '(l response.• 6 . K< 1 C .. ..·nlr = 0_ E ~ 3.1 (H':l' l) ' .i• .. ~ _ 0 o c • • .Jo( ' ·aluI". 111t' I (M·t'ri n ~ of ' h ltll'lll pn·sSllrt· pnxlul.il'il)" pmfill'.~ h a lu .. For exam ple.fof( 't.r"" " I'Iy.event with conceut r anon. .-""'1 ..>-) is a plot o f tlu.. in I .. t lUl l<.L<. a~itj llsl pia. 11 on. allholl ~h sometimes complex..illlpnJ\'('lIlt'nl of pulmonary fun l1itJII produced hy tluhnmdll'lllibiur IN h ufalilw .' a~l'llt ut tilt.I V.-_ f"'. ...· i"'I"'''''' nwnl in pulm" nary {uIIl·ti un In(. lynami< " It4i"1t or 1. ' j n (· r.· "ull<~..ulIIt' fCSPOII"iCS.." . Ht't llnl illg 10 tt·rlmtali nt'.. IrT(·spt 't1i\1.. lilal i. hili h)]x ..1iu n.tn mai ntain homeo stasis..) 2.'olltm l li)'litt'IIIS tllilt s operate.. h"l "l't.. . i ~ death.. Hen.1 tin l< in . ..• -IfJ A6 !1.l('t'ssin' It J\\'t' rin ~ n f hltlllli pTt'S...1.('. 5-1. a poh'nliaIl)' toxic (·llt'1.75 10 p. of tilt' n 'spelJl''l' ran 1'It· <.. a limil ts St·t nil a gm dl'1l rt' SpOIiSl' ht'l o w which an t·lT l'(1 is said not 10 OlXIII" dini mlly.""indi<'-p" "r. aftt'r its s.25 • • • • wnh Ih .'illls(' the Illagn itud t.l nown r on ( ). ln. '" '' .'S .. A ll o O" \.\·d of information.rnlllt'( l n.J I)' ad n '\T rsihly ill t ha t tilt' e lTe ts u '\"t'TSt'l 1 UpO Il (1 n'lludll~ conceut rattou ill tilt' silt· o f m. '1 11:. admi nislratioll . .1 •..1.- of " 2. rt. III IIltr..-.<"11 the t'UlI(." . llo ma.OWTH 5 55 till' elements of abscrpuou a mi tlispos ition .\1..: t1 rm .te nsfve Imidt)" is said to Ott 11f u nl)' if l ilt' hh'lll pU'ssu rt' falls In IIlll ItM' a \1J IIl'.· of tilt' It.1..ttionsh ip 1'It'I\\. Tl w r .un'lll t'nl and tilt" n 'S!'ltlllSt'. sitt' of III('. l.('n.('l l h) ' th l' antih)] 'It.· h. m....('1'1I t ht~ intt' lI:'iity of rr-. SOllwtilllt"S.. therapy is an t'.\p lo n'll h)' I'xam i nill ~ t he fn'q'lI'P1oJ of tlu. Ma TI)" otllt' f phannacolog tc and to xic rcs peJlls('s tin 1I0t occur O il a cont in uous I"l'iis.. 110 pl.c . theS(' au' knowu us ({u(w lnl Of nll.. ".1II)' n'S!)flllSl'S produced arc j!..QIl) . F ig.fM11 ill Fi~.a mp lt..1S of its to '\.co m-lattonlx-tween a flualltill n 'sl'ltlllSt' and enncentru tion is t·. TIl(' inll' n\ily of t he n '!ipo llse varies with tilt' tl m ~ cmu-ent rution ill pbsma.... rm . ma concent rutiou.. A ucu rly lillt'''f n ·l.. ~ "'II: of ft·rhu. I' . .Ji.OIlS bill extre me l·x.Ii...)...'t'II' trutiou of . c. bill ti lt' phafm 'tl'tllo¢l' n 'sl)fIllS(' is ~Tildt'll..\1.~pi ..·a~ ... TIlt' arrt."'. :\lIol lw r h till' supp u 'ssio ll of all arrh)1 111I1ia.l<. Animal st udi es a n ' nfh 'n most IISt'fu l for l. r.r. S( ) called ht '1... B... th e conclu\I'It' ' ston is the sante: A rt-latkmship. " a me-asure o f pIlIIllOIl....It1h1. An e xamph.5 • >:. is tln.:l ~ . · ".nt"· ulraU..u ll i d(·.tl it-"b I(i'~n O. an pla u"a 1.iIlTt·... >1"".....J.L \inml n'sl'ltllls(' . e xists 1I<-'f'.. I.1nllll o f adhi ty of u pOb'nti. SpOilS(' ami tilt' concentration al ItJ\~' coucent r attons and " It'ml t'ltl')' to n'... ll expi r atory volume in I Sl't.tJ\\·I. 1\1116..~ :rl 3 • • ~c . I" "'1'1 _ . 6"''''1.I. n il'" n. C. 011"1) . St.1 palit'lI1s "y 3..

4..1..m (..' t. alld fur 11\('111 pnx'aiuanude is ('('rtailily lint lilt' drugof d llli{"l'. -of t'fT l'(.. mw'L. IY7.1....I...'IIIll'Ill.'l:.L..1 by <:T. I .. .I · .-I' il-l. li.uII..1i\" s (' Ihemp)' and \\..e o f p la. "'illo ('.(' who responded... tllis ht'lies tilt' THERAPEUTIC PLASMA CONCENTRATION RANGE Fi~lIn' . coneluded Ihal the m ll)!.. i...... J..{1Jllsidl'rt'tlll1inor wlu-n ('('ss<llioll o f lilt' d m~ WR~ 1I 1 <1 Illt'1.k-m. Illis d s in formation is unknown..J .· rn"I' .....' .In'lt fu r lh. .10.1s nr-cessilalt't l d ist.....L.uI. \".. U Sllall~'. ...IIl\\' -I.. llIo''' 1 .n".II1l:<' {I "'II: (1".~ Il pp rt's<....1 coueentranous 1)('1:'\\"('('1\ -l ami .('rst' (·fT('1..it. ~Wll 1II0 fl." . AI)( l\"(' l f 1Il!-i 1...' illl{.'). " . '-.. "".. . . pt 'n.-n .. alt'tl with ('lTt't. the toxlc t·lTt't.nh n '(.........'t'nt u f IhclS('()<ltit'IlIS who did nol respond to pm ca inalll idt" 1110<..')... .'1I lIu " r..1s should ht. ... aml lllllS(' whu t'\hihilt'tl S('riollS toxici tv. tilt' major toxtc t'fTt't. ' 1 1" ....·r. tho lll llnd llt' Imidt)· is -l to .lt~ ilh "..~dlrn i.. Pe-r haps tilt' minor toxi{' t.i' .. ":"JJ't·r. &.1. 101 79 80 1 ~6 37 r- 807 ~ r 60 n .. . ' t't.pk-tu n -.• .. TIlt'S(' art' ('o nsidt' ralious rt'l luirin)!. . Ol d. .I.. tilt' tht'mpt'lltit· coucvu tr ation must I"" r-stunan-d Imm co nskk-rutlon o f tilt' prtlhahility o f tbcrapeutic S\l{'('( ' SS wi thin tln. 1'.·IT i i\<· ' ''.: '" r1. ' n'. f 110" n 'llnl ~'r flf 1'L.inalllide ilssl J{..0(·1. it can 1)(... toxid ty 1J{'('Urs I)(·fofl.. ulo'ail 1 fn " n zYl ["'Ii/. tilt' ffl. This r."'il lt· ' ' ld n mj'.. t'fTt't.Ii mg/ L.· Furun ': Pr.. Thus.dm ~. nes s. Also shown ill ri ~ .lll ~(' is (1)llllllo llly known as the tllf'rfll H1' tiC n mcn d ro tloll m 'll!.. .. ll" . .. .".1 in ""... t'lm 1'"1"' " p. . . in ~-. ....h.it l.11 .><-h inl'-"'.rrt. Cl t'a rly. and Oil i ll i liali n~ tln-rapy.'t1 n 'S!XlllSt. .~'. .. j tltl~U lt' lI l ." n . ~ _ 1 "I.Iyp i{'lll patient pop ulat io n. for tilt' treatment of ven tri cular errhyt hnuas 1It't't1 ptlSIII. It sllould he uolt-I! ill part icular Ihat S('riUIiS Imidt)" · h(1Qlls to a pl"t"ar ah(I\"(.. . no l all patients n't1'i\i ll ~ pnJ{'ilill'llllidt.tin ' tlt('rapy min us tltl" fn 'llu {'lll')" of all toxic t..e .1(.. II therapeutie eoncent r atiou is most appr o priatelydefine in term of an imlhi du al l)<ltit'nt's n-quin-nu-ut .. illl.. In a few ."t'SS<II)· aml serious wln-u disturl xmces of cardiovascnlur [unction o r othe r al!\.· 'Oil"..... ill otln-rs. (Frn".I.r :11 0 1 n..I tI... Il uwt'\'('r. ·nl .fT 1 s shoukl not 1)(' wd~il tt't l {'llually t't. Edih.Ii lllJiI.. ag:lulISl lh l' dt'Sifl..I..lli...".r of tln. ·(.. tilt' arr hythmills ar e supp ressed al concem ratlons 1)(..'] shuws tilt.\\. . m a concentr ations of pnJ{-d..56 THE PA!'E UTIC PE5I'()NSf AND T OKIC ITY 100 " l..! " .3 1 11 M ). t!lllS(' who cxlubin-dminor sidt ...·rolJ.. Il l( rhi' .· . 40 .lT ('(1s.i1i"l\ " f pnJl·..· .· (1"K~'n l r. n .-n t" ..1s lIlay pm\'(' fatal. n" " n · ·"I .1111'1.......'] is a curvethat rt'pn'St'lIls th l' frt'tIIIt'II{'y o f tllt' mpt'ul i< l' fT 1 in '.' ..'" (' >m ...( 't l at {'OIl{'t'lltrtlliflll\ of 2 III '" mJiL.' wt'ig:hl. (·fTe s wen.I.. . "ith. This lIlay IJ{' a n illilpp rtlp riatt' meuus o f ('s li ll1 ali n~ tilt' concentmnou at which therapeutic suel"t'SS is 1II0si probable..1S.. Sidt. ~2 .onlinualion of II\(' lim" .o \. \". n .1· 1'11_ ~U 20 ~ o In 4~ 11-10 12-16 2-4 6-8 10-12 > 16 Plasma Prccainamide Concentration <2 (mgIL) rlu....111 ...t "f iTIlTl·.. Oh\iollsly.a rrll) 11 I1n iR~ art ' entin.( " f "''''1'1.1m· I.s m!-i L and occu rs \\i lll i n{'n'ilsi ll~ fn'llnt 'llcy al h i ~l lt' r e uuvutrn· lions .' ... Fmm lill'S(' d ata.. · rK~·.·utr...

3.Alr. I~.J!lSt's.. 1\173. In lh.is a rangt' of ccncvnu utlons (abo ut .UK! .'l'lr. TIlt' facto r is nttatiw for untlt'simhlt' dTt '1.T ()~il a . Sd"'n~ttil' n ·l'n ..·IT · .s a fun ct ion o f tl.t' pla. (n "I"'·' K) · I. of l1JUN'.1mli ng 10 OIlT 1'Jl. particularly umsidt' rillg tilt' Sllhjl'1. KI I)I:.\I..·W.. " 'n'M" I.'l * ~· ..5-.1 ...1(·1. ..)· of 1rM... each wt'i~h ted b)· a j U<lgnw lllal factor WfSUS lilt' logarithm of Illl' plasma conceut ranou.ITI'dr.."Ic~.."ts am i positin ' for desir. ) . .'r"py ....311..lgt' hm il~d.'rsc.~ .<J to these reSPO l1S~'S t1ifTN. ... 10 10 mwLl within which till' chances of successful the rapy an' high .. l. rdalhl. • ". That is.IT. m in.' ufK't·fft'l1r. t 'I mWI.i. 5-... of K.I" m_ ill n .'lIlk success is most ltkely...K. c."ti\1.'1..1.. .1.."ts and tht.·ts.CHAPTU 5 57 Therapeutk Window Let us expand philllsllphil'i...lk toIT ''l1i.. There is an opt imal umt1'IlIraiion (S mW).. ff''l'l I". For exam ple tlu.!iIT ' .lly 0 11 thts l'()n('t'pt of \\l-'i~htin~ dt"1. rl.' nature of till' utility CIII'\'e .l1y addi llg tilt' weighh'1l pmll<th ilitit.-IK "'Ifl.''•... and tilt' wt'i~ l ti ng a\s i~llt. Prec iselimits...-•. Then. .s.not dd inahll'.l it-nt.d..-' importance of each dTt'l"! mu st he evaluated to determine till' t!l{'m pl'u lic conce ntration r. F'<lih111. ..'J\sithi t)' and a.'!opt'1l for p r ocainamide lilt' iuforr uat um in F i~. and then..1...an' probh-ms assodated with tlte acquisition o f tilt! incidence o f til(' va rious fl'SP O IlS(·S . n.1WU(C'o l" f('lJ lillt' ) .IIM !.\ I J... .ff.·n.:"' C.. an.'idl'lIl1:' of till' d lllg l"lT.1·11n.' · i t" 'ro' lIl<l (. f pm.'utic 5\1(:(1'S5 u..o. ) at which t!wral'Jl.chance of t1wrolpt.''' Ii<' ~·IT''l1r.·r .-I.g. .. 'l"IIM·IllJl:'.. IIK. "d di ll~ Itn 'Jl. ' Each dmg pr oduce s Its 0\\11 pecu liar reslxmst... (/" I. PI' ror or.' I'« 'l1 fn >ll l ll.I~· ..1.·.:. 111.procatnanude data WNe obl aint'11 in p atients \\110 we-re some t fuws titrated wil h till' dlll. of I'nK.."\" lilt' prnhabilili('s of til(' re' SI'Jl.01.'3.. Ille dosage was adjus ted wlu-n till' patit'nt llad nut adt 'tillatl'ly n 'spo ntlt'(! or when Inxid ty was present. \'.'l'"lnllic". An.'>lill.: I.. 011 .. II. J.1 . Bo th low alltl h igh conccntrunons have a lII~alivt' utilil)'.. ~ l.. iJ .pt.. Thi s is lilt' tJlI'mp('lI t ic Id ud ott' or tlwm peut ic a mCl'lI ' ra t ion mn{!. n .' ·""1'Il ..e."lt.· Ih" r"P:". IM.·r . t ht' r..·nl ~ti.' 1'."~' is ohtahn-d that simp l)' SII(J\\'S tln. sign ing values 10 tilt' res SPOHstS al'(. I. tl" 'rdl':" "'K!I... . t'fft'1..mid.rl lil r. 111<l"'. " M ...! m~ II. 1. a utility n. p lus that of I I~l)( ' rwll s i l hi ly.I .lIui<lt in I>... (I "' ~ . pat ient s even Oil till' usual " u sin~ 20 o o 4 B 10 Plasma ProcainamideConcentration (mgll) H K....·.. hul !lot h tilt' ill(.Ul~e .sma c uux-ntr attcu.. n uf Ihl' fn "l" l"K. .'l'l'.I... n'l1-Mu l/: · lI..s. . at IIlt'sl' roucentr attous . Figurt' 5--1 sho.• In 'al l1" '1I1 rrl l~dll"i ". itlt· . ~') .KI " tilt' FIIIII" " l' n ol ."(. tilt' d mg is 1 )(lft'lIlially mort" har mful than ln-lpfol.:>lin .e......'st judglllt'lll ..

. .\'('r lim its d ifTt'r by ~ a ': II'lor o f 1J1l 1~' 2 or :1.nou..I."rrill~ " pm'" in pn'lIlahm' infants than ts 1Il 't't II't 1 In \ ul""l.-1..It·n\iull of III(" p"anll a(:1)Ic ~:k' Pfll l'M ·rt~ ' of IIII' t1nJ ~ ur I(lt all~' di ~\lIIl·i<lh"l.h .. Fil"'<il . r-uln-r... .lp.~. St·\"t'r. .1 Curve Minor Toxicity 0.. ' .. I('ad i ll~ rme.l fnull its t1l1'rdllt'lIlil' "fT.l dm ~' s IIlt' mpt 'ul il.".0 3 10 Plasma Drug Concentration (mgll) 30 100 .'n fratiu n aml p!J'lfl llat1..t1 from Fill: 5-J (plut .. tnUdty.ll't . "tllllt' dmg. t'()lltl ilio lls a re . i\ Ilt't'tk'tl ln al ..5-f.... the lIppl'r aml llJ'. ()( eourse-.. 11 ill T ahlp 5-2 for a 1lI11l111t'r of rt'pn'''<'lll ali\"t..mtially inlpfllH' pulmonary furw lioll in 1 l.hould h-ad to a ilion' rapid ('sIOlhlisllll lt'llt of a saft' and t'lli..llly mo rt'" harmful du " bt'nt'flcial r Or til<' lll.. flll IllI'rapy o f ' I'll'('ifit..~ .. 111(' p la. o f ("(IIIN'.t .I .5 .l It "t l ll m lll ~1. d m ~s ..t ll~(· u f l'C Ill("·lI t ral i(lIl.1I\t' of \ll lk')'lit· add In n ·lit"'l · Il. ..uun-namr. hiht.. all tilt" CHAl'TE 5 Il if sdt'l1it lll uf Il<tlit'uts han' (Jl:'l.)" al\t l 1M' dill' 10 Iilllil in~ dTt"t:'fh.. wkh-r. wuhm it.ffrct. . '111:. TIlt" ll('lIlurrha~' It'mlc'n. Il nwI"'''''r..1 da. To avotd this h i. amnn) . and tilt" IIw"'c1pt'nl il..L.. IIII' " pl lt'r lim il of Ihe.'nl mtillll r. uaT" Ott"\In al II mw'L and c. . minor lulU<'1ty.. in lt L.unp lt" a lu'Wt'r roncenr ranon uf IIlt"uphylli llt.'('nl r. K hellMl.s lII" (1l11t1'lll mtiull ra. IIII' mon..hlnl pmb.. an' wort h 1l{)li ll~ alMlut li lt.difficult is li lt" m. t1n1J. an' 1I" .1 03 1..\(.. of rnpon '" Wnul dw.\ITl<l l"I1<.llit'llh .'Ji."i"t: I n\itil~ ur.:. The ' "pl'M'r lilllil m".uf \"allU'..bilib. ti lt' d ise a... a).t:I''''' ptl rillt·" a result uf ti lt· 1M )<.:" Ihl' Ihl'mllt'u lil. like no rtripl~'lillt'" v a n-sult of t li llli ll i \ I...l'll!('t'lllmlioJl TitJl~1' is narmw.J by . Finally .IIII-:I'..111. tna rmnx-ntration may lit.alinn of the....'illtt'r an t·.IITt"tI. hl.'( '1lI1.'\1..o paa. K't·III.I .lti-t ms without IHltk" llhk' . 12 mWL . ('.llit' lIts \\ itll dmmi(' . 5. klluwl ("dgt· uf .WiOll' c1".'a . for OIl(" rt'a\llll u r al1othN .. t·t lJ kall~· un acceptabb..\I't'SSI\'t' or \\110 !la' an u n usual " "!ipon.'O T"KTnirationl .• a l a 1 1M' t'l IIl('l 'lit m h! In . an t·\ ('t....L.till.p l'L\m" l'Ulll. Fur t' x..1" "" '..·fft'(1h "III'S" .... lhe utility CU~ (cdo~ line)..' r....10 ques nou S "U"ill~ tll\ id ly lIIi ~ht l il r. --1. I'n >h.l. L hYl""""'ft..2 m and .1 hi~llt'r ('UIl(.l'\_ l'a<:h of tilt' patit'lItJi sl. 's.." t1l'\a~t · ~ 1 1l'w " witl.UlI. WL pnlt'nl l:. ti lt' na rrrever Ihis r."l'II(hIed..ljOrit~' u f 1 l. fllr many ot la-r d nl..11 pni nt.. ...' \ . ~1' lJl .m).· p h~ m.. killt'ti('S .Qlivity.althm of Ihr .prnhooh il. loll<-.chthty o r Ihrn[""ul k: . ('xh ihih lo\icit)-· hll'l"dU"t· Ih t· (InlR ('IJll'("l' n l rd tlo fl is (.1 .·lIt's. lik..:..' 'I\"I(·I<III't1 \'. I. i n~ ...' "ill. a.\t. ~t. St1...IJ:llI. linn 0 11 +1 Desired Effect n Ullioty Serious Toxicity ..i~1lS of 1 im ·n..0 ..."1 1 pmb.lxM. 5-2.(t· rt·W"WIl.' .' l... fur lIlust o r tilt..p l. a uli('t)..li rwa~' d is.l lu In 'al " "'·t'ml t1i\t'a..1ll~t· is 1Il1l(.patit-nl wh o ..11. ~ n1 rabon o f • •I~ n. ""CONIn'. h)T'Ol:ktnl h)l'"V 'lIIttvity .. 10 Ihi. war011 filll ~1' . IIlis ('()Jl(" lll m lioll r...ollid Ilt' n ·spt"N.I~' d iffl"f " i tl . Ilu.(I's .o d atl'tl wtt h s\ll'u.. -5. to\i(it)" ' "<1)"' lit.p la.h ('pi\lMu's of n't. n tis is.'it's .u li. um of I. of lilt" d"... ~ a1K"bnoioc ...sibilily of 1lt11hmlnudly .Our infunna- Itl\idt} mus t come fnnn th e.v-. dala in T ahlt..

~n i fiednl intt' rilltlisitl uill \"ariability Illil" oc cur in hot h rlul. Also .. 1h)' th e anlih iotk ~t' n t a lll i d n is iUl example of lhl' latter ....res p onse.1 to achi eve maximum dl' sin....... Th is p oint is illustrate. Tlus ~ lll JII ld b kept in m imi when 1... 5-5. DISt-'So! / CQf\OIICN Acetozolom.ffil'ill'y a lltl tm id ty n.. R heumo'. the Olo lo"id ty l'iIllSt. Fi!ttlrt' 5-. It'a<lin.. mode GenlOmicm tdccc...'5: shows a t1n l~ wi th 11 \..~l' n '¢llwn th<tt p n JtIUI"l. Fi ~lrl' .II lUIII'l·nt r."""OY d. 5-2• • • ~ ~ __Iate4 WIth ""c OOUG 1n.width o f a tlu-mpeutic wt udow.....e a.l:ocin Am.100 5-15' ~~ Ac sand ~heu molQ.·SptlllS(· curves .'5 B shows .." ..120 3G-60 3G-60 17-34 OOa-0S 150-750 750-2200 1800-3<XX:l 33-100 28-55 35-120 3-13 2S0--0QO 3 3-10 Desiprom'ne D'9'lox..<XX:la-0oo3 lS0-540 7-21 4-25 a 4-1 4~ 02-06 40.:!won Epilepsy Organ tronspionlOhon DepteuOon Codoc dysfuncbon Coooc dysfUOCf'on Epolepsy Gtom-negor.5-.ultilllillt· ohjl"t.'tITS \ tlesp ill' slt'(·p concx-ntranon..'l' in mlnd thut tlu.ltl..glo"idly.d pa.ide therapeutic \\im!fJ'w .ptyline flhenobolb<101 Pheny!oin P'OCO'f'O:Jm.II.12" 1-4 40.. 111l' \\idl' window OI"t..12 o 15-04° 012<' 001-002 o <XXl6-O 002 25-75 4-12" 2-<> 005-015 10--30 1~20 1~20 '-8 002-02 20-100 100--300 250--400 &-... .11y 1 "")111 1 . "'.CHAPTH 5 THERAPEutIC R SPON5t: AND TOXICITY E '9 furin..0 5-10 4.."t· t-urves IM'rlap wellbe low Illaxima l effiCill)'.-e infOClOon Dep.g ind i\i d uals ill the 1 0l'illillll am l widt h of tln.1d Iet:t .. seo~s Epilepsy Penic. <0"<:_ GrOm-negollVl? mfecrOOfl Throm~boIic d. ! SChl'llliltil'itlly in Fi~...t·ffil'ill'">. is all example of till' foruwr . ...oe ltlh'um Nortr.... .. 111is narTO\\1lI'SS ariM hI" Jlh 'S l'ilUSt' Iht' n 'spoll....'0'1 .__.... -2... PI.mo and ehrooie obsrruclo-.·plll'SS o f a concentrutkm... without S Ollie tI~n"t" of limitill. It is In ht· stn 'sst'l ! tlcu si.tlu-rapeutie wf ndow.1'lIn '('5 for b oth efficacy and toxicity .-py DnI... • ooq.folin Volproic Acid Voncomyc m • I\n<"O d>'vg ploA ~ ' ~ ...n Digoxm Elhow. c._.de Propranolol Solocyloc Acid 4......". U_..llio!lS wt'll uh"\"l· those TIt'("t..II'll'fesiSlQnl jnfedOOfl " 1\.de Am. 'nit" normal sl mh'~' wlmld Ill' III t'llsu n ' that all patients n-cefve a tluS<l. / ' o ~ """. TIlt' narrow \\i ndow OI '('UTS tlt·sp ilt· shallow couceutranou-n-sp onse l'u n 'I'S for IM efficacy and lo"idt>'...'IITS . ·S ple ma rouceutration s Ihat ae hil'\"l' maximal efficil' IlI'Y \\i thollt toxici ty... Thel... a dm~ with a na rro w IIlt'm lwlIlic wi ndow..tnptyline Ccrbceczeprre C~bspollne Oooccec GtOf!'l'l'lll9Ol'..:..1i\"t· is I" trea t l'ildl illd hitillal piltil'llt il'i t·ffit'ill'ious ly ami sa fdy ilS jM ISsihle am i not 10 ke ep his or her ptLsma concentration s wi thin tilt' n 'c...e !eve< Asr+.-e mlecbon l Ventricular olfhythmios Noon..::l.. ~ a..secses """'" """"*"". h .....lIIsil!t'ring e 111I' tlll'mpl'lIlk \\i mluw'i lislt'l l in Tahle . 0.....re sponsc t-urve andtln.... li en ' toxid ly OI"t.. a ')0. so that it is d iflk 'u lt to find ' pla. -ds 10 ht· made hetweeu the Stl"t..... " ~ _>hoIcl< ~ . OlfhyrhmlOS 10-30 11-25" 0!2-o25~ 50-150 0 43-0 QO 17-51 o 13-034 045 0013-0026 0 .s lllill·om'(·"l r:ltiol s Ihat produo.g to difference s amo ll. DistiTld iOIl also Ill.e ond recUfrenr depleMOOfl Endogenous dep<euiOn EpolepSy Epilepsy Venrriculor OlfhythmlOS Venrr iculo.ns onnllr...s Theophyll'ne Tobro'¥in Wo.. 111t' val ues an ' dcnwd from patieut popula5 uons n " /llirill/ot tilt' t1m~s and ap ply In tht' an·ra~t· patient wi thin thoS(' population s.. . WNj-...

..." II"... ticularly in the ahst'lIl'(' of mlditional Informa tion about til(' indi\i tlual. I 50 ge.1 !.... of .:Ill".... . " f .. A _ nIt· tl lt"T>I..60 CHAPTfR5 ommendr-d the rap eutk.... 1". fo r 75 If ) .J " ·imlco."'-rt.. However...s' of the· ••ffir.. lUl' II"...pe<llk Correlat. hOWt'\'(>f." lr.s).... . t1.('5 .111: ' ~' nit" " i .'l't·Ulk 100 li". in a popu lation of patu-ms ll("t'(lill ~ 11 dnl ~. B.... .i. ffit"lll . "'''I''''''' ' (..to lh" n' i..) .. ami amount of dnl~ ill the hody all Increase with dost" Still...." .aI.. . plasma couceutrattou has 1... lI... "''''1'''''''' (.:ridt)' . f.r~'1'Ii<­ ..up 1.. plasma conccnrranou is (·xpt'<.. ".JI i..rlll ~\Iidl' .r. So far."... wll)' lIot UM' doS(' as a tht· mp.".· .niOl)' «'" I".~ 50 E :E 25 o 0.wim!o"v."- A . . in most ( '<1-<. do"".1 1 10 100 1000 Plasma Drug Concentration (Log Scale) 10000 ...(''('11 assumed to 1M..o<'~ lillt".. stnce doses art' ad ministl'rt"l..:uli< cor: n -lan-P Ct·rtain!y.uu..' a better com-late of " dnl ~'s thera pentie rt'sponSl' and toxicity....... 25 I / t 10 tO O reoo Plasma Drug Concentration (LOll Scale) 10000 o 0. limn all)" utllt'r measure ..•..1 l.. ". par- n...m""· I.. I<_ (st-I<.ho...'nI th...( 1)I. f .1 lU~Kit:v. h. plasma concentration.!"" !i<" 'ir"IlJW b h""Il-d) ill wKIl· l ll"$(>il" shot1' ('OIl (-.. d"IWntb on the d"lI:ff"t' of "'''I'''''''' (... ."......1 B 100 ..IlI. ..1.1t'tl tn 1)(' a lx-ttcr . Q.8o ~ ~ ~ ~ 75 ~a: ~ ~ ~ :. rt'sP:lI\S('.·.. !l E . Thi s "'iml"w doe s St ' I'\ "t' it S a IlSt.-t\oo....-lap h.· 11 .i . ! i o ll · r(" p<H1w (' II " ·.l..¢. ' \i rt u••IJ: 110 .ot:>Ill. ' Il ! n. Th' t1..n ./ I Id l....

li.r'It'Il) II." . Phan nam! ogi<: Hes p . R. til!' ee dt"\... seiz ures art" usually effectively controlled at concent nations hdw('('n 10 an ti 20 m!ifl.1 1o·. rd ( .... 5--6.<-{. folio.a liolls wo uld han' h('('11 ("\'('11 ~n'ah'r . am i pRllonged drowst m-ss am llt"i hargy lIIay bt' seen at con centrano ns in exce ss of 40 IllWL For phe-nvt oln .a!>. Am... I.. explanatlous.I.. Another is thai plasma concentnation often co rrelate poorl)' wi th s 1ll{·.ty.. The fin l si?:JI o f toxici ty is usually Ilysta~m ll. as sho..If.. 196-1 . 6) sho>\\'s tin' relationship lx-two-n the steady-state plasma concentration and the rate of ad nnmstra tiou of plu-nytom..sillg the therapeutic anti toxic rt'S))(lIlS(·s.. plasma concentration is a be rter correlate than dose duri ng d m mk ad ministration b{'l'au S(' ph arm al'tlkilll'tit. plasma concentration ccrn-lan.t" This II1ml 1 true follo\\in~ a single dose of d r u stnce with dose )(' g.-n ill FiF. 11M.es.. T his subjec t is con sidered fu rther in C hap. ('xpn'ssed as the diUl)' dose pt' f ki l ~ram o f b y we ight.. ( M.11. KolMlj«"..~. p.. :-.rtl"" I" iii (... An"'. . I>h. Addi tional C e-l .. ADDITIONAl CONSIDERATIONS D('spilt.. II .. SOllie examples of l)()(lr correlations "ill.)..... ll.. Cop:o'rill:ht 196-1.riahilit)' within tht' patit'llt population is n' lati\l'ly small. It may also he true for conttuuous dmg administra tion hut for i t difTt'n '1I1 n-ason . .ric-lIll M . in till ' patiellt cohort stud ied .'S is til(' majo r source of va riubility ht.( tI.'('t'1I dose am i rt'Splllls('.. 18). 5-6....4. Tilt' major rcusou is the ..ollsidl' r. n .. tilt' plasma concent ration ran~('i l Imm JI('ar l)' () to .... pbarmacoknu-ric V'd. apr~. ami variahility in the concentranon-response cu rve is la~l" In such cases.. rit. III contrast. .t\urt'(l respollSl'.:. met ab olite s con tribute to act ivity and toxicity (S('t' b ow.. Thus.. " . 1l :6H----64..... alone 110 account is taken of tune.· It... <VTllr. meas urement of plasma concent ration is rt'latin·ly UIl ( 'O mJllO I\ in d inleal practice (St'( ..s .: 1 ). gait ataxia usually ap pt'an wi t h a cencentratum app roach i ll~ 30 mw'l....dt· margin of S<lfl't)-" o f many d m ~s \\ill1 dirt'l1 and Simple !lwam of a~o. C hap. when the dosiJl ~ r ate is 6 lllWddy/k!!: o f hot ly wd!!:t.Is... usu ally 1 by lIl ai n t:tin i ll~ all (·fT('(1in ' plasma concent ratio n. s1I(·1I as umpictlhn.• .1 tnu(ity. when. ) . plasma concentration is no be tter a correlate .kIlO\\TI. W .0 JIM ).. TI ll' objl"( i\"t' of most dmg tlw rap)' is to mai nt ain a stable t1lt'rdpt'u tic f{'spo nse ..... "nl'. the appeal. Had 110 correction b n made for body weight. ~ In p"'P'. 20. MenIal Changes • • •• • ••••• nil:. corn-late than dosa)?..."n...-iations in till' plasma concentration at all)' dosing mil'. cnse.I A-.tth rt's rxlllSC than dose am i int!t'{'(l may 1)(' "UfS(' if.lIt.:.t.""nl(>i n Illt .l. whkl. for exa mple.s n -asonablv well '\ilh effect ... of pI. Nystagmus • ••••• •• and Md )oy.. ifi<'(1 (nun Kurt .lhn n in pla'ma ( I mWI.tlio ns)..'ars above a concent r ation of approximately 20 mWl.... Fo r other d m gs. \\l nt.n~-{"jn 1f)("R'1I.. Coucentruttou vtonnortng. sidt' t'lTt'li s O("(1 1r with inl're asing frt'tlue nl')' and severity as tilt' pt L sma coucentrunon exce-eds 20 mWl. . f ... ."i".. "111Cn' an ' larg{' od inle rlndi' i d ual dl. • 20 40 60 Plateau Plasma Phenytoin Concentration (mgll) o ..50 mWl.. Figure 1--6 (Chap.

\i ll. 2 1. OI)WT t'.111lt l esamph-.llI<1' \". l · . whil'h o fh 'll tlifT r ill their pharmacokuu-nc a nd p l. whlch exp lains ti lt' appan'nl dist·rejlillll")'. " flt'lI Ix xlrly UIllII' rsl( xxl.«.!. g.SUIIJ of t he concentrations o f warfari n enantionu-rs. nil n lj..l\Say is t·llIpln~ l'tl .!. 1I111pla. then.. a n an lih iol it.!.\'t' ll as iI s ill~lc'lIral tlOSt· th a n wlwlI ad lllinisle fl't ! inl mn ·II()IIsly.lIll . n 'lx 'l ili\'(' ad minislmlio ll u f ma llY II ' pht 'l lt'thylil1l1iJ l t· . I'. Single-Dan 11teropy 0 111' do".. a n ' fo nm't! th e «leorptlon prnt't'ss. can di mi ni sh wnh contiuual u w.. iTll·fT ' ('l1i\'(· a~aillsl ll lllienX I~llll i slTl .!. poo r l"Om ·I'lt in ll:'l liMy ('xis!.I' na llt iollwr l"llll('('nt rat ion s to n -lan.SIIlS) 10 a cla-.1·ri n In n .. is pnorly luoavallable. A l! h oll ~h l ilt' slx't:i fk IIlt'(·!Iallism of al'lin n i..ln l'S \\i lh liuit' . whil'1.sistaM' tln l.:.·h'.ly clean-d hy the' lin-f.L \("() em its pl il\lIIil cnucentration.. Bt >(-.(lyl.{·. l"llleh ilillt· to In 'a l a ll a(" h' ~l)lI ly ll atf a('k... Even wlu-u a Sll'r't'oSllt't:ific . l·xpn·sst'tl l. Al"lluin't l n-s tstance rk-uon-s !11t' lIillli llisht'tl st' lIsith i l)' uf a pop ulation of ci -lls ( lIlil'n xlrga llislIls.lIIoll'{·IIII·.hloc :kt·f wln-u J.. ilmay Ix· compk-te-. within day. ToINlull ' m ll(.Ilt' . ~l l'l al x )l i lt' Kill(>l il's ..l. FaHIITt· to list' a stereospe -c f ic(:III'mil'. Il.1<. For example. the H· a nd Scfo rms .t!lIuOIt k ult aek. Th e fri<-)'l'lil' anli<!el'fl·M "'lIll i11l1il rip lylint· ofTer.trit'S.!. suhjt '(1 s run d t'\ 't'!o p a pr ofound toh-mncc but no t Inia l UIlTt'sIXJIIsi\'(' lll'SS 10 11ll' p llanna('lJlt~ C l'fTt'(1s (r-uphoria. · d ll rin ~ Chirality :\I x ml 41)q.eth l' Illt'talxllih' s an ' . .UlSl' of l' t1 iflil1lhy and cos t o f separation.> a s("(.(1 rm-asun-d.an..:. st't l!l io ll. In II W.III n ·spo llst· when IXltll t'n . ToJeraMe and A(quired R.lII(1· In lilt' <1'lIlml lll' n nus S\"sh'1lI {'fTt'(1s nf 1'llI allol takt·s w'('t·k.. 11IJ\\'t'\l. n ·spo nst· cannot Ix' n-lun-d sim ply In tln. 10 It'f'dnl1' d l' no h 'S a d illlillishl 'ti pl mn mK"l llo~~ l' n'S lxlIIsh'{ 'lll'SS III II d m ).l~IIf(' tilt' Individual i . T h us.IWlbtioli .m lim ·'lw u b r Tt·sIXJllsi\'(.Iwo pos sihll' mirmr ilTla~l's o r enantionu-rs.h-ad to probh-ms WIIl'II 11Itt'lllpting to co rn-late pl a.-am plt's IIf .2 Active Metabolites CH .!.o r mon. Ihl ' majo rity of S' l ll hdil' clural dm ~s a n' lIlarlw h 'tl as rucemlc IIlh !t ln's.l1lis t1 n1~ is h i~l.!.!.L~Y to kn nw !lIIW to ('(lIl1 hillt· the. Sill'l l .. TIll' t'fTl't:l i\'('lw ss of a TIllis.' r. I~lx· S)lIJIXll llo lllilllt' lil's . lIlotlll'rapt'llHl' il~t' n t . T ok-rance can d t'\ ·(·lo p slow l\". b u! till' n ·lalionship \"..li('\'1' al11t!· t'p isodcs o f a ll!O na . AI all~' mUlIll·nt . has IX1'/I d illlinalt'ti . it can vtill pnKIIll"l' ful l an til"lli. Fur exa mple-. Ollwr I·xalll pl(·s of t' fTl>(1i\'(' si n~I t' -( lost' IllI'ra p)' ind udt' l ilt' 11M' of iso p m h ' rt'lIo l 10 rl·lil. 11l1' n'''Y n' ll( k 'ri n~ till' a~(' II I . d lx's 1101 rt'lu m l'\'('11 wlll' lI all ihe ti m .'IOnal"lKlylla m ic properties .lIsst't l in C ha p . lolt· r.. TIll' t11'~n't· o f a("lillin't! n 'sisl.u!.. a mou nts of Il1d ilho lilt·s. (M.~Yl n ll Jt' l rk k h ira \) l"l.' o f ... " .ay t'wm iio lllt'rs can tln-n-fon.\ 't· a n lK'ull' a.'n h'n> in tjn .lIltiOTllt' TS coutrtlmte In . ~ .h B·\m rfa rin is II'ss p otent than S. a ('o r rd al ioll Illi!!:hl ht' found Ix·tw('t'll Ih(' inh' nsity o f n 'slx )llst· ami l ilt' pl'lsma l "l)lll't' n!m · tion (If lilt' dnl~. altl loll.PTU 5 VillI's>.).~lIla ('(111('('11 ' lralio ll wi l h n ·spo llst· full uwinj.u:. d l'\'( ·lup s \\ilh in lIIiUllk s follt r.warfa rin . TIlt' d('~n '{' o f 101('fllll<1' a lso vam-s 11II1 is Ilt'\l·f("lnnp!. or weeks o fits n-pe -ated use. till' (lS'(·mlll·fTl'{1 is s .1 a. F ur t'adl center.uf dm ~~ contain run ..h}d rn~11Ipn:' Il(Jlol.!It·\\. p hyl l\ is )..111 n 'slx'{1 10 the-ir p lmnllOico lngk n·slx lIIst· a n ' d ist.. a ll(l lIl0 T) !Iillt' lo Tt·lil'\'(· aClih ' pain .ll"l·nmlt·. l a~I' and .l' i"" p rtlll' n 'lIo l..l' pi ri ll l'~ lII l)ft l'lI n ·lil'\'l· a Iw. f o r exam ple.· a di m in ish t't l lllll'l-"l"lUl al""l Ol'{'ur 'll'uld y (t 'll'lJ. illdtltlill ~ an ad h '(' SI)('c:ic's..a. . i\it)' co rre lates 1 poorl y \\i lh till" plasma concentration of p aren t drug.ylllll't lthol ilt· is alsu ('llllsid t'rl" can IIst·fnl co m-la tions Ix' estahhshed . ad mi nisl ratio n o f l ilt' r..1l1 i\il)'.. in terms IIf tilt' pa rent d r u till' om) do St. il i\ not a lways 1 '. n -spira tOl)" (It'p n'ssio ll ) of 1II0rphilll·.. Its a lll id e p rl's!i. al p n-nolol Is mo re act ive as a P. O nly' «tu-n tilt' cont n button of its {! at1 i\'I' t1t·smt'tl.1t1in' Ilwt aholih's allt l III(> Implk-a tions \\.

Tumnw r COll('t' pts.l..' in s lJt'rip llt'ml n-sistance-.u. tln.of all uuhn-ct n.. wh en till' ta rgl'l II organ r('sidt·s in a slow ly l'{lllilihf:lt in~ tissue. the dt'la~' Illay h(· Illan y hou rs. 111is . Su ch mat t'rials an ' t'tllliinnollsly ht'ing n ·1lt\\l'(I.t1l'1ay is till' tinu.Ill.:t·1I0llS m.7). or ill b oth. Anolllt'r soun-e of t1t'la~' I~1II urise when Ihe n 'spelllst' monito red is all imlin.tiuu.~ . .5 THE RAPEUTIC ~ E SPONSE AND rooctv 63 km)\\ll: tlu. Uril' ad d .gl'nts . \\i lho lll (~al l.phys iolo~~k S)'SIt'1Il to wit hin nonnal ho un d s. Unl il al lilt' sitt' of act ion .dt ·lay ht'lwt't·u aUainmt'lll of" pLl.hlt· and po lt'utiillly Id ha l. ure.ma l'(IIlI't'lllnllion am llll'l\illlill im!."l'f lIlt'aSlln ' of d m ~ t' rTt'l'I.(. . 2..·SPOIlSt· is tln.. in mnliae outpul .s Oil tht' kind it's of t' "do~~1'1l0IlS (. It tuhrbns dtbydrofolatc reduct ase.("lllt'mpy. t'"hih il peculiar n -lanons lnps 1)('lwt't'n n'spoll w am! tIm t'. S.'ipeJIIS(· of thl' pmtllnllllbill l'tllllpll'x al'li\. Plasma uri c acid is anulht' r (·umplt·: ln-n-. balance.. a ft'\\ ' tb~'S . :my such correlation is s uultkclv.vr. These reactfuns can Ix' IuhjbIte for sho rt perio of lillie.1['(1I\('t'II" S then.j IM IIS <10M' .s i n~ lrn.. f or esampk-.di rect t·fTt"l'!: of Ihl'S<' :lnlit'( ).n-quired for t'ljlli lihnllioll 10 Ot"l111' hl'''wt'li <l n l~ in pla. Duration Versus Intensity of Exposure Sonu.fnr dm ~ ..(ll1t't' lltr:tticlll is mort.prothmmhin compk-x. TI ll' impad of dlallgl'S in inpul and lus.. ma roncentrution lIlay exis t. usually ill a IiSSIIl' . Wht'lll'lTtdin'.alt· can ht' t·..'i lIl:txinml rt·. \I ud .supprl'ssl's ventricular an-h)1hmi a.('ull linllomly dlall¢ ng I"t'spnnse makes allY cnrrelutinu b etwe e-n n'S!'M JIlSt' anti plusmn conccnrranon t·.• nu-t hot n-xate.(li. tilt' tll ma~t· is im.· t1t·Sir:lhlt·. lIlainh·n'lIIl't· o f a plot'iUla ('olll't' nt rat ion is '.III hou r o r more after adlllinish'rill ~ all Lv.of t' ilhN a dm n~..t1m~ returns . So mdill1('s.ly produced hy coumarin oral a lll .l.drt'llIcly d iffit11lt 10 establis h. Ihl'n'by prt'\"t'nli ll ~ lllauy 1I\I'tl lylai ioll react ions in the Ixxly. not alwa~'S a dt·sir:thll•IIll'rapt'uli t.' fl'ahm's of t·ffiedt'y amllo:-.ly 10 \\~lrfari n . hut I X~~ lIld tilt' peak. bolus of lilt' d mg. TIme Delays trutton o f .111 out-of. \\i th Iht· peM)1sin ' n'fl l"l'f in~ tilt' bal an t't' ht'''\l''('11 ' input ami loss.g lllani s is 10 inl lihil s~ll t l lt's is of tlu.tnstanl't·s of sin~lt'-(!l)<.ltt'ri"ls.dlan~t' ill tilt' 'St. 11 c orrelation hdwt't'n t·rTl' (·1 and peak phl. Tilt' mon. \\1lt'1i 111l' d ds l'SpOSllrt· is suffidl'T1lly prolonged. I II tln-se. Thi s tlday may ht· sho rt if III(' dm~ t'nh'rs III(' tisslle r:lpid ly.lnl s . t' . IlIJWt. A (h lll~t. wllt'rt·a.'m lll protlmnulun t'(lllIp lt·x al'fh.'f \·aril·s.'t'rs ihll· tlalllil~{.U11i<.{)\l'f('tl ill ~n'at t'r tll'I ail in Chap.rTI't. Tl lis lx-havi or fur lIlt'tllol n' x. fl"l'tlba l'k control s\'Sh 'lIls withiu the hod " mai ntain hom eostasis.lrt liae oulpnt IK'l'\lN \\i thin millllh 's.ma and that It o fte n takt·s sonu.I nu-asun-d re s!'N )I1St· to flllly rt'i lt'('f :1 ~ \'(' Il pla. Yl't another r-xamph.I~l l.·sslln· to a ehall~t· ill lX'ripl wr:t1 n 'si stan('t' or in e ...s wit hin a few minutes of ¢\i n~ . olljt"l'fi\'('. lidocanu. tilt' di rect t·fTt"l'f is all altN'dtion in uric :wid wnt hesis or elimination.s lIul S('t'll for J 10 2 t1a~'S aftN an o ml dOM' of Ihis an lil. in hllMM I pn'Ssun' is an im lin"l'f Illt·.CHAPTH .\ plaillt't! hy its act ivity as an anlimdaholitt·. TIlt' n'sl'NIllS(' ohst'r\"('tl n-lates rnon. Then-after. thiopt'nlaI iudu('t·s am'stl lt'sia ewu mon'ljukkly. a ll ll d llali n~ {'. Full rt'sponS(' in hlolKI pn. 1 MODALITY OF ADMINISTRATION AND THERAPWTIC OUTCOME As Illt'nlifJl lt'd at th l' I K ·h n n i ll~ of Illis dmpt l'f. Tilt" need for dm~ has now t' ntlt'(l.(lInpo unds and lilt' appruprialt· inlt' '1)rt'lillioll of sueh da ta . Ont· source o f tln. tilt' mudmum ca rdl.dosdy 10 lilt' duration nf dosi n~ than 10 tilt" actual dosl' uv-d or coucentratious produced. Tlu.m' (..uld tilt' pmlllrtJlllhin ('()mplt ·" art' t' :Gullpll"s uf t'lldtJ!.idly.n "l'1 .cln-motln-rap-utic a.d Tt"l'fs o f t li~ox i n are 110t seen for ...(li1h"lllant ( Fig.·t·rs. t1q X'lld s 1m Ihl' plm nJlal'(KI)1l.

. H..' lu Kk-l.1..i<.I....!~k 1 < i" "u ..t'x p la natinll lies in tln.r ' ''I" al...I()" of .. .. .1.<1 1.~...u~. .{ TI}(\ ILia p" ~nt$ . 11.gl' nts... " f ...•.·ft . \ \ l l(' n'll-~ dl "l'n'll-~ i ll~ III(' frl 'l I' IC'''I')' o f adllli rti. ffic.. 11.. s . I I. I Io..".. '111 p urpO!i(' u f . a ml lll'lIn' inc-reusin.n".. '. <I" . " f Lo '''10: . nl " .I r..111' a..-d.oi l~· . ()..I<' "r II..h .. ...r. Ki..j..• ""n"al I'.itl in l(· alld ..' i' I..(f1"l of t1ns in .) an.. ) ' o 2 4 6 B 10 DosingInterval (Hours) 12 .Ir · .di (ft' n 'nf 1· phann..·n >a.gt' lItami('in n-qutn-d 1 to produc.... ir K"" '. " f 1 .1 CroliR. l" r'''-1. 100 ' n 'P'·" i.l1i\il~· U" ri... 1 9"~ . ~I.i ..rin..."" " ..i.Ii · 't'1'I ......."111..Ltlir.. J. ~ .... K. 1 f lot'wral (I.. n "'I"""" in ""' 1' ... O " " I".· m iMt. ...".· liN 2 ( ~.." .vI. ·" I "all~·. It " ..• " ""pl.. "....<lI:" I.. ltJ(>!J I ' .1....lt lie .'''''Y in ..' r..t.'<i . ""4n"..<nll<'o.C' ~ f" l\u"'lIlt II. ..h Lt'W" r <I f tTft. T. e li"...rfan" I ~ .... a . Ill(' "..• 5( )Il of max imal ('!lit.. Figt lrl" ~ s!tows m aj or difTI' n 'll('t"s in Ill!' t. R . ...1 . tI. II ~1' 1 1 ...\ .....I.... i..-I 4 I" .I.tt <From 1" 10... ..tr. 10 \ '. · (m lo.. rah' . Ihij(l•.. all:"1 ' _I... i llo ~'n l ..~ if'lla ..:llly t1imi llisl. d1a IlI( .: mil.. rr.s ~ ~ E 2 3 4 5 E~ ~ E "0 100 75 50 25 0 0 c_ ~E ce 1l~ " ~ u ~ " ~ tI."_"ft·''' ''''1 .. 1 ". " ffi<.g J1 ta rnidn."lnw ill 1 'It"".. _J II~J.E.• "''''1'1.I.dir.~lmtioli .'.· "f "' lal.· _....01.. ion ...I('(Jt. i• ...·.. II"..·n·af!<" r tI. ~ 1l ~ ~ THEiAPE UOC R SPONSE AND T E OXIC ITY ~ CHAP1£R5 0 12 10 nfl:.hi al ~ 111 ..'l"~ a "" .nI<1" (1 .. · i' ".......i....I...... "' . .·ll(.·fla7..... r.> ..I)u:uu it' p mfi l{·s of ti lt'S!' IWu d m "..: . "rf"nll .r.1 .. "r lI. !'t·!:tl io.·.Ullill1 k m hial !Iwrap)' 1' is 1111' I'r...·il ~ ..m"wum im' in l1l'ul mpl·n it· mice...·rr n.·.01.."><i"l: into al. 1 1 .Iimn I"" ~ I( l u~ "'''~ ' I in S ".....-li"." . .... ·~ h" .ti"" il> "r ~~ . l 'Ir" "."'1011.llillll u f an infl'(1 iu ll with minim a l tm. 1000 i... r.c..".< " ....I... · [". " . H a'.: ~ ~ 0_ B A ' I).. 1.ozl< Ii"..-. il had mi n im al {·(f{"l1 t il l ..g fn'l IIlI' 1l1')" u n lIlt' ( ltit~· dOl"!' <If t .I IQI' rt.arf.'t"h· Io.• \\1l11... ... · "f 1. rs.nli". ·I" "i" alio.. W..· ral.I. in "..Lty....g tilt' d t-gn'(' of !lm 'hmlioll in ph~ ma couce-ut r atiou.c..1 I" ....l.Lot ''I''''')..< ".. lin 'l1 ".... ' t·.". \ \l.. ""..inr."" ou ~ ... "f II. I... " I.1. ·" . .. 10.r " 111:2 2' . rfarin ' lO r "... 1 1m ... S-7....'U li"~ II. 5 ri .n..II. '1. n "" I'Io·\ ii< il)' I" inl.· .... (" "' 1 \' F"r .~ '1"lM li ~ ~- 6 4 2 0 e .~. . · ...· ~ 0 " z 2 Days 3 4 5 p olnt ts well illustratr-d wit llllw alltimkmbial a.inl _Ira l io ...ho -r.·" all II.... (F n lU' .inl(tI.id f)'. arf....... " lio".1"" m.~. ......i"~ i"lt·r. ... Tln..) lI\ f l. .v... II..I" n · ''I1 ur..· """1'1. .01".d~·. ...m......Io-Wa. t1m\t it.... lio."'ir.· " ." ..5It'l tl f .1.i.. af" 'r "." 1 •. .."...II'uL.1011. II .ri" .· 1i"'1 .1..nn ' I..2'l I-29'2.· . .ilo ...· i"....... r""I..'"'''' 1 ''''' 1i'il~ ri ..I..ltll-I!ip .~'.. n . ...... ...-arf. .{"(I IItI' (·!lil·..f'll.. "r rf. n l{' infl .<tin li: 1".. I"'.·~ •• ""pl \~ " I I " .<1 ..mI ·" (I "..11..... riM " ill.j..·1•. " ral "..'rf. " f .__ I" m < I" II.t'. l(')" in pueumnnia tim! is d ill' In 1\ldl.hl<-n.Io ·ft·. . ..10 • ~lll l . r. ".rud .Illtihiot k .idilllt·..•.1 J.wlC lt'u (I<. t:I"·...II•...ili' al.onn i_ ...ui" .....

wh eI"('!Jy bacterial I-.i. Toh-runce.(lllllll(JIlly a.. (. C hapte r 6 t·xamint·s featu res of constant. to 1l\ 1)\"l' From a Ihri ' . Dt'fim ' till' It'TIIlS: a . b. ~t 'III. s In cont ras t 10 l'l·ft. tht. Tln-rap -ntic \\illth. of IIt'l't'Ssity . All add itional reason for frequent ad ministrat ion is thai 11ll' d uratio n of thr. c." o f udmtutstratlou o f lilt' sa l1lt' daily tinS(' alT t'l1s tilt' therap eutic out come. 4. 2.\l llid li alld ntl l('r alll i llu~IYl·o.(ll( ~(' He-spouse STUDY PROBlEMS lAnswers 1 Study Pro ble ms o re in Append ix II . ~ coucent ranou..1 U II ti lt' raIt' am i extent o f hal1t'rid tlal al1h i ty .is \('1) ' sho rt with rln. \\i lh dose an d couceru ranon. U s! the plasma concentration r.1in' and po te ntially mrm.1Il~(·s l.. TiUl}!. .lS t·fT t't. 1\\11 situations for whidl f rt'l IIll'Il(.t.\11riahlt.lingly. n lis ma~' explai n tilt' It'm lt'lIl' '.~ · lal1 alll antibioti c .idt'S pmd lll'l' a pmlml ~t'(l postan tihiolie d Tt'l. A ltholl ~h data in pal it'lIls with infection s..'l1 (de-sin-d lIT loxic ) is ofh-n 1M. ( ..·-tLtily 10 a olll'(·.( HAF H 5 T . with examples.). 'j e xamines tilt' prtncipk-s 1l 1l(1t' r1~i l1 ~ tilt. P!laml al. stud ies ind il" 5 dtl' that rlu.s of till' concentmnon.pos ta ntihio til' d Tl't1..'pt'lllll'nl on time aho\'(' the min imal hal"h 'ridlbl roncent rution than 0 11 the lII a~n i tude o f till' d n . possibility of tlu.plasma concentrattou falling too low. ACHIEVING TNERAPEUTIC GOALS Chapn-rs fi am i 'j pn'St'lI1 till' basic principles fo r l'stablishi n~ and t'\"dlna!inJ!. plll'll Uharhital. do tend to Ix'ar out tbe findings ill Fig. Ccftazidinn-.re ponse s rt'lalio nship an' addn-ssed in C hap.'i .l' of cour-eutra tious \\i lll h i ~llt'r \~lh ll'S ha\i n ~ a mon ' pnmlJlllll. dl's can 1 · re)( dlll'l'l) hy a onl'(·-daily n-w nll' n comp an -d to more fTl'llut'nt admi nistration. trtJ\\1h is supp n-ssed fo r s( 1Il lt' tune after Inte r mitte nt ('XIX1Surl' of b acten a to th e unn nuc r obml agl' nl. th an those ohta im'l l ill lilt' exp erinu-utal mouse modd.n 'atl'T Ix'nd it is tln-refon.) 0 I.rat e input . radt 'll n ·sl)(JIISt'.so than smalh-r mo re frequent O Ill· S. and theoph.adlit'n '(l with ilion' frequent ad minislra tion Ihat minimizes tht. :\l'l·o n. pln-nctoin. 'Bril'lly discuss. .'isociah 'll \\i lh tht'm lx'll tic n"SIXlllSl'S uf cyclosp oriru-.lal'till n unt ibiorics . dosa~(' n~­ mens for th ost' d m gs thot! shu\\' n"I. iii\(' other ~. T ll('y also exhibit marked couce ntranou-de-pe-ndent ki llill ~ O \"l'Ta \\idt. 3. 20.'ltN co rn-luted with p laon« con centrntin n than wit h dust" U s! uud brit·lIy t1iSl1ISS four sit uati ons in whic h poo r plasm a d m g couceutrauon .laily ad mlnts trat ton of ~t ·ll t alll ili ll .'l hily. lIint·. d .largt' lnfn-quent doSt'S of gen tauucm an ' .tzid illl('.rcsl)(lns(' n-latlonship s an ' likl'1y to occu r.W. Utilitv l'IIT\"(" e. alll i n~IYl'lls. d i ~oxin " ~t 'lI l a mici n " lithium . ill ~l lll t· IIUitrtt'r.-"'JIlahly valid com-Iatlous o f respo ns(. -Ji. an' mnn.lIl'ph m loxicily o f tlit. exhilnts onlv Illininml concenrmnon-deIx'm lt'nl bactericidal l!l. SO Il l(' mltlitional l'lllllplt·xi!it. Explain why t'1li. so Ihat bactcrtal ktlhug is more d...'(ll'fTt't. administration o f d rug ill disc rete du st' Sto attain andmaintain tlw mpt'llt il' l'lllll'('niralions. Mon-ovr-r. AII -or-nom ' n 'spollSt'. while C hap.

n-stricted p rima rily to IU I' pital M ·lt ill ~' .·s of II. elimination role COO$lOnl.I ~ pc ·l'la s lll illoJ.( is in fu"l"t l fOT al)(1II1 IS half· lin ·s. tim). .ts n. " '11t'1l ~i\l '1l to pm(lu('t· a s~.\l-'lIously vi a lsla d t'itl ll'Td rip o T:I pump.n d in). Th is is lIIost rt·li"h ly a( . It is. · h<iSI'1l as . dm).. 2. hlimole the values of halHile.... Define pIoleou and describe the factors conrrolling it. and fJoetoon excrered unchanged "om urine dolo obloined dlJl"ing and lolbwing COflslOnl-role input..:: illtr.II hi) mill ..lt im l lIT amou nt in tilt' lx)(ly_ In coutrast to tilt' short du ratioll IIf .fe of a drug and rime required 10 approach !he pIoleau follow-ing a COI'lslOnHOIe inpur wim or Without a bolus dose.! t~ IlI{l 'II! r.. :'1:0 ether mod(· (If administrutioll pro\'itlt·s slldl prt '('iw ami w ac!i l. 5.I <l ll t . t1 t·sin'tl.\ \\id"r applieal ioll of (~ JlIs l a llt . volume 01 dislribJ!ion. .( constant (ra h') infusiun when tilt' ink n! is to uuuntuiu a 0 sta hl. To lnailltail. Descube the relationship between hall~.. for th e pnrpOst' of under't a tli l i ll~ tilt" p rindplt " ill this dl. So nll" )( I l'\.lIl1pl.1..:: From hours to Yt'an. .(~ llll p lis llt'( 1 h~ in fllsill).lUlll tln. )lSnlTilllllw1.· may rapidly procllll't· .t1I'\ tr.-ices an' adlll iniskrt ."a ('ll1(~ 'lltralio.lM' devkx-s. 11tJ\\'(·n ·T.~ 1II 1t" possihle.. -111 pl.llIt. wln-n ~T('alt"T p rt'(>isi'l ll is dl·. infus io n..It· lIl il' elTt"C.l (111 llt rail'.\1 .rah..i n'~IIIll'rapt 'llt i l' «mcentrauon .( a coustant -rute in fusion ure sho wn in Fi~.d t.lIll'(' lISl"{1 to tn 'a ! myo(:anliul illt.I (~1l1slallt plasnM (~l l l n ' II I rat itIll. 3.i.:: must lIt' uchmuiste-red t'd .. · wlu-n lIIaillh'II<lIl l't" of ph'IlI•• o r tiss\lt· conceutranons a m! {·IT i.v.lht'T d nJ ~ for a 1 'ritM of ti nlt' t·.. '>0 IIU' dTH l.md 11'1 ' of t~ )u s l.rillt" rd('. fl I lilT ti sMIt' .llil'lll ft'aturt's o f rln ..~c ·n at'li"lto T (1-1'..:: < ('lin'I)' frum tl lt'~· sys te llls is assunu-d to hI' 1 t'tllli\-alt'nt 1 a l~m .. Eslimole the values 01 holf·Me. 6-1. .\· ( ~ lll t rolll ·d dm ~ atlllli llislralio u.t t1" . absorption is a pn-n-quisih.warcl a constant valur. a SUhS!. hut this mode· of administration is Il1lsuilahl.p lasm.iTt"li' lllS. bllmole the valveof [enol clearance from combinedplasmaand urine dolo 6.T<lh' t ht'mp~' has 1 1t'(.II ..\\i th the development .l iatd.ll t r. .\illl.to attain t'l1i'(·ti\l' ph.a (~ lI t l"t. which can b ingesh"{l or placed at a \lIri t·ty of e IllMly sitl'Sand wllid l dl ... 4.:: dm).\ S i ll~II' do... in ·t!.l\w« ·lllarly.l l il ll l riM 'Slc. 0 TI lt' ' . Such <!(.CONSTANT·RATE REGIMENS OBJECTIVES The reode will be able 10: I.sl' dl'\it1'S aud tlu-ir <Ipplit'iltiom an' g1\'(' 11 ill Tahlt. how('\'t'T.( '\( ' 11" lilll. Use phofl'l'lOCokineti<: poromelels10 pedct the pIoYTlO drug concentration and the amount of drug in rile body wim lime during and following coosontroe input wilh or without a bolus ccee. DRUG LEVEl-TIME RElATIONSHIP S .. Th t' half·lift· (If tilt' nmlj'M lllllti ill th is pa til'll! b .. · t' "ftN the .'>'2 mill.lplt·T.infuc km u f IA lrIWlllill is stllPlwtl .. and clearance ofa drug from plcnmo concentration dec obtained during end 1oI1ow-il'l9 ccoscoecie inpur. tim !!: is said 1 I.

1 ill Jo'ig:.('W ills <!t·p il11'l.of d"lIl~t" in tlu.st·ul iu1 featun-s of rln.t1 m g:.e plasma ccecewcrce 01 pher¥prop:trOOm'ne 16_ Tmn$do><mol for 00501 0 . T ilt' t·<.lW Applied 10 ho. o/he<s O' llt implanloblllt 001 30.ty f't>enyIproponolom'ne 25 rng rrreedoe .d"''oQ bullOck! a nd abdomen.na pectoris Syslem a"T~ 10pl'ovide a (OI'\$lQnl plasma concenfTCll>Oll 01 nillC9!ycerin R ecommended oppliCOl>Oll S11e b"0'''''''''''''' .t'Wllts followin~· a constaut lnfusn m (':111 1 ap p rt"t i:lh'il hy l'un sidl ' ri ll~ tln.'s ogoinS! ollOCk 01 ong.. TWice ~ty 01 O5IeOpOI"O$IS 7.n'!>Iefed do.' : The Pioleou Value :\ t an y t imt· dll ri n~ an in fu sion.. a QO mg/dov odm. M Pr~ a 'eoloOllObty conSlOnt plosma concenllQ1lQtl 01 nicotine Polch pIoced on front 01 bod above 'NOIS! 01 on uppe< outef pert 01 o'm p. tilt" run.. 01 body.f\es.·h\"t't '!1 tilt" rates of t l m~ tnfuston am ] elnulnanon.ophy4o. o 5 rng CNef 3 days U~ 's Ioleral cbes M.60. Appel'1e suppressont System o..CHAPI[ i! 6 67 infus ion o f a ho llis dost·. and 2 1 rng/doy (40 ltg/ em1/ hrl ehonged doi/v o I 100 6 mg/hf oYttr 1211.. t ilt' duration o f ouotant infus illt l is IISIIa llv IIlI KIIIOII~t'r than tilt' half-lift· of tlu.ill ~ k· A Cc euc nt role o f inhJsiOll Rote 01 el iminotioo tilt' equ.1 rng/ doy T lmen t 01 menopausal reo syrnplOm$ and pl'l!'\I'llI'lt>Oll AppIoedlO I nlrd:. Used lor i v.2..amount (If dru g in till' hot ly (tI..Vtltl is tht" t1i1Tt"n·m'i·IM. infll5ion Soma ~ a le pcrtIble.ms 10 prov.nltlg'Ol. inck.ng S)'S1em is designed 10 proede a eonS 'Ole 01 -eecse lor lont 2411.de a (OI'\$lQn t a nd effecb. dA "' or t·\prt·.eIeo~ and 3 4 rng/ht for 16 hr Coburn ehannelblocker l\Iond's... 6.. lor prevention 01 mellOn n deseed .s area behindeo' o. M. 14.uton ill terms uf the concent r atton of d m ~ ill plasma.. leos/4 hr beiee theonl~1( elfect "'.

.• a... C ......'t"5.....<"""I'hulll ti ..2"jj. .A.. _ Q lnt) l l" ri"~ tI.." .. Ior...I ('Orn "l"".a h"tf· 1.k..c.......··t)l I'I"... "'. _.1 W.. infnsiun.1 1' ...... i " (... 1 n .. Th· "I'I.. . 3.. t'.. " n il "/ rnin CONSIANT -iATE i EGlrW: NS CHAPTH 6 1500 / 1.. .K"...ou . l" oIns ' k..itll ' ..... . II.. 1320 ' (1 _ .....dM'1. y 1'"_·1 hmiti nl': .1"n ~' I".· lt.>lu> injo"C:- o 40 80 Minutes 120 160 lin" .... "r11. 6-1. lUll" ' t • lil.... l1 . t1.!tUlle: 1'1' '''' tI.df·lif..... ""....b.n''' (''-' ' TIlt."ml of l..' "". th..· o f II. \ lIn A KI" rl...1 YO'..• .~): Ka'f'l·r...I"I" . tl. I".... . I ·..'. rJ. l"hann..." n..'111I n·.... 5O:2fi7.. id. I'.. ... _t.I"I:o· a1 lai"' .' wilh .'.It'.I 500 11.o<·I... lift.i''' 'ltl'1l * :1. In' l: D'1"'-1. 1 mill ... 1i"" I...-i¢ ..1il a .3 4 Half-lives 6 .... i' .1.· . uf 5..... " ~ ~ 25 / From bolus dose 0 0 2 6-2...2-min half·llf.b "'itt..tn>l k. IIo" I'I.. I .h n n-c i.J. ..n nll ' l'o ~ i '1l'lk.0 . S..• til..t in p..n ino At th... t· r A ('t" K't'nl · linn tin. ) 100 90 t -.• 10'1' KW.df·li.1 will."'rnplo·I1 "l ary ri.• o en.." ....... patit >!lI .. r"l"'lI)' 1.' I'LtIt·.. 8~' 3." . a. n l l' 1 >Ln". (UU Mt·j!.. R.2 mill . ' f"ndi" " C .1iu Ih... ."..U .""ta"l ..o....o.. rn~' Il"olnlial infa.: n. From infusion 75 ~ ~ <. ~ C ~ 50 a.• af" ·T """inlai".. II...-1 ruWlIlin ) ~' ('t'fl>tallt'TlIll ' in f... In .."..o . (At4Jt 1 ("»11 K..". ' inf" Iit>!.. l!:l!:l l. in .· "' ''~' . a1 ".' 1/:.....3 It.~. nN li"...·.Ju.."tI C • 132l1 ' .. ....1t! a n ""lanl i" f".Il1s . I " >t~· falJ.....101' (I· PAl rapi...'". in{" ...· ft·mainillll: in II. . ' " utl u( II....« or I. of dcubl..rJ....· 4 . elin. til." "...• i" f"'. ..•(ll imm.~ .. .. .C.. In p1ah. Williw.1 In 11 I u. i.tl..1..t!.. 1000 lI... A.u II n..of tl.illlal. -charn ' · I' A (d ". t'IJt.' " . in ".· . "'''' rur /:Ill .

r ate. tllat con trol the plateau. 111l1s.CL · C On s l a rt i n~ a constant in fusion. T1!!: tilt' plateau {'oll('t'n tm !ion ( 1.!. :'\nw l1ll\sitlt'r the next statement: \ \ l lt' n infused at 111l' Slllllt' rate. amou nt in rln. rate of t'li llIitllllioli equals ran.1M tl lt" sann.g \\i tb tilt' "<lIlIt· dl"ar.t!!-:l' nf tht· plah'all \"ahlt' at 0111' parlkular infusioll mit' alluws prt'tlidioll of tilt' infusioll r. Ihl' amount ItI . in Ihe 1M M :\ t plalt'au.!.\·t'r. Silll't' till" rate of d lilll~t' of amount in the IM at plate-au is Kly zero. I!O . This st. tile .t.14 hr . Ill(' rate.of infusiull.entrution .b odv is zero.tl al tln.. tilt' n'lluirt"tl in fusion r. for illllslmti\'t' purpost's.for all (Im.ul('e is tUllslilllt.. that a slt'atly-sla ll" phl-~ Tl1 a Iheuphyllille l'tJ!lt't'nl ralioll of (. 3 ).IIt'll1t' nt is tnu-.t h ti ll' t1mj!. SUppU<.11t' is 60 lllW'lr. that is.gin till" IM )' at stt'ady stall' is 4V) III~. Similarly.5 mg/l . Ollt' t'xpt"t. 3. Concentration at steady stote • RoICL Infusion role 4 Clearance Cll 'arly. Onl y wnh drugs for which l'!Pilnllll't· and \lllulIlt' of di slrihulio1l art ' ti lt' "'llllt' nn .!.1s Ihat a rode (If 40 mgt11r is Iwt"tlt'tl lo .lk·lIlah 'll hy lIl11[ lipl~.is no el imilllitillll.sann.t· ill plateau n llll't-'nimiion . As ti lt' t'limillation ratl' consta of Iht'C lpllyllilll" is 0 . wh k·h continues as I() n ~ us till' same infusi o1l m h o is muintuiue-d.of elimination dhi dl"tl II)' til(' amount of tim. on ly infusion ra ft' and dl'aroUll"t cou tml the stt'ad y' stall' ph~ l1la t"tll\('('ntmtiOll.tl 1IUIl Il I of t1mg in the b(ltl)' at plateau is the sauu. amount in lilt' s \H htltly \.l. sarne platenu com. it follows tllat El ls. Altt'nmti\"d y.bot h plasma concent runon mid amou nt ill tilt' IM OIl ltly plateau th e same when illfnst.ari('s wit h volume of distrihutiou. mit' of di minatioll is l'l lual to rate. He nce amount in the lMMly at ly. TIlt' di minatin n rate constant is tilt' [ructional mtt' u f <lm . I>m!?:s wtth the Sillllt· half-lift· han ' lilt' sunu. a dlilll~t' ill in fusioll ralt· p n Mlllt't·s a pOlporl ional dliut. 2 dC V · 71 = Ro . Bdllming 10 lilt' tht"tlphyllillt' t·xamplt· .' tilt' fadon. !\Iluw lt. TIlt' rise con nnues unt il ti ll' rate. Sim'{' tilt· dt'arolll{'t' uf this d m ~ is" lAir (C hap .g amount o f tlm.l'milin' to di (ft·rt'Il{'t's in tisslll' distribution.o f d imlnat ion lllatdws tilt' rate of infllsion. 111t' liver and kid neys ran d ear n l\I~' what is p ro senn-d 10 tllt'lII: tlu-v art' in<. Alt holl~h tht' amoll nt in tilt' ' IM I)' is 11ll' sal1lt·. To l·lIIp lal~~i:t. At plateau .uu .gs \\i lll tilt' Slilm' half-lift" Thl: stllh'mt'nt is also true.g r-limmution.. TIlt· rate o f ehmimuion t1q"M' lltl~ onl.fort" amount ill tilt' hotly rises .n. Th e pl :~~ lIl a l'u nt'{'lllmlioll must then-fen.'s M \"lllllllll' (If di st rihlltiOli. til(' {'t IITt'SPOlltli ll~ platt·a u l11Ilt'l'u tm tio!l \'Uril'S ill\'t. Amount in th e hlxly am l plasma ccnceutratfon lin' tl u-u said 10 ha\'(' n-achcd a '\'II'm l 'J sta te or "lalt'(I/1.elimi nation rate c uwt.und hil\. is dcst n-d in till' pa lit'nt whoS(' i.1.for all ' dm. AfTIOIJnt at = Roll Infusion rate Elimination role constanl 3 steady stale c.con stant. nndlu-ncc then. thi-n.!.u ue r an. .ng Ihe sallie dl'amlll't' n-ach Iht.I!t' 1It't"tII't1 10 adlil'\"(' ollw r plll!I'iUl \'il!tWS.' Ull dt'aml1t'{' and plas mu concentration.CHAPT£ ~ 6 CONST ANI-RAT ~£GWolNS £ . pm \idt·d that d l'a r. plalt'ilU must 1M ti lt' SiIllU' for all dm ~s witlJ tilt' Si. till" {'(IITt·nt SIXllltlill.I'.1.v.of infusion..lIIW Imlf-Iifl'.ly \\. ti lt. hoius da la ansho w n ill Fi~.U1('t' if atl millisl{' rt'tl at Ihe s ame ra te. conskler til(' follU\\ illg statement: All d m~s infllst'tl at tilt" .5 mWL ) by tilt' \" UIUllW of cun lit' (" d ist rihulion of tllt'llpllyllilit' ( ~) L). I am i 2 s i lTl pli ~\' to : A. lilt. only fadon ~o\'(' m i n !-! amount at plat eau an' tht ' rate of in fllSion and lilt' eliuuuatiou mit .

fNS CHAPTHO p mdlll't· a plateaueoncent rutkru of 10 lllWl. II. The sol(! Iacto r l"l llli mll i ll~ the approach to plateau is lht' hal f·l if(' of tilt' t l m~..tate.lII n 'sidl'II("t. To appn-ciate this point. as lon~ as tln.is eXill11 lIlaldll'tl by y .. Amount remoini. the. CI. • e _. l111'n' must tlu-n-fcre lx. consider a sit uatio n in whid l a IM llus dosl' is ~\"(' n a t till' sta rt of a con stant lufunon to illlJll('lliatt'ly a ttain th e amount adli('\ '('l l al plateau: clearly. For ex a m ple.\1 HT) .. it is l'\ idt'lit th a t ~ 5 MRT .Infu sjon.~idl'lln· t jllu' ( .t\\'t'(' 11 the sta rt of an infuskru an d till' t'stablisllllll'llt u f p lateau. TIl(' events are d l'pid t't l ill Fif{. till' amount uf d m~ ill til(' hod)' at slt·ady .IIiUIISllip : MRT = F rom Eq..time all a\"l' rd~t' 11101 ' 11](' n-stdes ill tilt' Ix)(I)'.o f r-liuunathm "" roth ' f)f infusio n ) depends (Ill rlu. time (.si11' o f lIlt' hu lus d ust" m ust 1 Au . <l lwa~'S 9 Ho wever.\JUT is 7. ..69. rlu-u only U1w-fl'nlh of tILL' molecules in the hody a n' n -movcd IX'" hour. L'hr iu t he' patient ('_<l mpld ...0 IlL TI ll' II1t'. rune to Ream Plateau A dday alwlI)'S e xists 1)(. of 5. 6.1.20 x )(~ ' mul'~'II.. infusion nil .. Thereafter. ""!. a x value.. tlu.../\'.( lrrt'spollt l i ll ~ (E(I. in tne '" l. ImaWlll' thut a w ay exists 10 moni tor separately dnl~ f(' llIai n in~ in lilt' htM)" fm m tilt· bolus a nd th at al'l'1l l1l ll lat i ll ~ dill' to tln.in fus ion is maintained.\fRY is related to .s fmm l-~ I _ 6 tllat MRT .AA x ' 1/2 7 Furthen non-. a.. 1'1 1 12 I 1 6 MRT ~ I .lt l} I.... Tune Conceptually.i atl· its rt'1aliollSh ip In (1111t'r pllanJlal"okim ·t i{~ rxlnUllt'lt· rs . of ndmim strut ion is l'Iim illa!l't 1 ll~ tl l(Jll~h till' other were not p n-sent .(.a mou nt ill till' hody is maintained at IIIl' plate-au \1llm' )(' II)' constant infusion . and th. VI et 8 For t11l"'C )ph yllilll' (\' "" Z9 1. sinre an infusiull rah' (If fin m~~/" r results ill plateau couceutration of 15 1II !ifl ~ Mean ReslderK.7. pe r hour ami ti ll" reside i ll the hlxl)' for 10 In ..I A body from bolus dose • . TI.lated with eac h II11 Mlt. k "" CI. it CONSTANT RATf REGW. I> m~ in tlu.I>. o r.2'5 hr. a useful pardn wl N to (]t·scril lt. "" .. tho sojourn of t1 m~ in ti ll' (M ' is m n ltl> ra n·. consider tilt" Iufusam situation. a IlMHIII! in tilt' h. 3. as k "" 0. l hl' . T o appn'<.·s i ll tilt' "ud~" TIllis.hody ll"~l(.}' l i lt. 7) to a hal f-lift. if 2 X 1U1I1 lllo ]et:u l("S are d i mill ah 't! ('(. it follny.of infusion. Fur it ~\"t'1l constant run.[ rat e.. thi s rk-cluu.(lIl("t'p t is Iu rtlu-r di S('us ~'(1 ill App cndu I.t' amount ll"S(M :iatt't l with til(' hulllS doS(' declmes l"xpollt'nlially ami al any time.

odall"d with iI u constan t infusion (" ""nil is ill\\l l}'S tln.3 I. . in tilt' esamphpatit' nt is 5 hr.3 ha lf-lin 's (90% of tilt' platea u ). is shuwn in Tabh..!''''(-. . if O lll' want ed In lu:hit"\'t. tilt" vuhn. .'1I1 of till' 1(' plait-.1 for a ll infinite III11nlM... tilt' SCKll\(' r is tlu.5 mWl.of d islrihlllioll._he4 .platcuu n-achcd. Le..lIlst'' the half-lift' o f t ht'1lphyllillt.'11.' a p latea u concentration o f 7. hy d i\i tl i ll~ t hmll~" hy till' vnhmu. tI_. an infus ion m h ooffi() mwl lr. This mus t ' " " SCI siucc till' slim a l\\ll}'S t'(l"ills lilt' ' \9 .Jl ... one cannot d "llfly deduce whether a b olus or a n iufunon till' <It'1 h.71 amount at plateau. namely. Fo r pracncal PlI'l)( ISlS. tilt" amount fa lls hy one-half l"d(:h hal f-lift' . lin ·s is 17 min )..·Jl infllSl"l. . tilt' t h''11phyllilJ(' pllL slIla coucentrutfon at om..6-2.5 IIlWL ill 2..I'A (haIf-lift· o f . In 1111' fo nllN case....1 _ A .C...l11 value.·ss. the sho rter tilt' !lalf-life.3 hlllf-Ii\'t'S is 1-1 da ys ).'fo rt.l in 3. tilt' plateau is n-ached (3 . P.I_ .. In 2 half-Ih '{ 's.in 11 htM.' 11 Wn·lI. ~ 1 1.. I lltlt't. t"X pn..L S1"''t...UllOIIIlI rt' lIlai l1i ll~ Frmn the holus dust".') '1 of tho plateau value.. Ap prm:imatd )' 17 !1r (3.. TIll' .. tht· plan-au lIlay he con' sitle ft'1l lu I M. Fo r example. vahn-s of a drug. n f tilt. . howt'\'{ ' r.111I0 11111 of t1m. dOl~. or t he infus ion run..ly is .! (30 mW'llr) to maintai n a plateau concent ralion of 7. V-'_. Postiafusion Afh ' r S I(Jppi ll~ an infusion . 5% o f tlnll" 0 plah'.U..A .. I...·r of hal f-lin 'S. Fur t''(a mplt'.alf. A ...wI.llI vahu. In I half-lift·.'5 lllWI•.. So. 0-2. "'" I PfKIMQf 05 2 3 33 5 6 .the Infusio n. wlwrt'il. til(" ~ai l1 n '~lI lti n~ fm Hl lilt" infus ion. hulll lilt' umouut in tilt' hotly illld IIII' plasma couce nt ranon (e ho/) rise a. .t't1as a ))(·rt".is hak t"l.) lI lId tilt' .Il. il must I"" Infuv-d fo r 17 hr b efore plateau is n-acbedTlus is so whetln-r flO mwllr is infust'1l to ma intai n a plateau conceutratiou of 15 mWJ. Of plas ma couceutrutjou . C"" 11 Thus. 1111lS..g in t 1 l)lMIy.'" Q' Q7 Q' QQ f..")·lIlpt oli{~dl1y to ward rt'spt"t1in ' p latea u values follc)\\ill)tconstant.~ Hf'i!J o n l' tilt' Imlf-Iift. wn'n unly :linillp.. a plate au is only n-acln-dwh en tIll' d nl ~ has 1M. 0I 1t' woul d infuSl' a t a rate o f 611mwl lr fnr I half-life a nd then maintain this couceutration hy I mhl l1 ~ tilt' lnfusum mho In 30 mWllr.. il tukes 2 to 3 \\'{'(· ks of cousta ut phenobars lutal admlrustration (ha lf-lift. 111 important point to rememlx-r is that tilt' approach 10 pla teau depends .S mill) n-aches II p b te au within minute-s (3 .j . III Ihe '''tampl" of tllt'o pl l)'lIillt" H S 1Il ~ are in tilt' luJy at pla tea u follouln p. 7 '" " 50 75 90 . c.rc••• ef the ""... -'.5 hr. it is . Tln-oretically. of 100 Iir) 1M.at difh-n-ut limps after initiation of an infusion."l.half-Iifl' is one-half th e co rresponding pl ate au "ai m' of 1. .rate d m~ infusio ll \\ilho ut a holm.. . I." 10 O r.~ rt·adlt"l.~~. :lo ' It the refo re follm\'S that the amount in tile boJy a.3 1IaIf-lin ·s) after slo pp inp.. dUM '..d ifTt'rt'lll "l' hd'w{'('11 tht· a mou nt a t pla teau (A .

·!tli'It·) .1it II.."l lil" ·). . ". 0" 1'I.1t·""·" 1..yl1 il.~ O f 43 Ill~...s rnWl. ri.. l 1tis 11(. 5 E 0: ~ 0 0 4 8 12 16 Halt-lives 20 24 28 ..oIf·li' " . lUll'!t'l(t 1m I" .. lufuskm m ho tn fin mW'!tT.. it.n ... / ' In "l'p nl\i """" '1) 3 .3 h. fi.1 U II . which al'lunl ing In Fig.dlilll!-:( ' is to d T . f' oS m:o:t1 . fi-3 should prod ul'(' a plateau conccnrr anon uf 7. I"f" .1 i " " pp m\imall'I) 3.. t""..I11'TIl l' JOW I·f.1....u m.. dn l!-: {'o llti lilles to hi' n ·lt'il. 111t' SOUl II ' amu unt of w ould he found in tlu..1' W nlit tI.~ I1 Il"' ." III".r It. of ... ..." li"" nW" hulIilllit :Jl1 mw1... d . t he plasm a dnl~ {'olll't' nimthm falls mo re slowly than afte r sluppinv.r uf t11t~ 'I'I .· 11""'I'I.It~·" I""lit .. l... "'I)· 3 .!JeSt' in sl' IlWt's.•". If ti ll' object of lin. k t·s..._ pL'I"" " ..5 m wl~ Suppose rlu. • ''' 'I)' . Conside r.· ti"....l. I" IS "':o:t1.. nf 1 tI"~ 'rh~~lir .oft... silt-s in sk ill fo r a p p reciabl e pe nolls o f tune.t... i' Io~..· 30 llI~r inf.. Ih.-3.1 i"f". Infus ion.\\ ' plat eau value is achieved by doublin~ tht. I n .. 11.00.. for Illustrative purpO 's..:lf·Ii. t~ . Chonging Infvsion Rates The rate of infu sion of a d ntv: is somet imes d .hndy Ii hr aftt-r an i..3 h. tI...lr..1"...ol tI.1..S "'Wi..w. r"t. "".it .t2S III!{ of tht·ophyllilll" Aftt' r rt:'1!l("inf. I..72 CONSTANT -RAT'E iE ~ NS CHAPTH o only llIw-tenth of the plateau vuhn-.. bolus dost. " .I I... Sil""U..t'i..i<H' uf 3fl mw1. .f.... " f fiO m~ r i..r (tlo... 11." .00:10 " ... nf 3flllllitl> r (m l"'l .It· .. i . .. t"' K~'n lr"I i<". whel llt'f hiV.. I.· 10.of !.-.. uf" dm lit· A pl"I""" t"'I(~·" l rati..]..( h t1woph yllilll'.. ..g...1H 11. d n ...\ .ultlth" r t" ".>(.Lt.f.(! (m ill h indillV..u..it. ". I lll a~ l\t· thai inslt'ad rj c ~ ::l c 0 15 " 0 ~ ~ ~ ~ u 10 >' E ~ ~~ ~ ~ 0 . " Iit " n inf" >it.II " (. in "1'I'" ..3 tl"'f· lln~ . tI..v.....lal.-s ~ pI".t'tl du rin!-: 11lt'r. a ed uew plat ea u.. Ilt ".yo/e/y un till' half·lift· of the dm.l 3H' IlIW r infusiull run ... ltlt..· "P'l'n>•• .lpy ht '('llll'W of e Xl'( 'S Sh l' lo'(kit)' (IT au illal!t'(luatt' therapeutic n 'spOIlSl'. dt'lwm l~ ..hh.. " ".anV... " f 'i.. n-mutus in ti lt' hody.. ' IK. an i.....' r ' I"rti"jt . then Ihe tinlt' to ~l Irom ollt ' plnt euu to anoth e r... 11"' 1 '''''irH I' ..t .. f">llI' .silu at io n now demands a plateau t"llllt"l' n trati u ll of 15 mw'l•.v...· I'Lo. SO IllI' transdermul constant-rate rd t'iL'>(' dt..•. a path-n t slahili:f...llKl ' I"rtinlit .r I>i~lt' r " r lr"".

Figure 6-2 SU~l'Sl."tri'It'lx. Phannao:-nI.' ral inn 1.'C de termines the stl'ady .0.. th at the theophylline coucent runon as. 11191...5O:26j 27i. 111t' t'wnts illustmlt'(l ill ri ~. i••10 1 III 0." hjl 't"l. •IIlYreadjustment Iu the Iufuston rate ill les s than 3. Also.Io. B.am ounts of dmg ill the txxly 600 •• • • •• • ::..exi..'30 mw'hr ..st i ll~ value in I half·l ifl-'.. p!uom"•.A_ Illltl \\'('. tilt' atlditional . in flloi"ns .' the rape utic [eve].. 111 is. of <It".J ~1I1'jt... 6-3 shoe.· r""'~'n.. WW a b al olus doS(' equal to the amount d('sil'("(l in til(' hod y al plateau . and infusion mit' are (. the tot al concen tration \\. fn " n II finl ". Cousuh-r.3 ill half-lives for most o f the tlwuphyllillt· to lit' removed from the body 0 1l1'C the oriWllal 30 .w .u ... stah ' coucentrancn. for example. is tilt' ... and the Infusio n rate is adj usted to maint ain thl.as adnnrustered at a d iffl' n 'nt site and that a \my existt'11 of S('~lI'<l tdy moni toring tht"()ph~1I i nt' in the body From till' two infusio ns..is Iikl..2 J.. C leardll(. Collt'n f ..1""'1 . ( 1.. and Imi ni..ltiClllof ....'50 IUl m l. 6-4.· d nL~ 6. II. An ('\'('11 1 (J11 ~(. l1 u' theo phylline concentratmu associated with this supp lementa ry infusion will £111 tn half rln.' of the dlaTl~e in plasma cnuce nt ration 011 dJaIlW II~ from on(' infusion mit' 10 anot he r is a~aill dt'lllonstrah '(l hy dat a on t-PA in Fi ~.-'.. lim.ltt'(l \\i lh the uew illfusion \\i ll r ise to 7.3 mwmin .lo .. fan:1io.( lim e is req uired for dm~ wi th hal f· livt's greater than thai of theophylline.~ad ly matc hed . rl! ....\\...'(_1 . mw'h r infusion is slopp('(1. of 10 "' II: a'KI a t'OIulanl-r• infll.f 1" >1" 0 injt-c...is . 111l' half· life is thl' determinan t of tilt' spt'('(1 of att.3 Imlf.I . it.' half·lif.. (I · PA) . ..s a solution...5 to 15 mIQ'L.. it w take another 3. Usually the bolus dose is a therapeutic do ".r.. 2- ~ 400 c E ....-wri~'hl o o 90 Minutes lio n.'(isting 7. sol'i.tt·r.L" in the fi rst infusion: half the plateau conccutra ncn (3. 11. Bolus and Infusion It takes app roximatdy 17 h r of coustaut infllSion of theophylline b efon..: ..It-r \\.. In 3..s mWL in l'ud ly tile sallie time .J.• \-an lnft.d fmm K "..i nl/: Iln 1.O.. \ \ 11cn till' bolus du "t. Xr-edh-ss to 'illY. A lI (· ~lI l1pll.. P. ~ I'W rnLl fotlt.'tiNS 73 of i ll(. Sui.. < .6 min in t1..6 mWmin .·.n-qutn-d to go fmm 7.. of lho. n. ( J.1I1'W stl'ady state.. at the start o f an infusion .5 1Ilw'L concentration..75 mIQ'L) iu OUl' eli mination hal f·life (5 hI' ) ami so O il .) .O. K C..till' p late-au concvntranou is reached..ll l. th r plum a ("<)nN' nln li " n dn'l" • • Ih. 111t' d t"(:!ill(' Imm a high plateau In a low om. 6 ..• •Ialr 10 Ihr . 11 have almost n-tumedto tilt' p n '-(-'. ( Lpt.. F..J.) .. Situations sometimes dem and that the plateau he reachedmore mpi<U" ... Ka.dn.CONST ANli ATI ~(..ill potllrnh wil h 1Il)-..~"J(' dcn-munant of tln.1 ""I'" pn-11t"S p!at.h\to. n lial In .e u .ri}·.c. rllUrn i"'~"n n.. It \\'. Clin. tilt' (-'\'t-'nts after stopping III(' suppleme ntary 3O-mW'lJr infusion mh odis(:usSl"(1 previously.duUn I · PA (dUb. ' '''l ur nt l)'..( S'iO IU/m l. ~ inf" .. Adduton o f this rising conccntrunon to the prl'-t":dsting plateau couceutrattou shows that till' half-lift.liws.r.): t:IT 1s ..tinu.l"" r.'<..3 half-lives IIw a llS that a 1It"\\' plate-au coucent rat jou wtlluot lit· t·stahlisht"(l."in~ til(' in fusion rate. I . S(' n-lan-d to the half-lifl' .\'.)... 1" >1.... 6-2. tlu..IWm l... as in Fig.ti Tlill ~ tln.ltl. " " . ". c ~ '-' " c 0 200 • • • 180 270 ..<1 .:tin. fur 611 min Itl lUI irKIi\id ll. ion of 1. '11(.'n·a..a ('O'l('(' nlr..

It Sillmid ht· lIotit't"llthat till' tinit' to n-ach tht· plateau d t·Jlt·ntls sol ely o n t he half-lift· o f the d rug.k "'ppn. t'tlllllltlS('(1 of zoo 111 ~ n ·lI1.(' H.1.."1 of K c1". S . SllH" 11in Fi g:.5 0 ~ '" 0 0 '" .. nllt al II ..· pLot.3 half·li tu n ·.. Il1ili. e .infu sion...\(:h('(1.. 400 300 200 oS ~ ~ .I.. . "'1 uf tI.". I". D) u._\ \1Io:'n .. a. .. 400 300 200 oS ~ ~ Case A Infusion Alone 0.(lIIlilllltO Mly S until the sallie p latt'au ll' ill Case B is 1'('... Silll". . il1lli41 lo"tll' l " l ' \\110:-11.~ I"..'" (_ _ 1 I. .. B.. A. ..sla rt of a co nstant-rate in fus io n . I)). -c 6 .~~ lo leh ... ».. 1 " "' II. tI....iniult in tlK .It. rt'. . By 2 half-lives.· allK. Halt-lives 0... 1 II. Sow t'unsid N IWO sit untbms. e. 11l ~ 1I' . mid ay I ~ . pl"'I"a ll « (:as<" ..acl. M tI.. III C lSt' D.. oS ~ 300 '" .lo.1 plat.• . ..'5% (If tilt' \'~IY toward lilt' plateau. tilt· bolus tlOM' o f 2lX) m ~ tmnu-dtatcly all ains.• ". Iilllt· of ti lt' )(ly ly IMlllls dose remains a nd til(' plateau is reached .-\..(° A....·"'..CONSTANT-AATf R EGWlNS CHAPTER 6 a...5n lIlg ill lilt' IM lie s 7.\..'" <or . in ea. 2 3 4 5 2 3 4 5 6 Halt-lives ' ~ "'l'. '1111ls..m'h·I)' 3...S 0 0 ~ 0 Case B 200-mg Bolus Plus Infusion ".1<~ K"~·lll r. inf".rt or II.11I1 pL.klt" 11 ' ". ' Kit . l lt_ 6-5..lt'h i n~ a plan-au of 2CX) m~ in appmxim:lh ']y -I hal f·liv('s.--. TIlt' first .. 0 '" ..d " illl i" fn.... iur" ...<> prnt "od I ~' c · . . ti lt' 2.' " 0 0 2 "0 0 0 c 100 E -e 0 .... tlmg is i ll fu~"li alom' a nd till' amount ri ~'s . B ( '('U llSl' ti lt' mit' o f lnfnslou !l OW t'xt't'('(ls the rlllt· of dOlI-: e-limination.. "'Mil> tlMI at I h41f·lif. ti lt' amount in tlu... Jun 1Il ~. ..... ' t"Xf""wntial1~' (----) hill· tlK' lInKlI lIIl KilIl. lx-causc till' rate of IllIs loss is initially Wt-°alt'r th an the' r ate of infus io n.. In C:lo.'. . amount in t1 uolM falls.io:ll' in all . C...(:u mpltollw nta ry : til(" ~ai ll of (JIl(" olTst"ts t he loss of t he ntl lt"r..~.. ".. By app nn:ima ho ·1 hal f-Iiw s. 0 "0 c 100 E 0 .• r b " "UI il l h. .·'Kb "pun tI. T his fall {. lu l)-II.I".. 0 '. E 0 0 "0 C 100 . tilt' IM doS(' of .~ in tI. .. II "".]. sot'i ah'(l with th e two 1Il1)(It·Su f ad mimstranon an..i< l it I..'mplutio::. Hall-lives ..fUO IlIg is e xt't'ssh 't'. in CaSt· C at I half-life . kll' r.....S "...1 1 1) .l1 i..1 in tI.. " --' -..." ( .... 0 0 " . 0 Case 0 l QO-rng Bolus Plus Infusion 0 2 0 200 . tilt· IM IllIs doS(' o f lUll 1I1 ~ is b elow tht' plateau amount .-r iI I. . E 0 "0 C 100 0 0 0 ... .. «:... ri .... ..·" illihal .>1. .. In C.lo ."'.·...u il1l1s1rMI . 1).. ..n (c a....-.....".. e .. · ""KI "ol "p.. k.'il" C . 0 0 ..(lIItinllollSly rises unti l till' S' U Il I' plateau us ill t!le 0. -. is 0 11(' in whkll di fTNeut bolus dllS(°S a re' gin'n a t tlu.. ' .. lit·s midwa y htOrn"("I'1I rhe bolus do w anti the pluteuu value.... 400 300 200 oS ~ ~ '" . ..w..-\) n.o.t. .S 0 400 CoseC 400-rng Bolus Plus Infusion -. .· a.. 2 3 4 5 6 2 3 4 5 6 Half-lives 0. I" e 11.uning fRIIIl tilt' IM llus ami ]OU mg Imm tlu... ••1 I mt· . In Ca. •d or ). . tl.ll). n ·".hotly {... aud ti ll" infusion mi l" tllt"ft'altt'r maintains the pla teilll amount ... fh'5.-.

C. and by 10 hr plat eau is lI. For e-sampk-. 3 . 23 ). l1tis is see n in Fig. TIlt' half-lin'S ill the se.tlue . TIll' holu s dust. anti th at at plateau .' within this toh-ranc "arit'S with tile sta rti ll~ and final \lIlut'S... 12 For e-xample. 111 result is expect ed fro m tilt' is 6 . by 3 hr ( I hal f.3 half-lis'('s to n:'aeh tilt' lIppt'r limit of . 13. th e Iillle to rt'at'h tht' !fJ\\l'r limit o f tolemnl'(' (90%) is on l> I half-lift' .Igft.1. 6--6.IJ is dt'monstr.50nC! of tilt' final \. Snl\.. 111t.on uppr oa to plateau can ht.patient s arc 3. is C = C(O). it follows fm m E(I. = 0 . th tht. tilf' appn l:leh to plateau has lx-en consfde n-d iu ahsolute terms. (C hap. the sa me ho lm dost.1I 1 t1l1 rin~ an infusion has been p resented so far in terms of tlw time rt'llllin'(l (0 ~u from tht' initial cono -ntration (amount) to tilt' plateau. am ! infusion rate art' <Idm inish'R"t) to three patients. vnhu-s . As alwa ys . -. 3 th ai for a gi\l'lI infusion rate. is reach ed. us lilt' " mount in till' hotly at plateau (ll.-Iullf that of patient B. seen I. t1epit1('l) ill Fig. (0). the amount of drug in p<ltiell t A falls until t'S a new plateau value. TIlt" HIllt" n:. In tIlt' sec ond am i mo rt' comm on situa tion. lilt' " IIIit' !J1l-~ Ialk-u SO of tilt' wa>' toward tilt' plateau. one obtains co ncentration at any tim e du ring an lnfuston. half-life..(1.N ' S is n-ached. and 9 hr.6 min half-life in this patit'u !. 12 and laking into account that ( 112)" = r . ollt.ll g Eq. Cav . R-Spt t.6 IIlWmin. Ht'arran". o f 10 mg \I. a eouce-u- Pradicallssves So far.> e ' application of Eq. tilt' approa to ch plan-au is ~()\l' ml'tl so ldy hy tht. e amount at plateau is propo rtional to Ihe half-life . A. Pract ically.. then tilt' ttm e to reach this concentration ca n 1)(· caleulah'( l a-s flllltJws.llic'uts start \\. Patien t A ellnunates the clm g mo n . O U( '{' again tilt' time to approach the plateau is controlh-d so lely bv th e hulf-Hfe of the drug.is 500 J.'. and th e ( ' UII ccnt ranon to 1.·llllthat plasma cnucentrurion after an l. apprcl:leh to platt-. this amount '.IWL. which ill pancut A is only 3 11r. t!le plateau va hu . III (. TIllis. is main tained be canw mtt' o f infusion is exactlv matched bv rat e of elimination . hl. SilK" I'lim inat ion is slowr.mpid ly th an tlO patien t H.life J. Thus.L~ ± 10':1. 6.'n tration is . A("t' ln. by Sll lll lll i ll ~ th eSt. I I .b olus dost. mtrast . Th at is. if tilt' initial vahn.3 half-lin 's. TIl(" roucent runon n's u l ti n~ from a constant-rate infusion is gi W Il in Eq.ldy by the half-lift' of tilt' d rug in this patit·lIt. and C . By the ti me the plateau is reache all the d. 6-6. same amou nt o f t1nlg: ill the bod> In putieut B.CHAPTH6 CQNSTA!'lH ATE ~EGWl NS 7S pn -viouv ( '. dd e n ninetl by t''OlIIbining the pri nctpk-s ch "I n. 6----1 .(pliR't1 to e. bolus clost. 111is may lit. if the st arti n~ ' t"llll('l. ti lt' amount ill patient C rises until rate (. AIl)./kl is 15 mg.' qeautmcs . and C int n Efl' 13 yi elds (IIi tration of 110 I1WL is n -achrd in 5 .final value.. .-l.LS insufficient 10 attain ti lt' stt'ady state achieved 0 11 infusing 1.ldy It'aOll.f ehmlnatton ('(Ilials infusion rat e. Th e finn.to reach this lugher plateau \'alm' is go\'e nl('(! St.'" tiH'ly. Also .ltt'l) by t-I'A in Fig.1l25. with diffe rt'llt d t'araJwI> am! 'l-sso(·ialt'l l half-lift.v. it takes 5 . tilt' amullnt of d m g ill p atteut C is midway lx -twee-u tlu.lin~I)'. n-acln-d. p.amount in p<llit'nt C at plan-au is 50 1l lIigllt'r than that in patient B. it is lu-lpful to t'slahlish a tolc-runc such . 13 Suhs tituting for (. B. if onebegins at 80% of th t' final platl'all.is 100 J. ho lus doS(' has b en ellmtnated. ng for n.(' n-acln-d is 110 J. for tln.r. hy I half-life (9 h r). wln-n. Ht"t. TIlt' lime to n 'adl any vahu .Ig/L. As each t'\l'nl is imh-pe-nck-nt of tlw other.

.......' AlMI C)....h '""' I . 1.. .. 'ilh hn il> .. .t. w. IIw . .. . .. ". "..·. ""1'"1'.od> on plal ll k tI . ----- '" ....-1 (iw>~.." nl "f t1NJt in II. I . i.. !i is 0 ..... ·· .-:==~--~ Patient C Half·life l onger than Expected " 300 200 100 o tl lC.....rd ~ nt.p.'.. .'. ·..· Ii I.. Afld II I..._.." of J. at . (1oI1.'lh lhor n".t.. <5 ...."..Ir·lif.. In. !\ _ .fTf"RIn . ... 6.1 Ii incb...'h . .0 do: 'UI>( (. 300 C0N51ANTv.. II ._ .'h l m l in ..". .... rER[GlMENS CI-W'tH 6 Patient A Halt-lite Shorter than Expected 200 100 ... .. . ."if n"'l ........au d.t... »: -. " ..•.. 6-6. -I------.. Ih... .~ fNttt. . ..' I"J ut J.... m"' (polO ....tiI. I C . ~ (. 01' inrll"'''' ~ d pa." ... 1y \ h...~.. . K... .• inotl<ll l. ·' J .1:-· atlal 1 and onl i n lho.. an.-.. poot..) ..moM. . ..r ....t u in ' .."" .....d . . .oI." 1J\~ (·1"'". .j.. --- o ~ o Patient B Half-life Equal to that Expected ... """... Onlv .".ho . • .! Inr ( Ia.. ...:Jr.. " t half-lif . ..ftrr -rP".." 2 E '" S 200 . HI. .... . h<.t.. "I ~"" i.. I2IM "'It) In..j ~' 3. f . ° 100 ....\lMlI mf."! at ~ .....Ih l. 'n [""'liMllo A...""lOInl in tbe..Ln 'l1 !'.....n til.. l . 48 72 o 24 Hours trMlIlK II.. .7..3 t..I IJ"'4'..... a" ..ol oil. 01. nit· .. ....- ..Ir·In.. JOLot..~ iU ..

dt'"tees ad nums tc red extravascu lar lv. with Iln. After. the Italf·li ft. l'llllsidNt'tl.' amilahlt. !I()\\·t. ..76 0 . O n n. b eing the ttrne taken to reach half tilt' plateau coucenrranou. e. ho lm data. Indeed . no sempk..addilional absorption stt·p.v r.v.. o . " . ASSESSMENT OF PHARMACOKINETIC PARAMETERS Pharmucokhu-tlc parau ll'tt'l's are gen erally ddt'nnined just as rt'mlil~' from constant-rate dat a as from L \ '. \\ 'hut can 1 t'stiumli 'tl? )(' Finol.0. ma com-entrattou data ill Tabk .(' .CHAPTE ~O CONSTANl-AATl: ~NS 71 toh-rance.mus t interpolate lx-tween the observed da ta.L<...\\1l\ taken at tht s tinu-....mng mlu.ow estimates of pilars lIlat'Ukillt'tit' jliir<Ullt'tt·rs an ' made is seen hy l't mside rin~ the p la. Second. Now " ol li !II(' initial and final v alues must also bt..6-1. . estimated in cc Ilus maum-r. Ihis is so for an i...5 mw'L c ~ws ch-ara nce.1 0' 00 0 . .nlu$ion . Foll{)\\in~ the IISC of constant -rai l' rt·lt._. is t'it\ i1y ascert ained../hrl fer 12 hr ~I hrl... that measurements only dllrill ~ the infusion an.. s. (40 M.. I. infusion . Ad minislt'rt't! extravecularly. . d hidill~ tilt' infusion rutc of 40 mw'hr by the plateau ro n eutratiou of 9. alt hou~b perhaps mcouscquenttally. is appr oximately 1. TIll' constan t-ra te n-leasc ~"li le mS marketed ma)' contain a Io. for rlu. mA TMl'NT ()I 0..\~n~ those l'tllll't·lIlr..'at p reci sion byavt' r.1. Ollt' ohtains T. however...~" 0-3. regi lTit'll. in this ('..ntp id ad .infusion. o 10 . obt aillt'tl dllrill ~ ami afh' r an is . Al'('('plin~ a tolerance clea rly modifi es the statement: TIlt' lime taken to rt'ad... 9 . c. than that fellowi n~ all t'(llIi\'aleI11 L\' .. and s. thts is Ihe preferred met hod for t'St i mati n~ d earallt't-' Si lll't-· tht' plate-au concent ration can be de te rm ined with ~n. 6--7). the att ainm ent of both the-rapeutic concentrations and platea u wtll Ilu-refn re he 1001~t' r..5 hr.33 0 ..'.ttiollS that dt·arly lit' al plateau.. ill this example and ill most cases.() mu.'Stil1lalill~ tilt' half· lift. 11. whit.... S~lIt·tlll'll'ss. Pi. I){~ of the final \01l1 lt·.f . li st' S all tilt' datil ohtaillt't l durtng rlu. ( Fi~. plateau is ddt'nnillt'tl solely by the half-life of tlie dnlg.sioo I PCJ:S/.-. Plasma Data Alone Co nside r.ltlin~ dOM' 10 facilitat e the mon. uncertalutv exists about hi oavailahilit)'.0...1Il01l1t'1l1. .0.a 70 33 87 93 90 95 "' 0 02 i. TIlt' half-lift'.v. C).2 LAIr..h the refon.it\(. data . A mort' a urate met hod of t. .... infusion of a drug. 14 " " 10 ..requi res refe rence to t.it'\"l'lIIt·nt of th("ntpt'utit' l'llllt't'nt rat io lls.. Ct'rtoullly.'arT'dllgi ll~ Eq .

olt. since aflN stop ping till" infusiu n ti lt.<III I)1..· ]01I}!.... TIlt' iIlI N l 't'pl a t till lt' zem is the.J 1ll11 .-n-n.~ \'...1 • o 2 4 6 8 Hours 10 12 .. 10 • (C.s1npl' is . TIll'S(' differences in conccntrauou SIIl1\\1 1 by vertknlHnes in Fig.. .> a C'll"t' it is III L.1 "fh" a n ...> ami tlu..ll lo~~a ri! l lI lis yn-kls In Ie.-a h' a Ilalr-Iife of 1..5 0..L l.l·r tilt' infusion. 2 1 0...·"'il"\>tMitlllnic.~.lST ANl-iATf if(..rill:( " tI.W. pL.. Als.·n" ... " ' 'I'I"nK 11. · _ _ 10 40 mglh r - _ li...C) during infusion pl"tt. tl.\lIllt dn'Klu ..C.(' inru. 15 tilt' tlt"'Clim' o blai llt"'ll 11)' p lultillg St'lll iluv. ~_ S.n lU>t1 !Iw " 1.-twt...pl.71 CCt-..k-ulah'tl kll0\\i T1!!: d .na.. 6-7.. .2 0. · e ." .... (m ill which half·life l.t('o f".1t1 nriult 11. ... 5 o C postmtuston "f.lIlt' of distriliutfon is e.k.aritiullit~llly tilt' d ilTNt'lIn' hl'lWt'( '1l till' plateau conceru r auon and that at l'ar lit>T tunes a}!..1 In e.l'Okh.~·"t r. t tim ... of pL.. ...""a.platt·au l'u lI("l' n l ra l iol\ (C...fNS CHAPT o H e......k... . il.Li}!. - Cinf _ C.·.aillSt tilt' l'orrt'sp'llltling lill ll' should he it str. urr.\~-rtic"." ...h t Jim' .. . tI.·III·mll)'... 6-8...! .lift'. uf the plat euu haw l'\l'tossi\l ' error.. a"'IIIl't>and half...' eh-te-rmined.. lufu. -tl> " l~" ..IiIT.. t inrU~iOlIl . llI ri ....{' <"r\' values calculated frum ceneeutra tions ht")Ul 1d gO'}. 11l11S.~"lt c.1.. - k· .. phu .t.7...oI ·" "I.bIT.t' infusion... n. Tln...i"" """i n.u~l l t li l1e . n'tll r" titltl (0) "'Pins! tiu.lm :( . tht' \.presented ill Ta blt' 6--3 ami haw la -cn p lutl l'. The.I"...Um"IiOl" OIf I"... 14 which upon l aki ll~ niltll r. t ..tr"h....... "l'~'lIt ." s ~ plot.n = ..t (If tl..infu.pape f also ~\'t'S a st r.~ .. d ilT Ul ... It·dini. 8 6 4 2 o o 4 8 12 Hours 16 20 Flit ...dura illdi(.. I'lolt i ll ~ t1 1t'st" dat a 0 11 s(>lIl il( ~aritl l1nk.. it· ['4r" l1. ill this L st....7 IlL It sho uld 1 · I\utt-d that t h....nu-asun-ment .· . G.j... tilt' c1ost'r the conc ent ration is to tilt' plateau )( i ll ti lt" value a nd til(' ~rt'lIIN is til(' error diITt'rt'lIt. 1}. F.....I_I l..t1 in Fi!-t.I...u and ...t... CUllsidt>r IInw tilt' concentration data at ami aflt'r tilt' end of Il.

wlu-n drugs wit h tlifTe n 'lll ck-umno. I ' .reach tilt' SOUl I( ' platt'olll concentration when h . Fur example. ..lt("(1. m -!t-holim' ..I. (x1. infusion for xustaim-d mu scle n-laxation.t'll lll'l. Slll'l.\l on '(}\'(·r .lImnt II(' ('stim .asioually t!ley difTt'r.26 l Ai r. renal clearuncc mu ll(' estnnan-d in add itioll to all 01 111'1' pharmat'okindit' 1 >ilr. ami t'st im alt 's can 1M.v.'tl tn sll(lt'rim(lO'i(' 0 11 til{' pn " iu lls di fTN t'U datil l Fil-t. tlu. n 'sll('t1iwly'. I II tl l{' l>ilrt il'ub r {·'t<lmpll· studn-d . I Urine Data AJone If (t'ual dl'aralll. A typ ical initial dow is 20 IllR fnUnw('(! b)' continuous inru sion o f -I mWmiu.so plnth'(I. infusioll r ate.is . \\ 'lu-u hnl" pl. wllt'll tilt' infusioll mtt' is -10 lIIWhr. obnuned b t1i\idin~ excret ion rate al y plateau by C" . Tlu-u excn-nou run.y an .ltt'au concentration depend s U I)llII lIlt' rate of infusion . At plateau.at plateau for tilt' d nl g is 12 IllJ~/hr. ' e . 111' al'(1lralt' ll\t"ilSU(('lI\t'nh ran II(' nmdl' nf Il(lth plol ma coucentrauon and urine excretion " ratr-. 6-'\ ). Ihen-hy i llt l it.V alll('S an' infused itt the same rate .itl prt:lt1'lllln 'S. :\ 11 dmgs I l a\i n~ tilt' S ~\'(' n at tilt' sanu. :\11 of lilt' al li In' . 16 1'11('( ' \\11 t !le~' dilt<l un .t'lll'mlly reach tht· plateau con centration at th(' sa me tim e . values for volunn. I'. so fi' is 0 . is 1.'rintl uf study. tllt.11Ixly ut p lateau cannot he Ihl' sauu. lllllt' ck-arano .} I .. .lsm a and uriur. Esti mate tilt' r-hmtnatlun half-li\'('s of suel'inyk-ho lint' in patu-nts rt'(luirilii lIAIllWlIlin alKI-I TlIWll1in...o f t1istrihlltioll and c!t'ar..M Sl. Which 1 me or mon.s lll'l data.lll1t't t'rs .slIlll data.' made (If d im ina tion Ilalf-lift. Au t'stimalt' offf' is ohl aiu t'(l at plalt'illl From Fe _ 11:0le 01excretion 01pla reou Rote of infusion 17 !»t'('iIlN' lilt' rolli' of infusiou is t' llial to Iln.rolle (If d imin. f.nh'i('''l. a steady-slatt' experiment adlil" 't'(l \\ith t'u ustanl infllSio ll is 1 pn'fl'm'tl method for ('stimating renal clearance. Dm~s \\i tll tht.. TIl{' ' U lll lll ll l of dm~ in tln..p n 't'('tlilll-t t'xamplt . tht' mit' of t'X1'n'tinn is proportionul to tilt' plasmu couccntranou.t1 i ll ~ thai dm~ ' d i spt ~ il ioll hils d l<lIl!-( '( 1 UH' r tilt' I"lt. and fr a ction t'wn'!t'tlundmngt'(l (f d .of tilt' f(lllo\\ill~ statemen ts pt'rtaining to 1111lslant r ate infusion is 11Irrt1-1 :-' a .U1I"{' 1. Plasma and Urine Data \\'i1lumt pLl.t .data can ht· tn'alt'tl in a manner anal ogollS 10 that of pla. For prt'lloll~t 'tl slI"". XOllt' of tilt' alllM'. d .· or variatinu in thl' dU killd il'S of Illt'laho lism o f slIl'(.ollM.(' is cons tant. T Ilt' infusioll mllst II(' indi\itluali7.CHAPT 0 H C "C. 2.3.t1inll.. tn matutain 20 1Il ~ in tIlt' 1 1I1IIy.uu e clearance J!. n -ua l clearance. In tlu. tllt· llalf-liH's dt'lennillt't! from ti lt' rb i ll~ aud t1t'dillilll-t l'U"'t'San' t'(llml. nyld mlint· d llo ritll' is ~\'t'1I hy i.t'tl c scrcnon ran. TIl1' tilll(' to n-ach a p!. STUDY PROBlEMS IAnswers to Study Problems ore in Appendix II. .dala an-obtained.

TI lt'S(' <b l a imlil'l..n -c al <It'\11'l' contahu-d a total of . .ill~ tilt' infusion pump? c.\tHT of till" t1m~ . TabhM lists till' plasma ll ifN lipi ll l ' coneeutrution du ring and after tilt' infusion .ck-ara uce-..'t> .N ' n "(1al d nl )t... -I.-.. I)( ltt.edel . .DD Niedop . dt"lii~lt"(1 to dl'1iw'r d n')t at a constaut ratr..for IS Ill'. 1 _ _ . ..') lists tilt" mean plusma concent runon o f d mpt'ri dol obt aillt'd f(J IIO\."'.._.. till' expt'(1t. Is lilt" app ru.iH '!1 111<11 all tlu. lin tilt" ~m p hs Oil t ilt" right IIsing (1)lIl't'pls presenn-d in this chapter. Ite-Iy ..o f d istri hutioll . infusioll -mh' S<. In CON SIANT tATE ~E GW.....~It'n"( 1 illtran'lIllllsly ami intramust:ubrly. If the tlt'sin ' is to achk-ve till' plan-auconeent ratkm 'l~st )(: iah'l l with tilt' 3. rate 0. .:1 hy a one-comp artmental modr-l. C ak ulatt' tln. P 71 oect>I. 2 IJr.pat it'llts anti in patients UlI\ lt'rgoi ll ~ 'Ub o dll'llIotlwmpy .tnfus-d dm~ wa s absorbed and thainift'tlipilll' di sp()Sit i oll l~lIl 1)(· dlara<..5 mgzhr. do> ~..lWL " 'l... Dropcndol is currently atlm iu i.0 mW'1T inslt'ad llf 1.i ll~ li st ' of t!lis dl"\1<. h ..'t·II arlos.. IGJ _ ~.. what is thl' I ()adi ll ~ do<.. .:l ~ ~... Xu!.... has 1..prufilt·. Nlfetllpl... .C H ond e. D liriUl-t a n ill \·t"sti~ati ollal prt~mlll .1illlalt'tl a 1'lllltilllluus-n . ' procedures .. iU\1L . 6-9) art' '\\11 lIlutt ip l(.. I.I. am i at plat eau? d .we n ... I)"S.3... D ropertdol. 125 mW'lr..1 11l~ drot ptr-ndol..LS attaitlt'd .'t . 6-4.. . Gupta et n]. infus ion.t. rt'tlui rt'l l? 5..lt'.0 IllWh r infusion rate instantly.. 6 I 41 14 5 o 75 10. that lilt' tillll' scale is expn -sscd in half-lift' uuits.. Dwrl. ·-.v. .u·h of tilt" conccntrauon til plalt"11I in 'l~n":'lIIt' n t wit h tilt' h. Xo drug was fou nd in till" recovered dt'\1<...I.... and .f NS tilt" graphs on 11ll' fwd p<lgt' ( F ig. .( '('11 IIM't1 for tln..<l>"'<l ~.. what would ht. a hlltyrnpllt'liont" dl' ri\"atin '.murS('t11lS or \'(lIniti nJt. Sketch IllI" untk-ipated phl-Slll <l e uwentratton.~ ~ fho. Tablt. Tln.l tt> Ihat a ll <lH''rage plalt'an l't)JJ{'t'ulmtioll o f 2 1 J. ( 1002 ) 1. dt'l in ' I)' ' }"itt"1Il as a means o f <ldlit" i IlJt tllt"mp:ofur.lll I"xtt'mlt'tl pt'ri(KI ..._an"""""". 6... If lilt" infu sioll rute. volunn. iucompnrison \\1tll a 24 -1 coustant 11' r ate i..preveunou and trea tmon t of U t'a aud \'1 )lJlit i ll~ ill p s tope rat ivt . With .unn. 111(' oral r oute crea tes a p r o 'ih blem fill' path-nt s who are.• o 1 .. Tilt' total (:ll'a ra rlt't' of ti lt' dOl g is ZOO m l / min...aIf -life o f mfedtplnc observed on rt"lI1o.5 I' 110 130 108 100 18 0 110 180 110 no 15 16 17 18 l' 18 .:1 concen trarious at I hr. 1\l 84 _ . ~3Q6-4 0 1 a..5 mW'lT) via a n -ot al O SIllOtiC pum p <It'vil't' for 2-1 h r.0 3. half-lift".1 l'ri i'~ . Os.ody. (.. till" calcium d lalllld hlud dng agell t Ilifl't )ip ilit· WllS infuS("{! at a constant mit' ( 1..()".

10 ConcenlrOlion 1l1( 10 1 ! Img/U dev.6 1. 6-5..2 0...of dislrihulioll of d mpt'ridol? 2 1.v.8 0. c.63 0. .4 0 0 " u 0 0 ~ <. lc.\lHT flll1fl"'i lJ~ au i.wl I M 0 0 . . of <lnll)('ri<lol._ • .5 2 4 6 8 10 14 18 24 26 28 30 i. Esli ma h ' tilt' svstemtc h i()a\~lila"i1 i ty of II I(' dnl ~.~ 2 1.2 0.65 02Q 0 .ht I.ti lllalt' tilt' ' r-linuuation half-lift.tI II.6 1. t-.1h .40067036 0 0 0 49 OW 183 1..~ 2 3 4 5 . PI the U. From til(' pla. I I. b. . d.4 5 4 3 2 ·E "2 g '" ~ 0 0 0 C- ~ E 0 O 0 2 3 4 5 . e. .""" c. 80 2 60 250 250 270 270 2W 310 1.84 193 152 1. ..CHAPTUO CQNSTANlAATE ~EGWo.ce a. Infusion.lt· 6-9· .E N 5 II . 3 2 I 1 2 3 4 0 5 0 Time (in halt-lives! 2 3 4 5 l I. I. 1. Ca leu l" h' the t'xpt'('tt'tI . . ./f lh.p.) Plasma Dr.8 0. Calculate clcurauce .v.43 1. .v." Tlf. hntus..> 5 4 ~ E ~ ~ /1.illla t'Ullt'('nt rlltiu n dill" aftN slo ppi ng till' i. \\1ml is tIlt' volurm. infmion 0 OW. . M_.

input.t'xlx'(1alioll of !.i.' j( )( Y. .~ i h i li ty o f transc h-nnul t1e1i\'t' r) o f a new antidepressant rohpram .l~ TT1a roltp nun <"ll llt 't' n l m t iu IIS ill six su bj ec ts Illilt l t · d u rilJ.-_ c.. in edto reach this tolerance wln-n lilt' iniliill concentration is: Iialf-lin ·s.aml1t'ri . 1 1 "t1~m ft et d m ~.f of lilt' final (p laleau ) valm-. . till' time . c.·rd~t· ck-arauce and IllIlf-lift· of rohpr. T... d m~.· 6-1'). A dm /. <IilTc'no From that t'XIX't1c't! fClllm..a\"( ·ra~t· mit" that robp ram is I lt' il1 ~ ahsnr llt"(l from the.slks was "d minislt'n'tl as a ll i..9 1.I.tln. . tilt' pract ical view of the a p pnllid l to plateau \ \ Nd-S pn-scuted.i n~ con stant-ran...: that d isplays one-compart ment ('t..v. half· life .. All his lillie .1t•• 6-7.7 ohlaillt'tl on i llfu s i fl ~ a clm g . Ihtn.of 50 mw11r for 1 7 . m-c-d a. . After 24.5'l isn p m pyl m)" ristal t>Oil u po lym er "a(·ki l1 ~.. In tlu .. half-life. Six M.lsS hnw the absorp t km-t ime .otl ill I llilif-Iifl'. hrid l)" d iS(1. followl'tl illllllt'tliatd y b)" a ('()!Isla nl infusion of 10 mwtlr for li lt" durutton nf a slud)".<1 In forea rm skin an-as ..11.p r ofikI. ..')0 1II)!.uu an ' SA 1. ap plit. .patch la-tween 12 and 2-1 h r. 111t' p atches (5 <:111 X 5 e m).. instead of 10%.6 lists til(' meun l'J.. Esttnran. hpnuu lIhsorlx'tl d llri ll~ the 2-I·h r applicat ion of h.e. 75% ill 2: half-ljvr-s. .1. ('xp!n J"('(ltllt' r(·. S()~..of distribu tionelimination rate constant. and d t'ar.. '".J h r.tolerance at pla n-au Imd IX"(' 11 15%.the values o f \ 1 111ll11 t' of distribution. alcohol S >\1Ihs.. 6-6. of li lt' final (p lalt 'o ) value lll h. ~ lhfl o 6 75 70 9 12 15 P1a!>fflO dfug coeceenctoe Img/ll o 34 54 65 46 20 0 . . Estimate. holus o f 2.1 the r an.tjn. Dt'l t' n llilw lilt' total amount uf r o IlIc' patch.1' and 3 h r.11. M . the Il<lld ws \ \1' 1'(' rt'l!Iu\"t't1 and til(' skill an'a cleam-d "ill. wha t wo uld lx.Ull'C from tilt' da la iu Table fi. rt· sI)('(1i \l. hltlects- a.volunu.n-xt on Illl)!. a nd clearance from 11ll' dut u in Tothl. ill. If tlu.~ hr.IIInrtI... lilt' appmad l 10 sh 'ad)" slalt' follow tlu.12 CHAPT 6 U fi .me lhl) Plosrc drug ccoce-ecnce lmg/tl 03 50 76 50 98 40 ~J . Doc·.. .:: and aftN a 24 -11 1' ap p!il'<ltiu ll of. Cal('ub tt. . t. alltl .n ' covr-n-d fnr 2.. T allie fi.c' 75.l 25-t·m 2 !l<ltd l of "ilit'o ll(' adlu-sive-.·I~· .hr De. TIl(' a\l. .. am i so o n? If lint .1 Ap"nctlfl•• I..

. t'llll~i.e regImen 01 a conIToIIed-relea5oe lormula!lon 5 Det-~ phormocolo .llicm and . .1 (UlllIlHJIl nllt·..1 in·ly."ilrit·. ·tl.\ _ ..J.linill!: Imm tln.' lowartl a " .tiltll'lI' Ill"'1'" lgl.. r. k ..men hom lnowledge of the phaflTlQc¢l. 111..(inlt'lJ <"('II1IIO. Ii Ill! ' \\"111'11 l\.1I'ot' dm ~ [rrnu pn'\inllS liu'lol"ll has nu l I..r· respond 10 the.llioll ..' M till ·. ~ illl i lar 10 all i llli l~ ifl ll . 11.. x-u <'l ullpl"h ·ly rt ·Ill. ~oc:i a l i o n wi lh l h i ~ lind plateau. lpll'T "IM·II Imlltipl"-o:I'N' n'1..1 I"~ill!: illlt 'n..II)'it· (wn m ~ ) 1'111\ lilt' ..J <'III.<111....." r-] t. fh. DRUG ACCUMULATION I> m~ a n ' mu"t ('l l lll lllnll l~' pn-scnlx-d to he l 'l~t ·1I 011 .tllil~ hI' 1'.. imhlt· ft... .)"l"( 1 o f " 'pla l ou.inera and therapeutic window of a drug 3. ~ 1I 1l 1 d(~ilJt: ill"'na] IliI (. • .ng 0 rrulliple-dos.. n il' 1ll.'iO 1lI~ (.· .liN' . I and nuuuuuru C\ _ 1. du!io(' i....s t'l ..-fon.. \ I _. nit' p n lIlany (It iulls diaptN llt ·.."ll'II'.prt'\i.. 1I1~ jusl ...MULTIP LE -DOSE REGIMENS OIJICTlVEI The reodet win be able 10: 1 Pfeaid the lote and eoeot of dllJg occurnubrion lor a 9'vefl regimen of fixed dose and filled interval.Ih(' 111'\1 <leN:' <.-\.lt "itl. C id .:ll l ll..~ .'iIlll'U\.1 an.. gin'lI in lrd\t" MM ldy ' ''l'~ dimillalinll h.• Il KI III ~ Ihrt"(· finn-s a <by.. l ..Ilt'S ~lIh~lalllia lh ... . llIlih u" I.tl llo ' " lh ill Ill\' 1.. IO.. · pl.I. 2 Develop a dosage reg...-J. Evoluale the liroetlO of 0 drug givet'\ in 0 mulriple-dose regimen IS EvalUOle the kinetic of a drug lo/b.III rt·.lh· TI"l. .\ n : lIl1lllb li.. \\i ll.(..\·UllIllb lio ll.-\I.lilll'(l \\.U1M M uf dmg ill lilt .(' and jil'l I...e regimen.t!IM ..).II~ h In ~\t. (UIl..... of Fil.netiC palOI'l"'letet'~ for 0 dn9 from pIcumo cooceMotion lor weel dolo foIIov.ll(·lilj·..lflN (·oK·1J t ier.11111 . Ih.· t1i\C. In ... I" ill ".Tt '!l. i. rt"Sp'.r. llill'S .t.wlt Ilt ~jllg illll ·n·ili. I'i {"ll\l'~ 11M' lIIuhipl..Ift"ll .11110'1111 n 'Ill..' lt '(1: t1W'lol ' \ . . n it' l 'llm"Sp')Iltlinl: \.ti th In 11K' m aillh' llalK't" o f l"lm till lll M 11 .K"Ilkindil' printiplt·' . 1111' II M'n' ('tllllllMlIl "ppn".-iate tilt' p ht'unlllt"ltllII of ." an' II'" tiM" 111. tun-s.~('( I ."(llillw illll'nal ha~i~ : of 'u lrHillhlr. tilt' .• <~ lIIdi l illll \ t l nJ~ .1 ~11l1\\~ \ III1\\' amount ill tilt' 110.:.t<. lSI) TI1~. III:' ('.lcrtiol lo tIM PlatfOtl Tu dpprt...11110 ' 1111 ill Ih t· botk 1I11l1l1ah._ .. '\I'n MOlina ond MiaiJna 01 Accvm.· r ti lt" sim p!"sl silna ticm o f a t1mag" rl'l.·m wlu-n a IO()' III~ hoI".d l a p !M nn..1\illllllll ..1 fiWt l d"w.IIlring til<' fi.dl t111~1' i ~ gi\( '11 ~ll('t' 's ~ h r-lv twio .al...ving 0 mvhlple-dos. \ !It.maximum t.1 "'(I(...IIII -r.1.. ad lll j ll i ~INt"(1 illlm\l'lIl1usly a t fht"(1 a nd " ' Illal li llw illll 'n a k C lln .al f·l if(" Under 111t'..l\lIl'1 IUll('t·nl r. b"l ll ~ dust·s I. ·r \\ 1••11 11ol1'lIO.· fi"l.tlo·. ri....':IlIllIlI. tht.IIKI lilt: 1.

'.\ . <.(O of that dosillj... f('spt"t... i5 1llJ... With d ist:rt' f(' d o sin g..... '. AN..(" ~ll il..ee--Nir] h body oft8l" Mh dose..).input.'.. 1" >1.... .. l...') mg:..(. t'\'l'(. At rlu. 111\' amou nt rt' lll<li l\ i ll~ at tilt· {'li d of ti lt· Stt1md dllSill ~ inn-real (A b . e h 2 body a t plateau.lin n .gt'lw ml sit uunon i ll w h i(·h a d r u ts Wn'll at u t10 Shl g.~ ) and at plah'llu (A . 1"'.l(l l nl/l is n-ao hed wln-u rOlf(' of t'li llliui(tio l1 lJlatdll's raft' of input..lmini'. t !l t' I.: . T1.Jy . .. t he amount 1II1l.:..dost" 1U0 m g.. 111 term I.. Ollt ' half-lift'.· ".l' IlN a l g t'(lliatiollS dt' n n '(! in Apl')('1II11\ I.l.Her-s han' t'lapSt"t1 Sj lll 1' its . Moltimum amount in • Dose - body after Mh dcse..iliut'(! \\ i th in till' int t-rva].llIIiui. cont lruu-s lIu l il a li m il is n -ached. ..". whit-h lIlay t1iITN fr om rlu. Ihl' duSt" I n thi s exa m ple. _ 3 nil:....bodv.. !)t'('. llt-gin llillj... AN.losing t' sn-udv-stan-condmon. t . wlu-utln. 111t' g.·. 1)o .min w. th.Xtli tloS(' (As. li lt' maxtmum und till" minimum amounts ill Iht' hod y al s t('ad~' stilll' an ' 200 1Il~ ami J(XI 1lIj.limit. ~ .... urn ] sinn' a t tilt' (' nd o f tluinterval. Fnl1O'\\i ng a constan t run.• ur drug .( thai 1I1l1·· half of till' amu un! just afn-r tilt' St'( Hm l dust" 150 1Il ~.I(llnJU is also applied to tl.·n.U·li f. tln. rlu.t (mill III(' first do.. ' is Ih al rt·lI1. 1111'1l till' Il'n .oximum a mount in • Do. ~11'" 1.E for t ilt' maximum a nd minimum amounts in l ilt' hody aft{'r rlu..t. ( '(] 1'\1' " . i .((.1i\'...l of dm~ in lilt' lltltly is constant...is illlt'n. This m u st ht ... 1'\ halr· ll lir.. 1 h. •• Kf'~' t ~ .....I-:. 1 t". : ml Upo n n -!waf iuJ. 1 ~n' n !iIIit' wi thin tilt' inte-rval art' t ilt' smm' fr om O llt' dos in~ interval to another.( Interval.d iIT rt' Il('(' ht... 1 ill n-n ns (If ('itlll'r maximum or nummum amount in tlu. M inimum amount in [II .sidl'mtiollS ran lit. .(IUt's it! .If·lif. F ig.: A .. tilt· CHAPTE P7 (50 mJQ.:this p ml't'tlurt" it is n·"d i!y St '( ' 11 k lll'\'(' n..lillt'tl . e"I'\" ".I ) that d m g uceumulution.. interval.>11\.lew! is not coustunt within a d os ing.... b UI til(' \'..i "R rn~ I IN'fK.0 sil l('(' rlu...t.. ' . {':qlillldt'(l for t h t. 1lIi1)' simply 1)(' calcula ted hy n..· llMt ti lt"· 1 . f) (lU "'10:1.) art' .half-lift.\ \ ~1 ill . ~ull ".Ullllillisi ml io ll ) plus that rt'lIlilini n g From tilt.(''011(1 dust" 50 mg. Altt·m ali\'t>ly.l.tWt'('1I t' till" maximum a nd minim um amou nts is tlu.: X III X 1/ 2 .(' lTl llll.un illJ.. remains at tln.. ot.it~.t·. mo n .. t hilt is..IIIIUllll! lost ill each 1 111('1"\'<11 e-q uals <1111011111 .i llj.umoun t Im l t'1lua ls tlnamount p.lII<. 7_1.(' ftm -going ('Ul\. AIa.. tilt' value. t behalf t lmt lit Ih t." " A l' n l.' t wo half.. .·n .. 2 5 Il\~ ( 100 III/.. Interval. unih B o 2 4 TimeIHall-lile 6 B .

illll c .1 ("(1usi n~ is. .fNS as A n - M inimum c mcc nt in A body of p!ot8(lU. o ral adm inistrutmn m il Ix' si111111<1.... di ¢tm in lIil'dy Illustrates lIIall)"o f the a~p("l. . r Il W Il o f 0...u ly uf d i¢ tn >. C . TIlt" an> l'il~t> amount in the. .1 1lIF.. Au ..cr . o r A.> lJlaini n ~ 1 in ti lt' bt l<l~' at ttnw t . -I the nrinunum amount alplalt'. ~ 7 and C.> r...lirt> o f d i ~ t mi n is 6 days : therefon-.I~t · r ate out. ho lliS do S('s.. Althnu ~h not as \\itlel)' us("l. Tll t> an ' n-asonuhh. is obuuued by Ulul t ipl~in~ rlu.-\.~ llwns ...CL ' .... 11.n~ extray vascular adt ru nistrutton . 8 TI J('S(>a re. _ UI:»e 4 R ('(..approximation s follo"..82 1Il~..CHAPTEIl7 MUlT1f'tfOOSE IlfGW... = = Awerag.-. Ilw)" show ho-v til(" a\·e rJ.. t' fullo"in ~ discu ssion ch-als with a h-ss l'e strit1in > view o f accumulation .~d. To furtlwr ilpp rt"li illt>til(" phenomenon of accumulation.. Irmu E(I' 3 the maximum amount at plat eau is 0..... when a hso rptiou is l~lInpl ('tt· an d ' i rtll:llIy Instantaneous.A.. d.sing lilt" ste-adv -sta te l'tllll't'pt: A\'t'm~t> rtltI' j f l mu st equul a\1.. (A...1I From C ha p . Sinl't· k = 0.. thai is. di~n'(i ll ....1 in the t reatment o f certa in cardia c dysfuncnous. t' . C. lIltl t> ~( I<'S considerable acc umulatinn when gin > dail~·. -irt ual ly instautuneous.~l> amou nt ill till' htl<l\' at .. 1I These calculations o f tilt' maximum andmtntmum \·ulut·s at plateau strili l)" apply only 10 intravascular IXllus udmlnistrutlon. Di Wtm. till' umouut ill tilt" ht l<ly at til(" end o f a dosill ~ int erval t of <l multiple-dose n. 111(' a\'('nl~t> lmlf. Similarly.. " A .. wll('l'(>. admt ntsten-d in mulnpk.....""" - .". e -h - . A . . is tlJ(' a\'t · m~t· amount o f d nl ~ in tilt" IXI<I)' m '(' r the d()s i ll ~ In terva l at platea u.......l'()m'Slxmd ing muxiIlIUIll amount hy (" -It ...AI is lilt' [ruct ion of till' initial am ount n. plateau.is .in> tha t ab u sorp nou is comph-te and ..in is F» D OM ·/t .9 2 1Il ~...l lI.... arul fmm El l..69. . . Amount and (oft(fntration al Piateau In lIlallY rt:'sIX'i-i s tilt" accumulatkru of drugs.. :1 that the fUIl(.t'lllil rmux-n tru tton :1 lilt· plalt·al t . USl"l. infus ion.1 as th e mo re pop ular d rug.1\1 is U..(1t )St*S is tilt" Slu m ' tll at observed follO\-i nl?: a consta nt-ran . 111t> U\ 'e rd~e nih> out is k: • A ... j.. " . is I'(·atlily t"lIk llt llt"l..... A .h(l<l)' at \ sl('utl)" state.......l' 5 f · Dose .t~e r an..i1l <:It·'II'I)" . -A.fundamental I'd atiomhi ps.- F 00.in .. TIlt" iln·r.). is the average pl..1It 112' lt alst... 1 follows that A ..~m(' n . Therefo re.is of accumulation and d t'siK! I o f dosa~(' n.. l"llllsidt' r all oral dOSlI~t' n1.... whi<:ll applies to ull routes of atl millislmtioll . ~ 6 when.Cu .

udnnntstrunon ami ho uf-Iift'. 111( '11 mos t of tilt' d m g [rom all previous t1oSl'S 1.·. ~· ... H....m.c " inlo: fn~l''' '''' :-'' H. ..<til ../"..'11<1" t ill rlu.. ti" .0. ..· of dnJ~ Fhutuution in lilt' amount of t1mg ill Iht· hUlly.-\M...· unih./..1 "'i"i'''''''' . Average " .... Awerage. j!.(· minimum n.l!t-l l tlll't l [rom Ell_'j .lIlainlt'U<llll't' dust· ahsorbe-d.s2 mg.. billa\"aitlhi lil~· ...../.lo:'' (.."lI: rn' I'''·'''· . fur t'xampl t' . ../..u..· lhat r. f"I1" .t il.-Ilaif tln.Jr·lif. IM adnunxly IllIS istratton ..l· d(ISill ~ inte-rval). . f.. ... .l...· llI"u. ('.. and clea rD Ol~ accumulation 1 nut a plu-nonn-uon thai <1('1 '11.' . n ~I I Il"').n..prupl.til..-Iu rt" under these ci rcu mstances lilt' IIHl imUIII and mintx mum ' '..) .I !'L . .l(" .1o: ..mlt.11111111111 o f di~t()\j ll (O....." .2 .of ah sorption...lilT ..ui/: i.· i Y .._ )...b li<o" .• ".·rty of a tim)!:. .... ... o o o 1 2 3 4 o Hatl-tife lOosjng Interval 1 2 3 H alt-litelOosing mterval 4 ... A .".l.4.. like accumulation. is a n -sult of tilt' frt'f IIWl\l'Y o f admini st rat io n n ·lalht' 10 halr· lift· lIit nr l/kt ) itS ShU\\11 in f'·i~s .. i -I alltl '..\ illust rat es how nurdnuuu.'."n' ..·)..It" inl( i" I"""" '''l'n....oollll inht mh"" ..llt'sl for is ..I)..l l.. 7.. s . .I" " ...·ml" on mi t' of mlmin istration ( 1)1 ~ ·lt l.t('· (n . I" " ".'.. l li../'1<'''11 I" tiM" " ~..." Ih i" . n·btr.S2 m!!:. "". ~ I IIt·n' ill Io.-. 10 tilt' aVt' rd~l' value. "f dml{ I" 1 h..J.·.11I t'a. « CornpariSOI of Maximum." . .lr. St'\'('m l nhSN \'illioTls art ' pertinent : ( I) TI lt' <In' raw ' amount im-n-aws ill din-c t proportion 10 fn 'tl' lt'n<.olil't ' that tilt' anm l!!:./. · r. T his simplt' uu-rhod is a S n '.f ll .92 mg am i tl..2. " 11:..I <or tI.O '" n..l'itlllahlt' appmxinumon us IUIl~ ux lilt' tlc" in!!: inn-rval dut's lIot t'M't't't I IIlt' half-lift. NO/ .·..tlion .· I..Ileu b h'tl by <Iddi ll~ <lnd s lI btr.. that art' not.•II.·r . Si ll ('(' m k ulati llg the aH 'mgt' valur.. utu'e. is liB'.92 lIlJt: A ".. flor 5 are then' t1m~s that an' ('u lIllI Jatin' and utlwr. .. i"l( d. 10.. I.... \ I"n ' fn~I''''' '1 ..· n'(.~ · 'I". is O.' .IUlini.wm"". Fi ~l n' '.·.f:-../..... I "~ ."'r~' ( t ..... Flul'Iliation also depe-nds 011 ratr... ..~ily ht' ('. :".lnllo: ./. 1'"i"i""'''' ('-\M.v.'> "" 11..\ .. Iil's mid" 1ly l 1 \\'1 )('1 '('11 tilt' maximum 0.~.. "f tI....1"'ini"'''''' I. "f <l mlo: I" II.. (2) TI ll' maxiuuun amount is JlO! much gn 'atl'r than doS{' if drug is admhusten-dh-ss fn 'ljlll'llt ly than OUl1-' ( '\'(' f) ' 3 half-lives. r".lt·ti Jl~ Illll./.S'.. n ·spt "'l1ivt'ly..I.. t \1ft "" 0..r II. <of <In .._ I .· ....n ...· ...k (.."of administra tion [iuverse of tl...i "l " . and Minimum Amounts at P1oteou 1IIlt'IK.. in p articular till' extent of it...·... an d Imlf-lift" and how tIl(' l'(J IT('spc Jlld i n~ a\"t' m~(' conce-ntrution dept'nds Oil tilt' first two fal 1or..33 or less. \ \ 'ilb d i¢tuxill.1 1'\. . " r "'. "'' ''r./''''''''10: II..(\ 5 4 A 5 B 4 3 3 2 2 ~ +. it is ~n'.wr.2.4!t"r ("~n~' <of ..IIIll'S ('. ... l.I... ..-\.':\' l' tI..is lilt' uuu-h simpler p nl('(.Hi TII~). bolus adminislr. R... ck-pe-nds on bul h In-.· ..lIll1u lalioll ..1t... and an'rd!!:l' amounts in tbt· IM at plate-an dqx'ml 011 lilt' fn 'tjllt ·' It)' o f i. mi nim um .. CHAPIH 7 sft·<ltl~· state tlt'ill.' + 11..n'./.\l1..li n ' ..to·.

llion of di~ IlJ'. FiWlrl' .lrly t"i de'lll for low fn'l IIWlldt'!> Ilf adm inistrat ion .. . Rate of Accumulation to Plateau TIlt' . · (Eq...'-1 which shnw tht· ratio of the' minimu m amoun t d u rin~ \'arilllls t1osill~ Intervals 10 ti lt' 1II11'(iIllU Ill amount OIl plan-au. ..n-huiw fn... Fur d i~ I .75 18 18 0 875 2A 24 30 30 OQ7 .dosh l~ Inn-rvul aftN tilt' .".'(llIt·nt" of ad ministratio n.t' n'('(1 for tilt' minimu m a moun ts o f di¢tosin in the IlIMJy.. allli mimuuun amounts (anti for tha i matter til(' amou nt at any ttnu.2.11 plait-au e dt'I)('lUb till fn.t) den-rmtucs lilt' small llu!1uatio!l in ti lt' ..1 16 d.tratI_ ..111'I01 11I1 of dm~ ill th l' hody at y.I' .\ . 6 ).\hlt' '. ti ll' (/("f'tmw!tlt .. is all index o f tilt' extent o f accamulatiou... AI'l.lto.J ly d nst'r 10 tilt' minnnum th an to tilt' maximum v alue. ob<.. ". kt ) the s nud h-r is tilt' 1I 11l't tmtioll . plall'au: 0.all st· of rd ali\"t'!y fn. Ih(.11 10 Tl lI' IllIalLlily.' \.app roach to tilt' plateau depends 5(l1 l'1~' Oil ti lt· d m ~' s h"lf-lifc·. In Ill' at . to Ill' al '..'..y . 1 'abl. _ Dally AtI. when then._ · ..u lrn.st'n 't· that it lak t·s I half-lift· (6 days ).'S!ltmdinJ' vuhu-s ut finn.I.ratio .l" Nymber 01 dosed M 0 1 1 0 11 2 2 0 21 3 3 02Q 6 6 05 12 12 0.1 p1a!c'au ) arc' H.. 1 00 [~~::~: :=~.... ant! so 0 11. Ihal is.] " or plcreo" "1.. That is. t!l(· maxhnutu..wit hin tilt' t10S irl~ intl 'n'al . S o h' th at til(' .\ <I..·ullll llalilJl'l is t·\!c·I\Si\'l· .'l.vtl l dosc·.\mOlIlII i n lilt' ht llly riws 011 mu ltiplt· dusill!o': ju st ilS it t1c)('s f(lllo\\in ~ a con staut -rate l..oll indr x (n.')% of tilt" plateau v ahie.h).l~l· amoun t ill ti lt' l)lllly in rlu. A«vmulation Index If tilt' amoun ts ut slt·ady sta h ' an ' comp an -dto till' l.allst· of its Inll ~ h.~n.I)('(... This is part kul.lrt.'(III('1I1 admi nistralioll . The frt"lII Il'1I1'y of ' achuinetrution al<.t~c· amounts.. Approech to PI.'(1 \\i th tilt' aH· ra~t· amollnt ill lilt' hody. and a\'t· r."'/ . -I). do.1\·t·TaJ!:I· is arit hll\('tk~. (3) Dt' fi nill~ Huc uanon as tlu..1 Il'l~ is IlIsl t'\'('I)' dosin~ Interval.. 9 when. -2 8 demonstrates how fluct uation . tln.9 1IlJ!: ill th e 11I1I1 1111' appm. 11l11s.'IJdi.lIl'nul.I. 0 OQA 1 . t .'(· of · 0 · l' al.'l)rn.t afh-r lilt' fin.v. or 6 t1 2 half-li\'l's ( 12 d a~ 's ) . is lilt' "\l·r.. DI.. ~ ~ •• • l_ ~ .1 dust ·.~dn (k "" 0. 11I'(.'aI N tln.llf-lift·..D).l. 7-1 . infus ion (C hap. ~n'll hy t ).\ . a\l·ra~e·..'(IIIt·II(' · of admluistration ( II .·l> lltllltlinJ' thnt·s 'Iftt·r u si ll~11' dust·.is alllllli 0.) is 9 . 111 dt·~n. TI ll' clala fC clih lr rilo'(in..I.5()~' of the value at plateau. in T . OS(·s. O!.CHAPTE P7 17 III·t·1I dilllillatc'(ll lI·fn rt· tilt' llt'xt dnst· is admuuste rcd . T h maximum ami m inimu m amou n ts an.lt'h til slt·ady 510111'. tln. . I/( I . iIIuslm tt' thi s IlIlinl. "I-'\(I holds true fur tilt' maximum (p mo f in Appc. i n takes a 1 1lJ!: tum.\ I. t "" I day).' I·al·h ' 't:IIIlI'J. or 12 dost·s. T'me (cioyl.2 turn-s tilt' values at tln..

. f or d i!.] TIll' F astest war to :It:llil'\"[ 11.nth' of ad lllinistr.v .tt i()n <lml mi~h l \\1.' in lht. .u linp. Th ese equattcus fonn tln. a da ily mai nu-nance doS(' of 0..'e s the therapeutic response: subsequent do .\i M if the mainlt' lI..v..o alld IIn. it t ' IKt ·S I half-lift· to ~II HIIt··half till' way (m ill n.amou nt '. For {'xamp lt. TIlt' manueuaucc dOM D. That is. I . for diwtoxin .n') IIIWday.50 mg t. r..gt· n '¢ lIlt'n l'( )lJsisti n~ of a priming duS( t'(llIal tn ""it"· tilt. i niliall~" followt'(l by 0 . 1 l00di09 do$9 .0 . to n. n it' fn "f!\I('IIl')' of admillislmtioll for stich d m~ 'o lITit·S fnllll 3 1i1l1t'~ a clay 10 unl't· tLeily. 3 relat e s to tilt· maximum . follo\\1. In this \\~d)" t'al'h patient is lit rolh'(! III till' inilial tllt'mpt'lltk dost. first o r initial t1o~t' is in h 'lItleti to lit. St.·lI l)('l-a1lt." nit' rano o f loading to mainteuarx-e doses depe-nds 011 the dos iJ. infusion . then ECI. Maintenance dose - [~~ng I'll e. In this eot. initial dust· ls often achmntsten-d in y divided doses.!linll.It is referred to as tilt' " ti mllll!.. nit' similarity ht'I\\1" '1I Eq s.tlosillp. Di .9 1lI~ . mp id ly ad lil.(!c"llto maintain that amount. tilt' initial dtlst· can he es firuated: ·.. · A tlnsa..body. For d i~t mj ll tilt. a ~n'n clc>St. and so nil .half· lift' and is equal to tilt· accumulation index.1 1Il~ requi res a le). tll('rajx 'util. 2 half-live-s 10 ~o three-quarters of tilt' way. n i l' n-lanouships ure tilt' S<lIIW. <r .eintt'!J.9 1lI ~ . a n ':lo.son 1Il ~ ("l (!wn 250 -mg edpsult>S) initially. al i lloll ~h IIII')" we-re dt'ri'1.Maintenance dose - fl 12 Thus.. ECJ.e ral procedu res an' follo\\ '('(1.rt-spun st.lift·. o r lomlttll! dm(·. lost du ring: tln. BIIATIONSHIP BETWEEN INITIAL AND MAINTENANCE DOSIS It miKhl Ill' I hl' r.' W plateau.{.'O Ill Ul UIl to dl'l t·nniut· tilt' mainlt·lIalll't..1II on <ld llli n i ~lt'ri np.-15 II\~ wo uld he 1 ' 0 d ist:uutinul' dm~ fo r I " 't''('11 (app mxill1ald y I half-Iifel lwfon.(II{'(' dus.. is constden-d to pn l\idC' (·fT 1 i\"(' annnucrobtal dm ~ ('o ll('t·nlm liolls. il is IlIOl"(' (.l' o f :150 to SOO mp.' lIlainillg at til(' end of tilt' d(Js ill ~ Interval .1therapeutic Tt'SponM' is obtained. hut till' t1i\idt'(l duSt' is (111ll1ll11ll1 ~i\"(' 11 t"'"('I)' 6 1101I ~ unnl till' desirt'f. f(lll(Jw~ (m ill Eq.'(IIL~in~ di fferent Ic'We .\it'\\' point o f l K " ' Imulatl ou. Tlu.ollahle sdlt'd ult· is .. itoxin it would lake about 12 r days to go 75% of lilt' WOol)' to tht' 1lI. j -J. tet r acwltnc has approxlman-ly anl'}-hour half·li fe in ma n. is Ihe dtiference b etween tilt' In. As with i. \\1ll'n tilt. V /.une prind plt· applit's to an i l1(:n '. (TIlt' s..U IlOU Il I al plall'. lustead of t1t·t l'nllin i ll~ the loadi ng. ~ Interval and Ilu. rolfe uf di~toxi Tl udmiuistrat iou. lll.-.1 in Fi ~ .'(1 1Iy 2. II indica tes Ihl' dost· 1J("l. 3 and II sho uld ht· 1I01t'(1.J.Iwart elf multiple-dose d m ~ atl lll in i ~t r.' by rt'plad n~ d n lp. f(·pt·t it i\"t·I~·. illtl'l'"tl. 11('('(1 for a twofohl n -dnct ton in tlu. to cs tahllsh till' n -quin -d amo unt of di~tm:ill ill til(' body on till' fi rst day.ldin~ eloS(' nf 0. dow «'ll" in'll 10 sustain a t1lt'rapt' lll k amount in ' · tlu.Lw in tht.p(·t1l kall~· dt'simhlt.(· alld <l ' tlclSillJt inlt'n" of O llt· half-lift· <In ' l'()lI\"t'nit'lIt for t1 m ~s " itl. l1l(·T(·forl·..AI.initial dost.(·I)· half. dost·. tilt' patient would requi n . dost· wln-u tilt' mai nteuanee do st· is ~ \"(' n .." ) e- l 1 II Likt.III<-'" dost· is known. n-quin-d. .dosa~{' n'¢lIlt'li equations. If the maxim um amount 'own' p nt into the hody in il iall~·.l~ she"'1. J(. hal f-lin 's bdw("l'1l Ii and 24 dl hr .un to liAS 1llJ..mp. therefore..II CHAPTH l Change in Regimen nil ' SUppOM' thai the decision is lUoult· tn helve till' amount flf di ~l oxill in lilt' IlCKly at plait-ail .-s maintain tl a.. Frmu tlu.l lh{· . and 1I dose.1 1lI~ daily. 1"t.i llit iat i ll~ till ' rt'(IUl'\'(1 mil' of aduunistrution .

1 K . " I. with a hiWI the rapeutic ludex 'S 11m)' lx. .. A t1mg \\i tll a low t1w rapt. such is often 1I0t th e l-. !t' nallt'l' dos(' n-qnin-dto ensure that drug in the hody stays above a minimum I'lT t'l1i\'I' \'alllt.. ... ld.. for which larxt' r do l't's sluw l!il\lri c e lllpt)ing am i . th e ~rt'ah' r is lilt' main.. ('1 .. . ll. lr.'" " f II" .. t'.l.'.~( I \('l1 d t · ..dosin~ illlt. for pmlript)'lilll'. n "·n·aft..\(' !!rt'i\tN than tilt' mumtenauce dosl' seems ilp pmp riah' for tlm.. an anal.. M.' 1. ('(.·1·1)· J to 3 halfh li\'l's. t = 1 day )..glllant (..t nf 111r. HaH-lives L Than 30 Min ess C reat di llklllt~· is l' lll~ )II n tt'rt'1 ! in tl')ill~ to maintain tlu-rapeuttc con cem runons nf lillt'h dm.is tha t of warfarin (hal f.. !!rt'ah 'r th an 24 hr.(IIlS why this is j. t·i~..linll ur SC M Ill1/: illill. II. tlu-rupe -ut ic ccncenr rancus are listl'll in Tabh.. this rt~ l1Ie ll is oftt'l\ Impractical..'u tic index IIII1St I'M' ~\"t' ll appr ocIllat t'!~· l'H'l")' hal f..·n·. 0 0 0 - ~C. DmJ.L\t. Sm.lo(. .1 tl.elopment o f therapeuttc I·ITI'l:1s is also dt'la)"t'll.gt'liid antip)Tt't il' \\i d l a half-life o f 4 ~ hr...oto-. o r uron.. n-.. = JJ.In-quently..(1.example o f a dr u for which till' dosing interval (4 10 fi Ilr ) is g mallYtillll's l"lI~N than its half-lift' (app rm imatd y 3() min )..tiM! 2. Half-lives 8etwftn 30 M and 8 Hr in Fo r sud l d m gli..\ t.'\.lS a half·lifl' o f app m xilllilh 'ly 3() min. tilt" mos t eonuuun ildn'rst ' l'fT t'(1s art' !!a.gh illlIl low therapeutic illdit'l's am ! wit h vuncus half-lin 's. which s.'5 I 0 "" ."l1. 1 "... t'fTt'l..·r.\ ." I.h it d m ~ must hI:' d tllt' r tnfuscd or t1i S(~lrt ll'll uull'lis tnn-nntuent concvntrut ions are pernussihh-. p1..g with a low therapeutic Index.NS •• rt·li!'H. I• • ~' Ii " .u"1 " loIi nh ·I...(an t'l'1 unttdcp rc ssant with a half·life of 7~ h r). . \\1"'" ..In· II.JI~.'1:lin'ly.... Lidocaine.. or 1' \'1'11 It'sS frt'q llt'ntly. .· '"Ill" ' .0". I' "i wit h bu lh medium to hi. 1 " ..... I]..\tmintes tillal reactions.1 ).. Such n-act ums ilia)" lxilll"n 'iL if tilt' llM iul! dl l\(... A ( Im~ \\1111 a hi.' is thn 'l' to fou r times the mainteuaure dOSt' (JJ..\ ".~ 0 0 250 ...... for wh it-h tht· i1l1til1M .~' A. 0 -'" E B j" il i<al l~'''t' "'If .g Tlu s is pa rt il"tI la rl~' true fllr a d m .I"· ..g rt'¢lIl('llli thai ill'!lit. ."...(! only II{' administe-red (IIlt't... 0 I... fur examph-..~ ~ 500 A ~ E ..~. h. allt! od ll'r t1 m!!s.r 1 1. il taL. (If Ih.. t \ '..1I ) .l in 's. MAINTENANCE Of ORUG IN TNE TNERAPEUTIC RANGE J)OS<!. I't'nidll ill is a notahh.on' I'''''''· 1i. For piroxicam. There art' il varid y e of n'<!j.i ""'tl·I~· ..g iLslminh's linal ad hit)" (im tid lolint'l}. tilt' llliljor t'1 ll\Sitll'riltiolls an ' tln-rape -utk.~ . k-ss th an 3 hr.d "~1... bill till' ~n'ilt N tln.index am ! t'l)lln' nil'nt1' of dosin.. "Pf' nn..·.~w n It'sS Ire-que-ntlv.2 for tlmJ. 111t' t1ti'>t' ~wn ~rt'al l)' ('U1'l'l!S that rt'1 luirt'1l to ~idtl phsma conccutrnttons of antihiut il" 1'1 ll1i\'alt'nt to tilt' mluimum inhihil ol')' (111It'l'ntmtioll for most mlt'm o rxani sllls. Aitholll!h a load illl! or initial dn." intll'x llt'l....-s .lift'.gs \\i th half·lives lonK r than 24 hr.lT develops slowl)" wit h time..i .• ln-parin.·f" . A t1linl example is th at o f prctnpryltm. " 0 0 8 16 Hours 24 32 . Fo r d nl ~s wi th \"('1')' short 10 short half-lh "t"S.1 it·. IIslIall)" fo r 2 to 3 weeks . half.g.r (3 I" 4 1 h. 7.... Allotllt'r exampk. the de.ou i~ r r. or b WH'n h~' Iufuston. or wi th w ry long . Sl". .g tlwrapl·ul i(.!t.Jf·l"•.&1..lmini. am'M.life = 37 hr ).. Furthermore.. resll1till ~ in slowe r am! mort" erratic ubric sorp tio ll of tlli..CHAPTER 7 MUl III'tfOOSE lIEGME.'·' 1 dill" in II. e " e ~ .

the dnl~ uccu nmlates to tllt'mpt'uti c levels..A.tAl..1 <1 l1equile$cOleful conlfal... .. administ ra tion (lillO(' lIai])'" is (''Il n n ' n it'n l and 11 promote s paUl'lIt ccmphance..... mc.. bulle» Irequenlly ....$~oct>c. I'oIT!:r... and the mngt' of plasm a couccntr auons asso ciated with tilt" treat "W ilt of ca rdiac arrh~1 Iun ia. Nllfop'u»ide l idocom e Theophyll.1Q Gf:I\lRAI... _ ~".5.. . in which case several doses Illay Ill..nfu$i()ll 1-2 ...-.. a.tI.. __ """ .li~...... I ____ .:ts to large o ral doses (ga.... t1WIl. tlooo/"""'~ " ..c sallie . once fQxl('Iy .1 half-lin 's greater than I <1.ro os OOSNO oose """'""'" "-"'U..""" . Thi s d nl ~ must he.. Ot lit'n\ist' th e initial and lIlai nteuallt"t' do~'s . • •.l! dose must he twice the maiuteuauce <lO til(' minimum and maximum amounts st': in lill' hod)' an' equivalent 10 One and twu mai ntenauce closes ..oL Occcececr gIven once Nolfogtveefln Cephalo..."" conlfol infu$iOl\. rt> spt't1:i\'t'ly..<1)'.d....... conlfolled-releo!lot! IormvlatlOO 8-24 hi >241'1f 2-' >2 0..*..li fc . is on1 a). .is des m -d...." by . De..... ulIsly mentioned.. 1-2 2 >2 Ccrdcce lor com.Hf! R...."•• 7-2.... If all inlllll'tliah' the rapeutic d Tt't1 is dt-sir('t l... _"'0 <> io<Jd.... """'0 HAl.' Ilt'<. HaK-U·. "'-.g doM doooogo . ct Side t'fft'<..$ peodcced drugcooceeeosce cod IQxic'lydeclu-..bOlly may I\('t'('ssitate a slow accumulation....r do.90 CHAPIH 7 has a half· life of 90 min. 3-<> 3-8 hr 8-24 hf >24h..1 """" . .rwl' 0'9 'IO><.o ut thn -efold..... c... .. n it' decision whether or not to WH' la~I'r initial t\Ost'S is oftl' n a pra ical matter.. .ooce doM ""'"' doug> ....fQnl-fO!e odmmis/l'ollOn ond/or lhorHe<m lhe<apy 10 be gIvenany leu aken rhon fNefY 3 half. drug muSI hove '>It!fy high lhe<apeut... HaH-Uves BetwHft 8 and 24 Hr Here.....eq.kh a close is ~\"l"1I ('\'('1')' Imlf. . .. the iniH. tru illft's ti nal side efft 't1 s) or to acute-ly hi~1t couce-utra\ tion s of dmg in tln.tic e-. ~.porl~ 1-3 1 T etracycl.r..'. t ill ' most convenien t and dt'simhll' n~ IlWIl is o m' in wt.c index V~ommon cod ifObie 'eglmen... ""'" fQ floed'um High ""WI"".n ..'t'ssal)' lx-fon...._IIC • . Once dolly ..I.TOCf NT\OJ... or leu I."ity... 1"""'. If im media te achievement o f steady stan....e ~ C1a.~ .._•• M. a tln-rape-uttc dose neetls to he ~\l'n init ially...lrt't l. 11~6$ 3-6 OO!l6$ pel . No! 0 callClidare excepl 011. CCWME NlS Dl1VG !w.ne J-8 h.' ¢WII by Infusion )" to ensure pm]oll gl'(! supp ression of arrh~1 111 11 i.¥Us <30 mIn 30mmlOJh.. prt'\. '..'\& Sulfamerhoxozole ChloroqUIne Iwppre»ion malario) <I weeUy..Jyneed aI IMIO! ceee fQ be much glea!el !han ma'"" eocec e dose <30 min 30 min to 3 h.L" undmmtmal tox ic.1.. Grea'er Than 24 Hr For drugs \\.

lia tt"ly aftN tilt" next d ust....u slt'ady st.. hut tilt' amoun ts o f them in tilt' bod y wit]! tiun.4 39 .us for all t1lf't'(.lnolamillt ' is minimal.. Tn summa rize l ilt' fnn~(Jin~ di scu ssion .'spt't.. is th lls n '.. 2. n..1in'[y . 7-3 ...' Fo r It'trat) 'd ille tln.. """... alld '·\ .' kh-ntlcal ..first in tr-rvu]. .'u nd int e rval. a nd Iln-ir nd l dusa~t· rt""Il'IIS ~hl 'l l in Tahlt.lin illg: a t till' end of r-ach <losing: int e""ill is 0. I.')(1 mg returns t he It.S H+ 37. . and a period of 4 half-lives is Hi h r. FiWm ' 7-. . conslderutiou sho uld first lit' ~\"('n to sc ahng tlu.. Tilt. Dm i ll~ inh''''. A••••• ef D-./.6 ' ··O.nW~ \ ( III).t>.llli n ~ t1ost . dmj.. Ixxly at plateau an' 40 1II ..dc )Si n~ Inlt·" a I. At l ilt' endof rln..lIltllmu illt' in lilt' hellly wit h tunc.-mfa.. '~ 360 22 500 Pbeoobo.. -I . or Dow 1 2 Tillw (I.. Fi~lI n' i -l is a sketch o f tlu-a mounts of pllt'nylpmp.".l1 .. .. a....7-4. ' fACTION Af H'() Of .4y 1..S('t.. At t he llly end tln..1 . tilt' "allies of A . 0 A ...l\Slllllt'{1.5.m a rt'. .25 .hod y should II{' scaled to the maximum amount al s l t"m l~' stan.. 7-3.ue.MUTIPLEOOSE RfGINfNS . tilt' nasal l"tlllgt'sta ni pllt'nylpmpiulnlamillt'.. ...5 9 .. and 10 mg. As wit h allY graph.AGf: "'I ADY SIE ST "'TE& ""'" ~11rle oc.buc! 540 40 556 " .a mo un l in the htxly im mediately afh-r tilt' fi rst dose is 500 mg.. 7-. ~"'~_-I·O". by which tinu. .a n ' l'I. Tilt' initial amount. tllt' plalt'au is virtually achteved..3. Jjsle<! in T ahle 7-1 art' Iht.. tilt' average amounts . 1.ed. Xow couskh-r the sketch had 110 le ).::) 7..l(lily \ isu al i1. am i so Oil (cu rve R of Fi~.II{'t.roe 05 025 0901.__ 30 ( 111~) .A. tilt' fruct ion rem.unoun t ill tilt' IM illlllll't..5 half-Iiw s. {'OrTI' polJ(ling F s ract ions of lilt' initial amo un t rt' maill inp. 11lt· e-xplauat iou is n '. 111{' dust'S o f pllt'llylp mpa uola mint' "S and pllt'lIo hilrlJital an' alsu tilt' sa me . 500 30 30 250 30 30 8 8 8 8 4 100 .is 2... a tilt' an tu-pilept je agt"111 plwnobarbita ..:~ """"'"" '""" SlAtE' ".. Iustant aneo us am i complete absorption is .' "''o'f 9 .' tillS(' of 2.')(1 Ill~. all.'lI ' ~\·t 'll.5 II1R. woul d th en decline to 125 III ~ al till' r-nd of the.1. .". al lilt' end of a dosing interv ul. . unillg is 0. . a nd th e amount then-fen... A maintt'mtlll't.plat eau is a<h it. 1 lfi IH By tilt' third doS(' (24 hr].3)...axes. t-urve.\(lil~' drawn. 111t' amount uf d m~ in tlu..'el 10 sou Illg uncl so OIl ... 111(' fraction P n 'IIl....'rtai llly 1101. .. ccusklc r tilt' a ntihiotie dm ~ te tracycline. ST ATE~ '""" 250 10 526 prop:mohn. ' Fo r phe nylp ropanola millt' the maxi mum and minim um amoun ts in 11. I 1i7 1JI~ \m uld n-mam .1 \\ i lll a ske-tch...(.1. tilt' acoumulanon o f pll('nylpm p. anti tile' maximum ami mtutm um values . 01••• 1. therefore.Ow.. IX'i n ~ gin'lI en'l')' h \1I half-lives. \\'OlIld ht' 37.')() m~. 111(' tlme axis sho ilid II{' scah-dto -t In .l't.) ..4 .

...'al' . 0200 I ' 00 o >----------~ o 5 10 15 . to tI.~ ..• IM with lim... I1.rf·lifl'.In''' 1ll Ilf 1 p1. '0(.it. alid ~ ) 1111.·J:.!.i m "t. n M'na.. 1""'1>.u". lic. TIlt' ft>lrilt.'K"'''' of ".. IJc".>6 m~) and the Imlf.. of 311 "'l/.. i~ .W fi Accumulatio n the-n IX '('urS un til till o 5. '''III ... · 11.92 CHAPTER 7 TIlt' s anu.. t'lT('(1i\"('.:.l \\i ll .".. 111t' a mo unts in th e bodv a l IOU h r Is 1I 11l·-ha lf Hf till' stl'ild"-sfll!t' amount. tI. 60Il hit... tiM . 1..>/. ·.'~"S (Fig. tilt' fraction re maining is O.d i ll II. II.l(:timJi~·... From tln. .. t"l... 'll tm!in llS is ' 11\('slionahlt."...."""." ini" ulI" .nl at plat eau (5.. SIe-'dy·stale Values: - 5. 7-5.".'lIl ~I'Still ~ n llll ....u't" ~1I""1' '''' tI ri J.'t·S It d raluatim lly cliIT (I' n l result .1tI. " 'jill plu-n... <Il 'sirahlt'.. <lmll' 1. rcgtmen W"t:s rtse to la"Rc flllduat iolls that may lit..1<:11 interval is equal to til(' dust" am i til(' amount ill tilt' !Indy at s steadv state is the re for e ahout 19lillll" till' <10 '\(' .ni'''· in thi' ". . l~df·bf. ........·.... .of :)II lUI( "I... JWoooOl.. llll' maintenance o r h i~ .101"h"" p L..11 " .J:...dosagl' n -gill1('l1 fur pl lt'llol l<lrlJital pn Klll<. hlOlti" n i.I. Tilt. . 7-4 . The cu rve is sim ilar to thalohlaillt'i..o-' ~ n I» .....t.t>..." . i~ Lu.1% losl in ('..· .. 10". t !tNt > is Iiltl... clinical imp lications or tllt'St...') ...1..' 'nt h ti.".·mlll' 1.'W" 40 30 20 10 o o 8 16 24 Hours 32 40 tllC ...·td. I. dt"(..ullm. 4 '~'" P tn·..... " f II.. Sl.·litw rcgtnwn is dt'siJtIl{"(l lo uttuiu and lIIainlainlllt'rltpt'nl k levels. 61i>.• <lII...·...l..1.....I.....' < ~ "i "!t .(l ll.... Tolerance to tile t1m~ ek-e-lops rt'ad il)'. s1<rfd..iti. illK int.n. ''''' 'f)' ~ "•..rim t'lIS art' manifold..· 1<"'1: .' ~t ..li ft" it is appan'lIl Ihat a sk..• . t ...·.-. 41 in"..calculated "aim' uftlll' maxim um .m t <of p}. ..cr .t ". 'h. and at 200 hr the lew" is 75% o f the piatt'au amount.">6 allI l :'S2fi n.c.. j .·.' n 1.1 ' ('(1to fiOO mg and to aho ut 15 dl. til II .·loti". nf II. The pht'llylpmpa nolamint. constantrate Infuslou .t~ I" . ...I ~.' IWt"(! to coushk-r tilt" min or lIU l1uations. Pr..'' .I t . 1 1 . At t' the end of cad i dnsi n~ Interva l..1).....'!l hr.·td l mu st lit. ." of al'l'l"nlll.· I.n i..n~1 ......

.. n KK.... ·..·ntpt ·"tit.. ..single (l uly 30()· mg dose produce s a much 1 0wN min imum concent ra tiuu than omission of a l{){)·mg dose for twn reasons.) is -.Uld a laTgt· priming doS(·.rt.'~" K~·lI t 1'lttic .·..il ltlo-.oI<i'''1it' pc·I1Ip'. : ...."tit-..appmpriale n '¢ I1 U'lI depends 011 whether tile drug is 1I!it'(1 for sedation tIT "-'_ .Ii..... 1 1"'" " .wi'....(fI.Ie. 7 I" 2n II.'t · s.-.:..'o· 1£0') G. ct. \..·).'. a . • . First. PlUM'1 A: Who'll " 1 .. tI.L. consecut iw' doses of the g· lulIl rly n "¢lI1t'JI (the t'1luivalt'n l 11' of a m w(·... ull ~ ill • t"'''1I:1...... p. ....(' is till' tlt.I... If 3 ". ·. a "' i.... chronic administmtillll u f pheuobarhital tim"..·h... 111t' impad o f it missed doS(' is sho\\11 ill F ig:.l....." ..· ~~lrt · " * Lph. -d ..... .d T t'("! dt·w lops wil h lilll P ..· 1e.'''d<. i. .ltin. " Iit..I tl lt.... ." of 2... total dai ly dose is tilt' same..• ('o ' Klilio m r..sioll of it .) . 7-fi fo r Tt'¢ mt'n s of 30()' 1llg: (JJl('(' daily and WO... 1.. .lily <lOst·) does not produce a Iowa concent ration as tilt' omts ston of a sing l....1)' " h...' ti lllt' S dailv is IlIl Jl( '(.i"'n ." "'K~' tlaily' I" mainlai" th.I I I':. ~ •. ill that lolt'r-IIl(. . .1111).. .J.. " .... . .· u" -' n ...-n.... "..~' mi.df·lif...· L.54:U2·W.:}"'!VI.1):t·r II... IW...5 11f. In'1I: with a 1 I'. dt'(.l-(' in ('ae ll dose) lIlay not improve Illt' matntenance o f \ l" Olln'llt ratio ns wirlnu th t... h·.g 10 5 ~ € 10 0 ~ ~ . I.... l. 1I"' '''' I'''"Iil: . i.... mi" i". A B 20 20 ~ ~ 15 ~ ~ 11 u 0 ~ ~ 0 <£ E 15 .·I0-'" tilt· Ie".11 ' . 11. ar\".....tl ic"....III'WS 10 0 ~Tt'a l a cent ral dep n 'ss in' t·ITt'(. Thus..u ...LuIMI Ii".·n l r-.il..1 fnll" ... As an alll it1lilt·pti c.>1 ·"' 1 "t.7 fIll: i... FrUin ~ kill il: pc pc ·i"' .' cof 1.d"•• " 111"" II. . u 0 E ~ ~ E ~ i1.I. omitting: a s i n~lt' tinS(' du ring: a U ll(~ ' (bily n-gtnu-n lIlay ha\'t' a much g n'atl'T Impact o n therapeuttc n ·spol\St· than oTJlilli ng:an 1'l-1lOurly dOM... Fo r !it'(!. tln.s 1/:n -.Lt. TI....IIt..1".... (•• . 10....I>.illi.. ....till .5 mw l ~" .... 3... "f2.1. O mis. Second. d Tl'(1 i\"(' range.• tht .· s dailv do!it. 0 0 24 Hours -" c. ..Ic "'" "'i •... :"0:(1 I hat ('\l'1I omitt ing t 11Tt'(.m ...•tah· mlllti. .d.1i'.'(11.' '' ·''I ...tII La{·k of « nnpltaucc is a major problem ill pharmacotherapy. ''''!t'-".• ""ltl l h..}M • that ... III.I . ·. a hltling tluS(' may Ix' 1 appropriate... ~ 5 0 48 72 0 24 Hours 48 72 1'1..1hn. >l I1I>1i.• A pllitn'lO. <:' ".9 .C HAPIEIl 7 barbitaltln. In hot h n '¢mt'lIs tilt.. howe wr.. 'Ot ·lll ntlic....I Ie"'1I..is rk-sirahh-." I.....!>: . ly.! (o Ie.. '11..('(.'t~l-siu llal omitt ed d nS{ or fajllln' lo ta ke several lUIl'i.. 7..t..... ' Ht"¢Tl1t'lIs " f multiple daily d n"t·s teml to p n klu{'(' lUt'a ter frequencies of missed duS('s than th oM' ill whi<'h a d mg is taken (l m't ' o r twice daily.1...Luly.. a lJ ...11. .l~. 1.ing Ihl' fn'1IIlt'IIl)' u f · s dosillg: (with lurn 'spo lltliug: inl'n '...' ·hic 1art..l rih" Ii.•.'.. OI K't· dallv administrat ion mav lead 10 la-tt er 1:1I<l111't· S of com pliance. .......ttioll. ' til till" !it'(I. < mii'..' · ("(·" I.·.....ml it·p ilt·pl k-. l1 w 1II0 F si n-queut patten! o f nOllu lmpliau l..i.mg ('\ ·t·!) · Ii h r.. ..· . n.uly n '¢mt'u . fn'(I''' '''1 tI..J Jo. til(' amount lost d uring:till' If)n~N lnterv a l (If tilt' fomu-r r~ II1I 'n is gn ·ull'T.. ." " 1/: .. u K..lic". "'i.7-6..·u tin' do!it'S.· 1..·)11.. li". . A lt l u lll~h IlTt'\illllSly pn-scnbcd as such...~ " "' •• "f . ..·" a .' •.... I I ~ ilIltl a '.1. I.Ii • ..d l l..· "f . finn mg.· lr"f"l'-1 "f a ".. (.100..I Ii: \\ l "'n a 11X1·n.. i ..• "f .it " r t l. t he aW rdgl' millimum couccntranou a t ste ady sta te is lowe r for li lt' n!l{'(' d. However. 10..". d... n'.o missio n u f a loadi ll ~ do·. " .. P.t1. (-.. tI.

oceu p anon ( If path-ut.· to \1lriatiollS in ahst'f)Jtiun ratt'. hul nol ill hioavailahili ly.].m'S pollt li n~ t"lluatiom dt'fi n i n~ amollllt IIY\ul ulllt' Ilf di. (If dn l~ absorpttou alTt't. . sltMl)t'ss Plasma Concentration VHSUS Amounl in Body Dll ri u~ ltIultiplt· dnsiuv. » ilT ·lIt. tilt' p l:l\ll\ ll ('()Jlt't·lltr. btrIYascvlar Administration Tln.1'''1. ht.an ' m~t· plateau {'(111(. or t lt lS. at ("l itlally s!l.t\~l'it.'a nS(' " the awrd~l' amount lutlu.·lin·I~·. for phenobarbital.llll. As illustmlt'll in Fi. 111{. 'n . I' mhl l'llls n-lated toum-qual {lost's "'I t! dusill~ iutervals ami to missed dust's ure coer-red in C hap. 1l\ I. t ch n mk.tlJt'(· rt'lIlaiu ('(lIlst. {"f)n.tlt·. and rt'l·tal ) utiministra tillll of d nl~ n-qulres an add('t. hilt va hlt' of.. ho lu" iuje-c ions .( .st.t' {'llll(.ttio1lShips of Eqs. 11. T hu s.tlt-lIlah 'l l llsin.l' " alf· lift· of tilt· t1 m.-ntration.tru i nh's t i l lill trotti . til(' avt' mV.i s lilt' dt·.till appl~·. SIIIIt:'lItalll'tlll\ [s.l\i rnmn s n lllt'('ntrd!iollS ma.sidt'ratioll Illl\ lx-eu J'iH'n p rimarily to ti lt' amount lIf drug ill tilt' hody follo\\in~ mult iple l.ofpuh·ntial lllt'r. PRACTICAL ASPECTS OF MUlT IPlE·OOSE AOMINISTRATION So far.tIld tlMt ill p1:t ma 1"I(('s tilllt'.t tilt' t'(·!i pmhab ilil)' o f l'tlllJ p lia u l'l' a'Xu ITlt'1I1s in f<l\ll f o f mort' f ({'(jl lt'lI! dn" i n ~ . with a half-lift.• wln-n !imi!t"ll hy tilt' transit tim t· within tht' ~.· .ad ministm.l'>('ular administrunon.·ullIulatiol\ of d m~.. of . In tilt' b ttt'r ( 'IN'.· m~l' pl. o r tln-ir equivale-nt. as "talt'l l p n'\iousl~· . En. major d ifTt·rt·m.1 1I.t dos i ll ~ inn-real.•• The ill l 'n 'il '>t't! CHAPTE R7 by olin' daily dm i ll~ is ("OUlIlt' rt't ! hy kim'fic \\ 'hen.g.. 1-:'1\ ' I to -I appl~' to t·xtr..g.v . Concentranou \ I olli torill ~.i1ient ) am i t!lO rt' lal in~ to tilt" pll<l nn. lilwliholJ of ("Il1lip lia lJl . 19). ob st·l"\'(·d m..·iah ly .t1ioll is ilpplit'ilblt· to any ".hoJ)' at stt-ady sta le is SSfi 1IlJ. tilt' (. (' .c. a{1..l{'t"'l. mn'ntralioll 11m.K·()d~ll a lll i{' d mrad t'ri"ti{"!i of 11 dnl ~ (sh "t·p llt·ss St' ll' of ("f)IJ{'t'lJlrdtioll-n'S!ll llJ\t' cu rves . IIlt't llllt:l u f iltim illistmt iuli .' rt'!atillnships ullow t'slimarion of tilt' un·m. Ot her den-rnunant s of th e opttmal rt'J~hm' ll Illc!lI(lt.g 'alt-r lhan t! UN ' (1tlt·lIl. T Ilt' t'xt" ptiun is \\'11t'1i ah"u rpt inl\ Ix'('u l!wS so ~ 1(Jw rhat then. app n't. I>j"trihlllion t'tillilihri ullI Ix·t"'t't·n d m~ in ti lt' ti"SUt·s . In p r act ice.7.ltl t. not l i lt' rt'Spt't. 7.· tn tI.'rsisl and un.mt wid l Ixltll tilllt· and dust. n·btin.. hi' (·.('lIll.(' d (M'n 'n t)' illlt i llillu rt· of di M':L""' . tilt' omissluu of a si ll~lt· d uly dost· o f 911 Ill~ O f a n S-ho urly do !\( of 30 111~ is o f m inor i lll p ortalll 'l' 1"-"<.l~t· form . a co rrection mu st hI' nuul c 0 if hinl1\·ailah ilit)· is It'S" than I . !It 'NlIlill ily of p.' J'iWlI illfn "llllt·utly. \ \ 'ln-n ahst''lltinn conttnues t h rtlll~holli .t'tl l!1N.Spl'(·ts an ' lIlIW considered.ga "i n~lt· diN' unl"Ill. Ilu-n tilt' n ·l. a {'(1TI(litinn similar 1 i. Inst·lIsilin. bolus adm imstrutiou. . 1I11ly d nl ~ couccut rauon in plasma or in blood r-an Ill' measun-d and not amou nt of d nl ~ in tilt' Ixxly. or 10I1 ~t· r ..ttlnl\ (~m lx ' t~\I('lI l a h't l at allY tilllt· hy d i\i din v..." l.v.n so. fact ors such . 111t' a\"t. 1It'1l tilt ' <Im~ prt M:lutis 111 an.L\ those a IT Ilj.h't l hy d i\ idi ll ~ E(ls. 7.·ntr. < bys.(·lltm tillll. of t ·xt r.].V. -ut it..' s S("t'n follO\\in.oral (also iut rumuscular [Lm. 1ft.is illslllTk it'nt ttnu.t tlw mt io o f tilt' t1osil l~ in terval 10 half-lift" tilt" k-ss tilt" ki m't it.·s 1ll.l.trl. l1ms. 111 dlt' mpt-'util' imll. impal1 u f a mis<.ttiu ll at pbtt'lm is rt·btivt'l.S )..t rihlltillll.. tilt' smallt.tioll Is usually hy till' o ml route.·tWt't·l\ t ht ' lII t·n alm"" t Ilisuppt.for comph-te abso rption.g Ell' ~ .. Furthr-rmon-.t (MO(' Fi~. \\i d th of tllt'rapt'lIti(' "ind(lw).·rtl at pblt'1 ". pnJ\idl'<! that ahsorptioll has t""st'n tially t'n <l("l i within a small frati iol\ of a t111\in~ Inn-real.1 intervals.l\·. -: ami k . For exam ple. T Ilt..tilt" opunnun rt WIIII' Jj lit·s <!t'IWll{ls 0 11 mall)' factors. I 1111113 n hy \ ' ( St 't' C hap.is t'(ltl.: ilS h ioa\1lilahilily illltl dt·ar.gt· p late-au amount in tI "'l x xl~' and tln.·lIr at platt'all wllt'll tilt' pn xllll'fs <trt' ~\ 't ' n frt"ll" t·ntl.'. l!lt' ( ' III( .lItt'.111111inisft'n'll d m~ prud mis J'iH'1l n 'pt'lIlt't U tlt·lll·nds ou tilt' fn '(I"t'lIl'y " uf tln-ir adnnnist ruhon..l<1 of <IilT (' t-n'n('("" ill absorption ki m-t ics . " i lh ('xlt'nsi".gn 't· uf lInl1l1atinn around. <l. «leorpnon. lnucai..1 stt'p .

."....-...ti. l. " 'Ki lla linn " f .....-t.. I. TIlt" maximum d()si ll ~ int e-rval..t.t.." < Iunull ""..s DESIGN Of DOSAGE REGIMENS fROM PLASMA CONCENTRATIONS ().·" tv.6 ~ ~ • 2 0 0 6 • 2 0 12 Hours • 2 0 0 6 18 2' 12 Hours 18 2' 0 Hours 6 ..L J."tr.""" .n ~". oE ~ " ". ...... t 1l2 .ltil't.... TIl(' \\i lldnw is dl' filll'ti hy a IOWt' f limit (C" .· .I...CHAPTE R7 . .. (\" ft 1"'.."'.t pl.. ad1l1i nis..L"...\ /.n " t 'N) the' ..".. \\i lh in till' dosillJ. "".·1) i..I 16 \ \ 1)('11 J)... )s. 13.....1." '(I Il<'n· f"f ....lit ·ntr.: 13 whe-n . n . ~·r." .....t..11. .... By n'arr:Ill~I'IlI(' 1l 1 of Eq....nIL....·utk· i" 'I_i .·'.." wI. inl:.tl. 111 lit' desiWIt't1to maintain ceuneru rutlons wtthm a tht ·mpt·lIlic w indow.. 1"'''1>1.1I11. an' l:i" 'T1 Iufn-. 'i ll:' 7_7. in tl... ." .69.. ...1 ). 1 ". and maximum maintenance dns('. ti lt' value of T is . is C.."""" ran he n'ad ily computed frn m tln-se.~ 1111. ' 111t·".·.a...0 8 ~~ u 0 0 2.· .1:""" is lilt' maximum lime Inn-rcul ove r which tl w~' Ilppt'r and IO\ \'t"f conccntruuons cnn oc cu r.·1) "Ill I · It m...IK r 1 ' a-'l.ll.. tha t can 1)(' ¢\'(' II ('\'(' 1) ' T""". T".'tvo.) and an upIX'r limil (C . 14 and. D \I. D.... V 15 TIlt' n ) rn'sp0l1(li ll~ maximum mainlemlllt't' dose. Imm 11\l' rdaliollShip.· n ·bti ".. ....ll ~ ( n~' t 1"'..L.. t1I' l111t'tl by 17 10 10 8 6 10 8 6 . Il~ a 'i"~'" .. k ::: Cl . ·1 I:n·..... V\I ..." ...tt' n'(l t " l ' f)' T .tr.~t· n '¢IlIt' Ii S {'....: interval . f"lI'.1.. then. · f" n.....ts au a\"l' rJ...·r.. · .n fn~ II l<·. I ru~ pn "ha.. is..'''' r.. ' pur" p".~l' n Jll('('ulmlioll pmdut't'tl . ).limits llS follow....

In IX approaches ..holll tilt' dos illV.. initially.' dl'silQlt't) hy Slotting ti ll' d ll~ i ll V. Bot h values ilia)' II( '('() to be atljllsh"l:! to llIalt· the fn"({'lt"lll) ' (If administm tion coowment for pat il'llt (1)m p limlt1' and 10 accommodate tilt' tk)S(· streng hs o f the dnl ~ p roduct s available. This . C < met hod o f rtOWlllt'1l dl'siRll It·mL..an'ra~l' o largt·h·d conccn tratlou 10 lx. less than tilt.. res lllt i ll~ in the st' U i ll~ o f tln.· that concentrations remai n within the t1lt'mpl'utic wtudow.. maxi mum dt'fill('! ill EfJ....I k 21 O n d lllosing a conwment Interval. depcuds 011 how aggn'Ssiwly Oil(' wishe s 10 PUrsllf ' therapy bul usually ltes in till' upP"'r ha lf o f till' t lu-rapeutie wi ndo w .' U p -ak conceutruhon ..1 at plan-au 10 bt· C. lI a\i ll ~ chosen a conventeut dosi ng iIlIN'" !. 15 ) and tilt" ('()rrespond ing tnalnteuauce dose.I.(or If'ss) \igomllS Illf'ra py is desi red. allows till' grt'ak sl possible dosi ng Interval.. I i ." k concentranon..../C.. However. lth couce nt rat tous an:' maintained wi thin th e tlw mpl'lI til' window thruuV.. 16 ) mil)' nol Ill' practi cal. interval. MaillttfKlMe of a Peak CHc:entrRtton TIlt' second approadl 10 till' design o f dOsagl' rt1Q lIIl'lIS is based on tln.. The maxtmum dos ing Interval is: MoJilim um dosi ng interval - I'IC.IIt'sin' 10 maintain a gi\1. AI • or to maintai n a pl.. this ratio tn Efl.-ious om-. t smaller than t .. is \ ' .21. Maintenance of an Average Concentration Choosing ti lt' a\'t'rdv.highl' r (or lower) than Cu . vahn. ' till' lIlain tl'lIalll" do~' is 19 ami the l(}i\(lin~ dose. 16 by E'I' 14 and (..it'\1· tilt" average conce ntranon . appmpriatt' to attai n the stl'ady-statl' concvntrunon.. r . III 1)(· snupler than the p n..of C. This dosing interval (Ell. mIl' ('itllt'l' lu ad.l.. C. be. is 20 If m n ..._ Is ~\1.' IEq. one may wtsh to adj ust till' dosiJlK illte r'\'ul to l·I1SUn.... 1111' pe-ak concenrratton chosen . Note thai C... howeve r... ti lt' mainn-uance dost· the n b comes e anti till' loading dust" if nl":t' sSUI)'.. C. C.....ond is tilt' same a.e conce ntration within tht' dosing inten.'1l hy CHAPTE R? By d i\i ding Eq . TIl(> ~llid i ll~ prt ucipht is lu maintain tlu' sa me rate of admt ulstrattou am i tllt'n ·fon · tilt' same chosen a\'(' rd~t' steil<ly-statl' l'0Ill1' 1I1ration... it is appan'n l tbu t t11(' 18 A dfJSllgt· nWIlIl'1l ma). ' till' d()si n ~ rate canbe increase d (o r decreased ) pro pcrttonatcly..o lllpa rinv..

.Io-ri~II ... .'l'S ill tlll'5e two approaches . n.. D llStvt = CI. I).-~-. '. Tht·Ic.. . n( .... Of l'''I"''' ..'1. Following r-xtr av ascnla r adnuuistrutjon.--. 23 Upper Limit 10 8 6 ~---. d :.... " . c lo~ilQ . a \u IUIIW o f di slrihutioll of 2.10. . l111'll S 1~1Il " ISl l Ill' 1 II'si~ Il"'l 1 \\i tho llt ddl'nnining bi ()..s E E 0 ~ 0. Il''!:ill w n .)'11' n..lCJ IIl WL.1 In . fluduatioll5 in till' plasma eonrentra ticu of dnl~ an .....t Interva l ' is 111t'1I . Dose Maintenance A B . 111t' maximum dosin/. F i~ lrl' 7.. 150 .ll~ ..-~.. " " " I I . 7. From th e n-lationslup F ' Dose = C I. l(npI.. " "lui". ..s fn"'ll' ll'lIlly th an lmhran-d in IllI' rl~lI1t 'ns dt 's i~lt "'l l by I'itl ll'r of 11ll' last two 1l11't1I()(ls. amplt" lunsit!t'r a t!m~ wi th a tln-rapentte window uf 2...Ih "":l:l. .-.· Ul'pl·' limit ." ..B " . >I .i L and a lfi-hr llalf-Iift-' (k = (J..II'ss thun thost' aft e r iutravuscular admi nistratio n. 1. ' C. Ill" . If an Interval of 1:2 hr is c hosen. Dqx"lltlill ~ 011 ti ll' slo\\Tll'ss nf rhl' absorption prlJl 't ' s ..." .1110.37 hr li n (l O 2 j.. 7-'1.- " ... l lll "' 1.latilillship F ... W1tea BioGvG~abili1y and Volume Are Unbow. ' .jT""·'M1~ in N t> UI..I). 6 ).. I I A " ..lIlt'n is dl' si!{lll"'l l llll till' hilsis of alt ai n i n~ and lll ai Jllainin ~ the a\1'rll~e ('( JIIrr -nt rution .I I" ... ('"'I1> lI1r. . C...).ill''' i lTlllll. 250 200 Loading A B r. ..> .inR a singlt.. dUl II . it lIlay Ill' !'lt lSSihll" III adminislt'r tilt' dn'g II"..... a 10.·... Orul t1llSllgl' rq... 4 Lower Limit 2 100 -c 1 ! 50 o o o 12 Hours 24 36 ..-"- AUC (single dosel/f . -. ntn.~· I".I(I .atr~' llIIIl till" nW"IMIiUII"'IIoJIM (II' '.nx-n . "''1\00. du rinR slt'ady stall' lIftt'r Illultipll' dost's (Eq.·u'u "... ) is 2S0 lJl~..... Illust rates 11](' dilT t'n·Tl(... it follnw.' " ".-.-_ _.. b n li< I I>I..lli'll' ) i.. Ilw "I>I.ll" <ll~. " " ....I\'li labi li~·. l"j and 19) is then 6... d osl'..1I.... n~ .. C hap.\ J.04:l 11r ..t· .....tllll' .3 lJr . 'il/:..-.lr TIll' load ing duS(' (V . 4) anti tilt' rt." ti ll' " I'lll·. '...itlo.10.o..1" 1 ...CHAl'TEIl 7 97 For t-'.. thai C• L.. ..<.• p"a~ ..i'1I11 "~II'n II..01'1 ...... " .'' ' a n' i'1I I1".<...." ""'" d . ».. .... lmd 10 .. till' maiun-uauce doS(' (Eq s.1'"xl. \ m...S. '11'."" _-. If till' rq ... tIlt' mutnten ance d uS(' /' llt'l'llt"'ll is then ahollt lCJ(J 1Il ~ ( \ ' . ...1 ~tipplo.'..r. ' A l!C after a si ll ~l e duS(' (Eq...1 o 1. ·n.101'Wl..•t"l r ('"II. . ~ ':.it"I' II... " " -.inlaill 1111' "'''11' .. C. Thi s is ri accomplislu-d usilLg tilt' an-a nnder lilt' plasma comvm mnon-ttnw l'U1YI' (AVC) fnllu". ~1"1I" "lnati<II' ""11...li.04... ' I I I I I I I ' ....rr (2 IIIWU Ii'nih It ' '''nll·'' It ((.'5 1lI~ and till' l ()ll(lin ~ dose (EcI_ :20) is !fi(J 1l1 ~..Io~i!:lI.." . I.·.I ). ..·.-__'_. 1"" II..'r"l:" 1111111·nlral"".-.

lit.·til ar....1inJ: f" • •).·"I>I" u.·utndit. 1m ally (ri!tl.· . " .. ami 2-t hr..". " I" .•·.1 ·a .. 1i"..of t .· '''I . y . By definition nfC....~~. "'KI SI..I.."J..It·r.~""..lio". 1..10. '1 .1 ..1 · ." ".lih ~) i..i ll ll~'. o 0..... H.. u"I'. l'i tllt' r lilt' dllSill ~ inh ·ry"IIlt'l." . . sin~lt· :zt:l-m~ or..hn".lo·r tI... 1.3 0....·11 pn..1.• ~. of" .........· A ( '<: . '''1' •.1"1. is tIll' £\ t'C ...ly (I.. n ...t". I. "f W "'!/: " I" ("'~OOIJ"'."hl."1:1. I-I) .J.. !l.l.". \I ....l it" " ..."i. '.l.·.1. H.· i.".· i.1.1.. i'." "'i... . 7-9...1"'" (n .i '''I:I. in Il....· i... S K...h...· .!/: inl...)41 m~ ' .. ~ . I"ur II.1-ij. " .I Ii" .10. -..A .. .·..lmi"i .. Jo:1· . i.J.. ( 1i~ I" r . • 1 or tI.•.• lIf th.l~l· s h ·atl~··st.... .. :'\. II...l it1if"....!/: i" I. Giwlll h(· plasma concem ranou s \\ith tiuu. \I .J.1 .<lIJ1"n. ".'1..· tI. ..'... 111\1s.·(" I". 1"·rf'''1 pn. I" po' n" i"'.... then tlu..J n~ "><·..I l "1 .ll .3 t"'· .·• . 7. uf till' pn'\..L"" II.1.i' •·.i'><1. \l ) (11.•• d.l r.....l.H ·C I~' II.! . ·... ~OOIJ" m ('{"".·I.· .1..1.>I ..It·.l) "" ..>\ I>IS .>\u..J t ·IK...i' 1loy .. lind fi hr after a singlt' dUM '...l tl' conccntrauon or tilt' a\"('m~l' roncent rution res u ltill~ from ad illi ll btt' rill~ tilt' doS(' (. d ell OOlJ""" " .." ·".) ..tlit. II..1.. « \.J """" pLa"1:" I..1 . ~ .....·.l...Iurinl:" '''Nn~ ill. • ...'1>1 it" .. II'.f..1 .. T" "·"l)·..•10....-h n" ) . .. 1 1 tI.Lnit)... . t his a rea is equal In t hai flllluui ll){a s i ll~I(' duSt. •L." (·.tiJ:.... 12.. ' -In....l.... ntk"I" I. 1 1"".".!l'(1.K I . ........9.u."'..duSt..·.J 1".· 1111.ru..... f...IK1 1 n . This p rind ple is SlllM11in F i~ . -...I . ( I "'Wi . I" clt~OOIJ"" '" ill .. C M . it"·n· ....a ttN a si ll~I(· o ral dost'.li f.i.L' i. <:n.\1· .a dt'sin ><! an·r... •..Inl~ 1:1"''' illlr.... lilt' ('(IIIl'l'ulmtiun at allY lillie dllrill~ repeated "dmillisiratiull of tilt' suuu..nu • ... -..· . .I (·"m..1:<' 11 1 tI.u us l!1)Sl·S.....'II' or .2 0. e li" ..-it hiu a dns in~ iutervul al slt' ady state....... I•.".. I .t.. nIl' ""'1"·lil"...I Ii.i ll i ll~ From (·ud .I. I'uri..trl . For ecnn ph-.·I·I)· dnsill~ interval can he 1'llk' II..~" .."" ll.4 I.lit......· (UK".. · 1"'11" " 0..S""· l(i " in "I. 11J'jJ..j _ 1. ....nil' t\'1l u. .. ~"''' "r U (. .·r I. L..!/: .4 Io rl.•• MlATIF'tf-DOSE RfGo'liNS OWTH7 COIIM'( jlWutly. l>.. I.. 1 '-inlt!<· . 1 nt"". 2:! (. and a pr actical illllstmtin n is SI1I1\\11 ill Fi ~..5 Predicted Average Clobazam Plateau C oncentration (mgIL) 0... Ui" ~1.... " ll' 11> 1 .. 1'"".. e1im..11 '''' ''' II. if dO'w s lin' Wvt'll at 0. I>w"'" l""In·"lr .• i. \.. i.·ssa ry 10 adJl e\'(.. " h. h" ....1 1l. SUIll l)f Iht' o 12 24 Hours 36 48 o 12 24 Hours 36 48 t' It..J lel tI.. im" \. lntLt...lr... ran he n ·mlily calculan-d by atld i ll~ tilt' c uicentrurtons n· IIl.5 0.. ·" ' 0.. F .· n"""'1.4 0.~' nK 1 IK1...·n... :•." lnt lit". .·..i....1 llUlltip. i .tlt'r I~ . 12 hr..concentrunon <II 3n hr is {'(!llal to tilt' values iI ! :In...' (u ..r. n .' lIIl'l"U muLatit.r . .·. H.. 1 ' .. 10. .. Ic..I nf fi hr ..). tilt' vahn.....

t' con 1'('lItr. • •• • •• .lp. consider tilt' t'\l'nts at plalt' all simulan-d in Fi!!.'ri Wtl fnr d. In lTlilinlain ti lt' plaMna l'U111't. interval . o f 4 hr. D. lilr tilt' 12-hr inh-rval.I I fnllo"'i n)!. kinet ics an' dn">t'r 10 Iirst-onk-r. . of Ih. an inconvenience. r""t'il-'it' is nnn-h slm\"('r than From ullI\·t'ntional tlos..gwere released inullt'tl iOitt'ly..n i n.)Il\l'uit'nt. . To maint ain rlu.. \\1Iilt. .ltinns is diflk-lIlt or illl't.ltion at plait':. tration.. .CHAPTE R7 ... . in a elrild with a half-lift. t j n. "i}.'ll t'\ l 'f)· 6 hr. for llm)!.. If all tilt' dm. eontrolh-d-n-leaw pn l(lLll'ls must p erform rehably..1U1t' frt't IIlt'Ii''Y as tilt' conventional fun lllll<ttinll Il'atis Itl a mar k.tt p lat eau.'t' . su mt' I'tJllst'U1I-mh' rdt. With tlw IIsll... CONTROlLlD RHlASE TIlt' mailllt'nalil'(' of it l't"'sl<llli plasma couceutrutiou. ~ •• • •• • •• N N ...l't.llion \\i thi u tilt' Ilwf'dl")('uti t· window.. and uS\litHy a n 'lat i\1--Iy const ant n "'poll">t'. Ihl' dns" of the less fl't'lllll'utly at!ministt'n'll controlk-d-n-leuse product mu ~t lx' l\.1.t' forms exist From which tim)!.7-5•••latl. ' ''11 tI. •• ./'.I)!. oral ad ministration of t1n'uphyllillt·..t' form s. " > 1I II> .l ·.. the n.it. h' ll d.l-tlnlt.. '"'9'"""'" ...o. Oll\i oll.g uml t"\~l l ua lill)!.I~t..1••••• EKTUvA.lj'll...LjX'ulk \\i lltltlw. .-d --.. Suchcont r olled-release p roduct s donot completely IIhlitt'r."ti \\i lh conve-ntiuual the-rapy.cout rnlle-d-n-k-ase forruulation can be )!....... ami an: pa rticularly useful wln-n maiuteuauce of tllt'r. ~ ~ <J 0'<>UCll doo. .lllsidt 'mhly theHuctuanon in the plil'ima concentr ation . . a dOS.\in' th ai of the conventional p roduct. Til illllsirah' tilt' poll'lIllill vahu. i -5 summarizes som ..'iQIf'lo-... N" N ••• ••• •• • No .III('t.ltiuns. an IInOlt'l'('pt:lhlt'1l 1ll1I1alinn ill tilt' plaona coucentrution would n -sult .I.-\ d m i n is lt'ri ll~ thrcorumlk-d-rcleaw d' lSa!!t' form at IIII' "'. ~ ~ d o ~ . .same a\'('r. Useful n-lationslnps han ' 1.in-II al a mort' {'t)ll\'(' nit' nt dnsin )!.. n-ginu-n " ill which tilt" tloS(' ami tin' dus ill)!.d" . 'J . tt'ms ha\'!' )I('t'll dt '\1.) n-duo. mo rt' important rt ........W rv No'nlenonce dose ActumuloJt. For orill .of ('tllltnl lll'll-n . t)lll'(' or twice t1ilil~' is t1t'si mh lt.window of 6-20 mw'l.- """""'*""appmo~ . .. than to .lol)('t1 (C hap ._ "'" N.s with 1I'llflin 'S ~rt'aI N than 1211r. othe-r dusa)!..i> ' ~ .. ". i ..:IV<M ..::..lt'il'il' products.tllVtio ll is rapid und.ly. tilt' t lm~ must II(' ad minish 'll. ah'\. .on '0'"' •*" "'" 11 » """""'" 1oICM' All.latinllS h i p~ umltlu-ir lilllit. •• • • •• PlATEAU AYE!loge omo.ulnuniv trution .r. oralcontrolled-n-lease products may Ill' o f [itth.1 dtlSil)!. Tahlt. aml slill maintain tilt' plasmu l't.l' form s and for whit-I.value .1... .. . Intk"t'll. int erval au' fixed... 1101 o nly ..wit.SC\.'\It il· n llln'ntr. .f. when l'tllllpall..<I}!.. ~ i)!. ~ '""""".'IIIr. imum C()I'(: en " ohQl'l Mnimum conc. 6 ). Al'l'tln lill)!.l'Il....'" R'tl llt1inn in lilt' IIm111atiun at plateau. is "ellit.'ily."nimlinn wit hin the Illt'r.... .. 12 hr. lt.:en"Olion .\-t"tl hy I'tJllslanl-ratt' ittllllilli. . which has a tlu-rapc-utk...I!t.

prc ced m pa rts of l ilt' chapte r.: " limit...... tilt' llsua l rt' w men is convr-utent hut IJol'l.1o"TI~"'" ti M " ' K1 11..· lO r rd. . admlmste r till' illjl'<. or S.1 ".· ..-- . .. 111t' fin-t imul\"l's l'St... t 11 lis sect ion deals \\..•. Ih how to b oth eva luate a multi pll'-<Imt ' n'¢Il11'Il.. ( K"l'. rt'fillin'li and o n t ht' IOI.'m lSt· pmlr-dl'Il'l1 rt·le.dosi n~. lil'" ill 1'1. . .Ul~t'l. J hr. tiM" "'11...'tiun \\1. 22).--case A case B Case C 5 Case 0 o o 3 6 Hours 9 12 HR. If pn-dicnuu is good . \ ' . . ~. Il..) l1i". 1 3 In III . . I.....}.. C . 7-11 .¢ITI"n j<:.') I ~ . in" .u ll l l'~ l il ll att' plmn n<llu killt'til' pa nUlwh'rs ..\ ..I.. events 0 11 multiple dosill~ an' p n 'll it11'l1 from si n~lt' -<lost· dat a..' illjt'l.· 1 .\ .JiWI.· . h.'(!.....n~ ~ n ... p n 'll it'lio ll is poor.· n trul.r..f. hr.. 12 I. tI..! I'" "lud . 1 I l li"'.. or pl' rll<tps as a Si ll~II' dosl' ..."". " ...profiles.2 . .l<....1' 1>1 .Jf·lif. 1>).. .100 CHAI'TH 7 25 20 I I f I I I ~ "~.. I tU .rt·II·.e".phanllilt"llkint.. C.u')i ll~ till' n 'WlIlen to adlil'\'l' pn rtk-ular plil\m<l coucentmtj ontinu... It hu ild. . For II d m~ Ihat is usually "rin 'lI i..I.J do.. ti l l' second slagI' is ft·lat in-Iy streightforward.! bin'l\"ailahi lit)" then l x-c onu-s a major couceru.lto ..rkr tI.... lt-ri ll /.e · III n""l"'n.. 12 hr .'l' kly..i••.1. si ~ll i ­ f)i n~ Ihal oue or mon. ....'l.m..l.."I . .1ahlt..1:" f"nn er.tf)· to . inje-ctions un. which ca n hI' t'\ "alllall"(l a~ai llsl IIll'mpt' ul il' rt'SPOIlSi-' a mi toxil'it)".1<"..i ni. im lil'atiuK Ihal ti lt' pil'lOnal'llkiTlt'lk 1l<1rameters 1Ia\"t· lIut d l .is f!.\t mi ll h·s ti llal transit is shortened..11.limit to ' '' ' !Quo" fn"I" . o r tune del)( ·nt lt·nl')' (St'l' C hap. "ot." ..·.lilt' rl'lt 'll"l...~· "t....onlmll.·"........¢ IIIt...1 Il ).•• ""1'"'..I". l ll pn n mulnpk.. l'\id l'Ill'l' (If S UInt' dost..r (C.. .. il Illay llnly 1)(· Ilt'l'l·s.. alMI tI.· II.. .' is compk-te..ha' )..'l~' «:..·r. AUC (single} 24 . 1Illlltiplt .tl d Tt'l.t1illk'ult when d ust' <llld filllt' t1t·pt'ntlt·nl"i ·s prevail.4l""'I": "i"..~ · (rnm tI."1 3fill "'I: . "".lsioll ally..N· ma y pUI d m ~ into tilt' Inwt' r in!t'slim' o r perhaps out o f Ihe hudy lx-fon. 1".thl ish i n~ wllt' tlwr t ht.· .i uconvenn-nt anti iI 1'tllll m llt'l l... g C lean mWBiua\·aila h ilit)·.· C .. h("('allM' Evaluation af a Multlple-Dase Regimen cmd Asseumenl af PharmcKKlnetk Parameters 1111' dl'n ·lop lllt·nl u f dOS<I~t' n"¢IIII'IlS p n ll'l'l'l ls in t\m st a~t'S.' ....1io ll mixtun-.. n. m. lil .. \\i l ll or \\i t ho ul si n~lt'-< lmt· data.... " ..1. ou whut has IJol"('1J s covered in tlu. "'tl..tll!...O '''It ' fj hr (C .. f" rm (3nl) "'It) 't.·. I·n·l. ..) "'....·.n.-nnit th. Dt'I)(' nd i ll ~ lin rlu..I'.1S of tilt' injt'l.n.ll d oSt... In ..litlll' l. ( I(JSll~t' form may IJol' ad"U1la~t'olis .· Ir.1".. O fh-n then.til ." .t il' panllllt' ll'rs Inls d IiUl~I'l1.' n'<L"l.."... The task is 1II11l'h mon. DI 'l. monthly.~·II"t ""I . Siahilit)" ill this ratio (CU P) 0 11 lIlult ipll' dmiJl~ is Wn'lI hy t he equation AUC.(Jod accord IJol'lwt'l'1I Ilhst'l'\11tilllJ and prcdlcuon.". It ill\uk es \.·ially in pat il'n ts \\ilh d ist'il\I'S in whh-h ~a.dic.\ ).fil... l's pt'l.

T his Iluan tity pn "lli('lS till' r.Tln.' n'at:llt'd wlwu M ·t·m l .Illllly ad s . It is lIsnall~ I·\ ~tlnah "t l al platt'all . and till' r atio of ar n onut tn ("llI\("I'llt mtioliS is onlv ("IJllst.l\ a singl l' (.(.llliN "I1 elll ~\ [:C ("l lllsitll·ratiu ns.LSt IIlt'lh. l 1w pn ll.(~dnSt· di stri lmt io. A plateau is takeu to IN.... '.half-life . is a IXlllr d lolt'(· to l's lim. s ('slima te of . Tlu..ll11t ·~ 11l·111ft.."I"tlnn.'IWt't '1l dnl ~ ill ti\Sllps and tlMI in ptlsma !ilk(·s tim( '. [nun Ihat <llltidpatt'C1. n'Sultin g in nnly a few tmugh \'.1) if '... C".majnr question i~ wlll'tlwf lIlt' c1t ·~n 't· nf il('l'UIIIUblioll dilT('r. Oh\i nn sl)'.Ih~nrpti c m is \i rtnally ("lllllpl('h' at tilllt' t afh' r 1I sinJ'lt.n.\ L'G afkr a s i n~lt' dll\('.. a pn't li(1inn h. O ntOpredicto r uf till' d(~n't· of iIl'l'Ullllllaliou.f NS . th is met hod is ~l' lJl' l'ill1)' nnl \ 1:' 1)' prt"l·ist·.Ul Ill' lrlt·asun"tl IJ\N IIIUdl IOllg" r !wril M.. t-s!)t'<.-J tn 1I( J _ . a.umouut ill e1w Illllly at SOlllt' tin lt' within ti lt" clusill~ intr-rvnl al plate-au to th ai at tlu. \ II c.~lsli lJK of El l' Zl.\(· ' 11l'lwt't'1I " hwl"\"(·d l"l lll('l'ni ration ancl l11 111lah"ll \11 1 Int·s. wllt' f(' C . -1 2. Tilt' vailI\' t1t'lI'rminl "ll by El l..\ ('tluil ihriul1I 1M. 'lSlilt' .n ·!lilllt1l'S ari. AI plat eau..ltio of tlu.tt' Iht" d(~n't· of .'\ L'C" = . is till' tmll~h {"IJ1l("I'ntm tinn al till' ('m l of till' fin. tilt.('sti lllah"ti wi thin il dosi ll~ iute rv a l with all)" 1"l 1ll ~ t1(·1I1't· when th e dm iJl~ int e-rv al is short er t"<II1 tlu.:lt· du. In pmdi('(.s llppru'lilll<ltdy t"llll.\ slll n i ll~ {"llll1 plt'l (· dlst rilmtiun.sa m(' tiuu. anal{)j.·rtainly..tilt' · 1It'\t di N'. show l U I tn-nd \\i th tune. Ct.IS di strihul ion l'llll ilihriUIIl is mon' Iikl'I~' 10 han ' IIl't'1l at'ilil""("ll at tilt' {'nd of tIlt' c1llsing ill!t·I"\·al....·l· o f F luct u a lio n a l Pl all·au.. wln-n... \\i I1l ("l mtm llt"tl-n ·lt·'l\(· product s.afh-r 11ll' fint dow . TIlis Iimita lion is a\ (litl l·c1ll sill~ a ("llll1l1lonly " l1l p IU~l"l l Jlll'tlllM. ami sn 1'."(·r. howt'wr.v~un .se)." of Accumulauon. phlsma concenIrillinll s .()1I1pa rt llll'1I1..tC. und . is iIIm lrah"ll ill FiK .\ L'C : ( s i l l ~lt') an ' Ill'. ~\'l'1l in Eel' HI. 11J1Illat ion is C. O Ut' ("lJlllmun IIlt'lLsun' of tl u' dl~n'l' o f .h )... As Shl)\\ll in Fi}:.t dl ". dd"nnim't l from bluod samples taken jmt lx-fon. which in turn imp n nl-s til" ('stimah' llf C [J F 'II plateau.e ml d(Jsill~ Intervals. () C"..j' I ).· plate-au is n-ached.11111 no t illllUllllh al'l' measu red . 2. Theore-tically. vlllul'S ( Ell.lift'.1.' d ilTit'u lt to cstnnute t1ll ri ll~ multiple dos i n~.. dt)S(·. III p ract ice.AC C" Obwved occumulo tion 25 inde x wlll'n' . TIl(' I..IIl M ti lt' \<llul" is eliffil"u h \(J11 · 10 I'sli ma lt.\ l "C" can ht· imp ru\'etl usin }: st..\\"(-\l'r.pr obk-m is IImelt· illlpus sih lt· if ahsu rptiem l"lllllinlies I hruu~"uu lt llt' dm ill ~ interval as nflt 'n lll'('u n.·uli\t· t ru u ~h l"llllt"l lIlmlinlls."l. 1I11\\'(".\ L'C (silll.. 1IIIJr-U fe.. TI ll' at't.. t'fIllM'<. this I.l\llt'nn is tlat" total .. t1n·n-hy Iad l i l al i ll~ an a("I'lmlll ' e~ t i lll at (· llf half-lift·. c1ist. ·n ll· di SlTl'IliUll'y is J.·." of tilt' esHma!t·s of Al:C.'. C[J F dill'S not d m ll~t· o n multiph.rate inpu t rl~ Il 1l'1l (I'p.. lnru uch till' sa mt· way .ls lIf tune afh 'r dtlppi n~ dosin g.~ons 10 IIII' Ust· of " . \\ liN t· Al l :•• = I: · DI)S(·/eI. T his pa rallll'h'r llIay Ill.5 i. If needed. A t n Jll~1l \'allll' is a IIt'th 'r t'ilui('(·.in~ lntl'n 'al lo hll ll' t .l\ily tI.riSt' to plateau follu\\in g a constant. an 'a IlIJIII'r Ill(' pJ.thlt's ohla illt'tl at on ly o nt' lim e.. t ) is lilt..L nn till' m l i n AUC ( sin~le )l~\VC(l.'ially wlu-n tl n.l\ l1lll l"lJIlt"l·IIIr.).. i\ tht' II"a nti l)' 11(1 .L\ dOIlt' wi t h pl'l\ ma eli l a obtai m"ll 0 11 tlu. .. lIan l(' l~·. F IIII'lllatio u is all importan t l"l lllsitl" m lioll of an y dosi ll~ n·¢uu'n .lit"s on \'.'0.lf. plastua l"l Ill{"I'ntratiom an' ofn-n much h i ~llt'f limn thlJSl' ad lit"'\'l'tl aflt'r a si n~I(' dust.'l·UlllU b lioll.. ural'. is till' ACC withiu a dos illK iute rval at plateau. 1}(. Equatioll 2-1 is a n'<..:rt·att-st at (·arly tiUlt's .'.. Tilt' l)t·st \\~t~' 10 I'stim ah ' Imlf·Iif(· is aftt' r stopping d m g admillistmtio ll.llioll-liIlW profil(· c1 n ri n~ IIII' first t11 ". :\('l1unulialinn al\\<I~'S occurs. De ~n"t. For this n'IL alltllM..ill p ratii('f'. ..CHAP1H 1 MJ\TlPlf{)()5lIi'fGl.'pt'm lent on lilt' numlx-r und t i m i ll ~ o f hlood sample . half-lift' t"l mld Ill' ('sliIiMIt"l1 fn nJll ntll~h values taken oll l hl' approach to platea u.Ied int' in plasma l"lml"l ntm tiHIl is too small en" r e this limp intr-rvul.ill~ illh'r"'al.J 'I"\I"l1 1 C I . lhe <It'l1Il1 lUlalion iud ex (n .dmin ~ .dmill ~ inn-tva] a ppnl<ild1l' s tilt' ha. t ) \("t1 \\ill lilait'll lilt' uhst'I"\'l"l1 mhu if . half-lif(' canuot l«.-\ ['C ( I. "1 n . .. TI lt' OhM " { I {~n't· of '1('l. IOJ. j'-~J for dl" J.lIll \\ Ill'1I rln.

._...• an 'a t1"n"KtI li"t .1 frum II.. wilieh is k-ss dept·ndl·nl Oil si ll~lt' observmous.... I".C...t' concent ration at plan-au (A VC•. is ~n'lI by 26 wlw n ' ...(1.n"irM ~1 a(h'r ' '''I'pi"To: ." .I.""".... 7_ 12. ' ..In' f( a11"..... < ... tWItI..] .(C .~ ....• .( 0.) 27 " 50 40 ~ g ~ 13 c 0 5' c 30 20 10 0 0 o 2 4 6 8 Time In Dosing Interval (Hours) '-' ... i -1 2.. 1o.f(.1o.. AUC (above c....J to IiIlM' t (ACC!1... tlu-u rur Relative b ioova ilobility IAUC.llIwU mu m llIMI minim" m ~~"M~·llt nolic"...." .. m· lalt~ of sa fetv and mtntmum (' lTil'l ll"\'.s "I pLol.. (~ltllp.1iwly. 10.• (Al'C(oiu0t.t""·r. E\~Mti..I' till' tol. bcotWt"t'1l t\'" treat nu-uts ( t" ~" dnsa~t' form s A and H).t· of th is IIlt '. IAUC.._: (10.alf-lift..tll)'l....• u r. n.. IDo.Io-l.· .. ".lic>ll . "f 0'" 1n"'I" " 1 . t) AUC" 96 120 144 168 tl.) I.. unless mOillY hlood s amples art' taken wtth!n till' dosin ~ interval. it ('lJ' h(· (~.1 ... C.'1 10 l't ... that ..--24 48 72 Hours AUC(I . 10 II.Qn.·.'1 .~.•.tr. > C u.'W'....tim"lin" tI.is that it IIt'als wit h <lirt 'l1 o llM·"'<ltiollS.. a n ·lati\'l·ly uuconunon cliuiea 1 pract ice ... which art' thl)lI~hl In havt' n-h-vunce with rt·~ I)(·(... C._J/{ :.jnK i ntc·l'\~ ..102 CHAPTfI1 7 f111l'tna!ioll is tilt' m!io (C .·....· .L~is t11'Il' nllillill ~ rt·lali\'l· bina\'ailah ilil)' or it t1m~ adll1in isl t'rt't:l t-Xlnl\1L \I:ularl)' ( t·.j"Klnlt·I'\" ..•.lSabu\"(' am l l"-' ]el""tilt" awmV.~ ._ .-_ <:: AUC(single) _ --.I.llall. .."1. An ad\'all la~t' o f this uu-as un. II. ) is oftt-n difTil111t In tosti malt' i11't.. " Il<'n...... n.. Equunon 2i forms a usefu l I l. Anotlu-r 1I1Oft· stahh. hihl~' of till' CU r rdlio "ith llo" i""('lJ. I...Js IDose). " it IIi" I... t lllt' 'o f which (.n· fit·.". 'S . C . r...m'. is '\'(' that it rcln-s nn only' roll ObSl..."mlation il la kf'Il"" II. a 01 11"'" .uinll: ... Other Parameters.. ) aud AVe (belo w C.• < 1o"'lllK illh·".1 f"r . t »)......'t).·".• " ""-11. 110\\'( 1".....· in. C.'S! ...·lIntlely...'alllf p1al. Al'e: (E' I_2fj ) ..'. Est hnat iou or tllt'sl' values is SIlO\\11 in I!\(' inset I" Fi~..t'lirt' .wt i.• nolioof' Al'e .I p1atf''''' (A t·C. of *. \I ....li ......}• .\Ue (al)()\'(.. 11.u.-I ..."" II..nu-asure of Huctuatktu. n.till' ..C m)/C.. C _ ..·l"\~ollillns.1 ...»). ) arr.II..lt.. .Io"'· " . :\ d isml\1U1l aV.... lnl\lr. io h.. l f dea ra lll'C' n-maius llIl('hall~I ..~-.· (~Il K~ 1.. · ..\. d... t1llrinK ....>I..·spe<." u( a II1 Ull l"" ... I I~' Ih · m ...._...

!-rt·IC'<l.>t' t-au lit.1. Cakulan. To ensure (.low(' r is tilt' a\'('rag:(' plat (""1t'UIl('t'ulmtielll.'n nint'(l from uri ne. Relative bioava ilability "" (Ae. Calt-ub tt' till' n -na l ch-anmce o f p rocainannde..aITnt'r'I'1 al. F = 0 .'nd s O il tht' In " l lll('''t~· u f dmg adm inistration. (G alT m'r.4 .(lIlipamhilit)'.(w fonnu 1<11 ilm.. am i SjOj.: Pharmacoktncncs o f proc 0 .rt'1I'. II. ( ...'-s tIll' r.('UI'S.rt'll'.S 1l..'-\t' tablets... dala itS follows .t" phSlll<l . « 'I.111'(:\('(1 O\'('r an x.'( ' lI l'oIl 'Y of tilt' a n ural multiplt'-doSt.llinll of p n K'a inalllic!l' at stt'ady state. G . tlu. AI'.on 226 211 a . .. 3 .64 V -280l Cl .. JO!IIlS. l1U' t'xlt'u l of ..\UIUIlII' of dis tribution.L pn lllud: .. the amoun t Ilf dm g: lost within a t10silJR interval equals the oral main It'n au ('(' deISt'..tpid .till' n 'bth '(' hio<lvailahil it)' of IIIl' coutrolk -d-n-lease Ionnulanon compan-d wnh th c' mpi cl. o f A UC . T Ill' la rgt'r' rlu. 17':414-12.t('( 'ulIllllatioll increases whe n drug is giW Il It~s fn'llut'llll y. f. I'. \t' h. (Dose)s 29 STUDY PROBLEMS (Answers 1 Study Problems ore in Appendix II .IU Ropd-relea1oe lormuloll()rl Conlfolledreleo!oe formulol..5 R 1'\l' I')" 4 hr . for a 70kg !Jot'r'SOIi an'.) 0 I.III n-ach plat('au follouill g: a multiple-dose ll'gi IllI'1l dl. .hr interval at sh'atly stall' aflt'r admiu' islralioll of 0. and Ih 'ual dt'i\r.. l1:enol clearance = 28 The rt'la m '(' h iua \'aibh ility o f . chlorthalidoue. us \\'(.lII extravascular dos(' lI\ay lit. dl't/. 111(' ti nu. dnam idt· intm \l'Il11mly alltl n mlly as t1mn'ntional and slow. Ther. IIIt'II. AUCIO.Il'lt. 111t' il\l-mgt' plateau coucentratum depends on the ahsCJ rp tion kint1it's of till' d nt g: fol1O\\i ng admin islration of a r~n1t'1l o f a fixed dail)' tlc)S{'.11 .. 2.tn'II.5 l/hr . J.'>l:' tablet an d I g ('wI)' S hr us tilt' cout mllc '(1. tilt' dat a (p reSt' n lc-<I in Tahlc 7 -6) WNt' ('(.. . Ct lllllllt'nt »n tilt' .'. Pharnmml. 1975 ) compared a rapid-re-lease wi th a ('(mtmU (.UH.CHJ\PTEIl 7 10> l lusi lJ~ Interval al stt'ad~' sta lt' . The. rt'lt'<l.)B (Dose)" (Ae.'\(' furul1ll. U.. :\('('lIl1l ula tinn '11"1I~~ IK.pt.. follU\\in~ statements " i tll n~lrt l to d nt gs gin'lJ i L' a. c. d . CUll ..-\1 plalt 'all.po pulation phanwl(ukilll'lk s of th (' 01""011 d iun'til' aRt'nt .1. .81 . t'sl illlilh-<1 from tilt' amount o f dnt~ excreted unchanged in a tilt' \"aillt. G ..

Giwn that the half Iif.t1til' do".'1'11 m .> rt~lIIt'li o f fllllirwl. wha t is t1 lt·lu.and rapid . The decision has 111. TIll' absmVliull of tl ll'oph~·lt illl' is complete. ~1r. Tl u. ? h. 111t' l<lramMer \"a lm>s fo r a typicoll pal it'lit p opnluttou with this .time p m file ohtailll. The timt' reqoired to 'ie h il"\'t' 50% of pbtt·au h. ].(! f()llu. d . If requi red.hody at platt'illl 2.yllilw ( 100 . Complete..0 (lor theophylline} V . T [Iv] ime o o 23 2 4 8 12 36 48 0. il llonsll1oki n~ fi().tlu-ru ap -uuc window .f{lll ( l\\i ll~ wilt·" a 50-inK dust" of d . is to lJt>start ed on an oral regnncn o f alllinopt. TIl(' accumulation ratio 3.h 'n llinal half-life is 5 hr... and tln. c . A conrndled-n-k-aw dUSlI~t> fon n 10 h(" ¢\'I'll ('\"('1')-' f) hr is t!esiWlt'!! to rt ·I.1to maintain all a\'t' m~e plate-uucoueeutration o f 10 m/ifl.. Pn -pa n.r/L.t.· k~ pat ient . ('tllldi tioll at plah'<lu ? 4. 11l(-' A l 'e is f)U..ylliJw (&")<J. \ \ 11011 is: I.'ith chronic " hstn ldin>pulmonary di ~ "lst '. W to 20 mW"l.a sketch Oil ~ llar grap h p.rt> !t'aw d()SiI~t · form l. o f til(' drug is 4 hr : a. '!1 d rug is 50 1Il~.na cono-m ranou . Show the salient fea tu res of il( 'l't lll lll lat itm of this dnl ~ dll ri n~ tht·mpy.g l)esiWI WI ora l dosa~. 5 ..Iist'jl'w plmm llK''f)kim'!ies 1 an. \ \ 'hat o ral dosi n~ mit' of dnl~ is 111"("(1''1.. I.(lIllain? .tlwmpt.' : F II: 1.ll lt>l o ~ \'(> till' d nl ~ Hnl'l' ('wry 12 1Ir.(llllplt·tdy ab sorb.11I~ doS(' of a d nl ~. ill tlubod y \\illl ttmc..the tablebelow for tilt' t10S<l!!: ' n'~ Il1t' n o f d llllrthalidol\(' ¢Vt 'lI in (a) .0 3 47 52 40 28 06 01 4 a. calculan-tlu.l(lill~ dust· of dilurt halitltllll' II(·('{I('<I to illllll t'tl iiliely at tain tilt.\1.."(I? 2. TIIC p lah" lllt rou~h concentrunon t':o: pt"l1t'l l? 6 .04 CHAPT 7 Ei a. . > il<it> its con tents I 'H " l / y and cmll/lff'fIo/y (nn IOiUli ll ~ dose) over IIIis dos ill ~ inh-rvul.fi m ~..tlx· r of tilt' amount of {'hlo rthalidollt.ami 20n-llI~ tablets an ' marketed) for this p atien t to attal' l ami maintain a p ia. of whlch is tllt"(lphyllilw).· 7-7 Iisls a l)pkal plas ma concent r ation. 111l' unit doS(>s t Tt" n~ h o f product IWt"(I. H ow much d m ~ should the ('()lIt m llt'(l.·limilla tioll ) aud (.. T alll.i thi n rln.. TIlt' maximum and minimum amounts of d nl ~ in the.. in ~ an oral 500.>o f a mpid ly (compared to . /.5l/kg CL . Givl' n Ihat abso rpuon is instantaneous n-lative 10 eluuinarion.. O. { .. 4 0 rnl/hr/ lr.lnrt lmlido llt' is taken da ily at breakfast.. Th e mini mum plasma couceutration al pl att'lUl 4.

lt('-fl.~\lIla atlina/Jllam coucent r anon fnllouin ~ IIIl' administration nf lilt" controlled-release p m(llId? h..( I()st..\ l"G (~IIl~ i dt'm tinn~ .~~_d 04"""'*"" ... a."'.II'a\(' pnM!lll1S an .... (ltla? d .lt' a nt! 1l11lltiplt· d OSt' s o f immt"tliah··n.. . ..n '.at ioll for the treatment o f depn-ssion ..~"'"'." ' .... an' ti l(' p1<l\lll a concemratiou data nh st'rH"(! Oil mult iple dn" i Tl ~ (T ah lt' 7-8) Ihost· pn"(lid l"(l fmm si ll~Il'. For b oth p n ll!lll1s.') and U...nlalll of III(' {'tllilmlll't!-n·!(·a. <J..<..L'it· pn'pamt ioll o llly is u ¢H'T1 (iJ ('\l' ry -I hr (ii) ('w l)"!'i hr (i ii) en' l)" 12 hr..._.• IJrll(Illl1 ('()lIlpa n1 1In till' illllllt·diah'·n..tllli pan k disun lt·n...lt> and (. lmg/ U T (t. To . pn l\id(· till' rl'lativ(· amount s of d nl ~ i ll tln- hntly vr-rsus tilllt' ('IIT\t'S l'Xpt'<.." Te<m. .-l.0t61 ..'it' anti lilt' coutrolh-d-n-lease n'WlIlen~ ~h l' n tlml IIJ(' AVC(O 10 N IIr ) and AVG(O to 12 1.U1U' ~r.it"\l' a p rnlllpI I' ITt't1 ... n'Slx"(1i\'d>'? Ba.(ulltmllt1 !-n. In ('J1~lI n' that II plate-au sho uld have lx-en n 'ut'hl"(l? In ytJur an swer. ' . D.1') f"llu\~ill ~ tl. Adinai'nbm is it t1nl~ nmh-r iliwstij!... products w 11("('11 ¢n'lI I(JII ~ (· nnll~1. M_" A.t· s(· '.... Tahle 7--S summarizes v um.. c. h._ J... Ivltlech- PIMI '6 _ ••I..1 are tln.a~t· form b ¢wn? e e. \\1..n ·lat in' hioa\'a il"hilil>' of adill:t7 . 011 multiple do~ill~._ ••I _.IIMII e-trelletl•• • I__ II . 9 .t' ~ i ll~II' 40-m~ imm(1Ii.'.ll'a.It"l.l'i(· pnl(lll{1? e. .o-~ ~~.I Orevp ..1 t'1l wln-n till' (."p&o.( sillj!......... han ' tjn. .....at is tln..nftllt' salient p lmr m 'll'o kilw l i<... JC O"\d W'<jo C E ~...ltlpl. \\110\1 mh '-limits III(' t1(·(:lillt' of pJ.UC 1O-14i _ 'do¥ <I ~ a.m1ks of udiuaz olam afh-r udmiut stranon flf til(' Iuunedlate-re\ It'iL\p alll! tlu. In tubular form or 1111 tilt' .· info n na tinll flllIC l\\ill j.(x"(1i\'t' t1u"ill~ Inte rvals at plateau ? f. { n ' IIIl' phart lla('()]....ll'...'it' product and Ihe fiO-m R conrrolledn...... indi (~lh' wlwllll'r iUl~' diffen-uce is eXpt'(1("(1 in lilt' tinlt' In n-ach plateau 1 1('lw('('1I Ilw " \ 11 product s.d( '~I't "('s o f accumulation a\StM :iaft"(l wtth the illllll("(!i. \ \ '.57< 0 11 f .. rqll> / l (hrl d o 57b 0 15 1 00 1..) ""... A Im tn/ll UC gC"".lt'il'i(' products such that tilt' terminal half-lirt' m il II(' tll'lt 'rtnillt"(l \~i l i l i ll the. FuIlO\\illJ. rt'lt 'iL product s.If('-n·ll·a....'it. \ \111'11 should till' fir!lt controllcd-releaw d(Js. <J' _O"\d ..>:Jt>l<o>...c .72< 020 220 088 b 007 250 550 1. >'tIur calculations 011 .7-8.-l..I_••I M.lp h .irnt'll in (h ) wh at is t hl' 101111 d oS(' (i) for ltay I ? OJ) for day 2? d.INtIe IIHI ..' nl rnll l't !-n ·]t·. 1991 'AUCIO-..t1 dOS<I~1' fon n is ad m inish'rt"l! in ilially.illllll("(lialt·· rt'1(·iL\(' am l l'Ulllmll("(!· n. ~ 7.. a rap idly ab sorh.(lIIlmll('(!.J mg-hr/ l.II."'""".I("l.".t Ih l' tIlJ~I~(' r q ?..

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I Se c t i o n III PHYSIOLOGIC CO NC EPTS AND KINETICS .

.

TIlt' an atomic and ph ys 'III<.t· honk. Sudl lufcn nat ton helps not (111 to inlt"'l)rt·t ). iu!ogil' factors that deknnim' 11ll' mp idil)' o f d rug tmnsport all. Di!>l.. mat rix e covered Oil r-ach surface by d t!ll'r a routtnuous lay('Tor a latt ice . I1~ dn l~ itd m i ll i s l r.-aluatiou of dC lSa~(' n..J. nwm bra ue ..' till' substance o f Ihis chapter. octoe tronsport. AbS(I'l Jlion ."(.K"t·§ wh ich . dislril mliol\ and elimination .l~ fion ami applica tion of pluu-macokuu-t ic princi ples to tilt' d t·siJ.at ton o f dnll?: themp)" tlnod . predominantly lipoklal.. k "!-.'.o rk of p rot ein ( Fig .~ It "funct tonal" lIlat'mst~)pi t.~ollS fare tlit... 4 Describe the cceseqceoces cl the levefsible IlOture 01 ~l 01 drug$ through men't bra~. ph .MOVEMENT THROUGH MEMBRANES OBJlCTlV£S The Ieode!' will be able to: 1..1r. Thls section explo res till' physiolo. slIrrnu lI(!ing e-tween some t't' lis .dt"S an illSi ~ht into the intern-latinnship s lx-tween d m g and b y...1. Olll't' ptS I l<L~k 10 pbarmacokmencs .n ~ physinl f ~l'lm ll"t"Ss('s control phar1Il00(:o kilwti c pam uwt Ns .. 000 permeability_ 2 . p roceeds t1 m Jll ~h rlupnK 'it'S of absorpuon . 3.ngui!J. in U AArt-gutt'. l lIIt· when phannal'tikint' lic P. .L'lril' lumen and the ca ptlla ry hlood and rlu. TRANSPORT PROC£SS£S Cellular mr-rnh ranes ap p('a r 10 b l'tIIllIXISt'l1 of an tnm-r. Define PJuive and focililoted diffusion. S. It hegi n s " i lll a chapte r dt'alill ~ "ilh 11ll' lla-~s.l' concepts. Littl e has ht't'll s:u<l about how lI11d(' rl>.struc- .Illt'IlS.. d m g tr ansport ... sllhj('(:t of th e nex t sect ion.a~e o f d nl ~ t1l rnll~h membranes. and elinunation an' all p n x"t'SSt. Tl ris 1I10\"( ' nl is kmJ\'T1 .. Xarrow a{lllt'olls-fillt'tl channels exist b iIIary membranes a nd intestinal epitlJl'Iia . obt at ned under a va riety o f ct rcumstances. So far ill tl.ing ).ill lll p" aCJIIt'()1lS envi ron ment.('!1 Ihe ~. h ili also to pn'tlid Ihl' Iikt'!)· 1I111t.. d ortlons of IIIl' lipid molecules li n' nrte nn-d up pe Tsecnon of d l" ".lJI and e.:rdlio n of knu. between perfusoon role-limited and permeability rote-limited passage 01 drugs through rrembecres. ami ends willi a chapte-r 011 tilt" in'('!i.lt't' S rhat lit' ht·l\o. 5( '1"\'( ' a. TIlt' I rdn~lx l rt o f t1n1 ~S is n ftt'n viewed as 1II0\'('lI\t'lIl u<:nlSs a wrie-s o f membranes uud SP.l .'s that require mo vement thro ugh membranes. emphests has lx-en placed 01\ k jud i<:{.lllt'tt'rs c hallg:l'. It alsn la)'5 a fOl!mLltioli for ilJ(li\id ua Ii7. Descnbe the role of pH in the movement of drug *lfough membrOr"l8$. }l ·t such infonnaliol\ p n l\.mmK'tllillt'tic da ta.t. TIlt' ('t·lls ami interstitiul SP.ncs and ph ysiolt' . di stribution .-en ts follu". TI lt' hyd rop hobic p tow a rd tlie center of th e me mb ra ne and lilt' outer hytl rnp llilie n. c l" .

.n I... ~ .~ ".!>· in .. (If II\(" \\1.': tra nsport ac ross t ht·S(' "Iuuct ional " membranes follows .'1 ' ).. SCl f. 11K.hil.m~ ".<IltlII l"oLar t'l.... ~ l l '\"l' lIl t 'll t n-sults from til(' kint'l k ('Jlt'~.11 mt·"' lmUlt.-f-.w l ri n•.• "1'I1t'r p..Arreetor pili muscle Subcutaneouslayer Fill:.. djffll."("ULu lo. . ami allYone uf them can rate-limit the o\"l'mll pIlK'{'SS.tS well . molecules..1f" "ll Sinl:l·r . IL Ilie>ll..it.rh.1111'1' "I' (.....J"'I .. 5. ' anc! tlud" "1 11. K. 197:t " 'P:' 'I'i¢'1 II}'l:2 to.( "1'I. .oI..lS till' skin (F iR... <lml Si lll'(' 110 work is (·).aI!('t...1" .... 1tIo. Diffusion and (onvectio.. "ilh 1I lipitl inlt'rinr ... Cell membrane .k k TI..Tactilecorpuscle ~ .t's of lim). 11..110 CHAiT 8 H tUIl'S 1)('1'\\'('('11 the sinusoidal spal" and the hill' canaliculi in tilt" liver.((.I.. . 1i1 I I""Ii.lpo.. Ill .hie'" . a ..it)' of struct ure that malws quanntatlve extrapolat ion of dm~ Iruusport (mill O Il(> IlIt 'mlmlllt · I II anot her d ifficult . ..trt uf tI"' papillary ~"r "f tI..m. lll" hic. the stra tu m cor n eum is till' major .. lt l " m)..·ndl"<I hy lilt' system ...I& TIlt' A "".. .A1\A S. kin ... tlo'J'k1. IfT"'. .al" I:o' :2 x 10 ... UuLu loaTTit-r n l"11t1s frum tI.4"'!>' ~ "rt ld " "".y (":II... TI.r.lch of till' i ll h''1)usi ll ~ cellular nn-mhruues and spal"" illll)('(II' dnl ~ transport 10 'll.. tilt' natu ral !l'mlt'lIlT for molecuh-s 10 s vo 1lI1l\" dO a concentrurkm gmd it·nl.· a..rrit·r of II.roll" '<lJ) ' . l ll..1 iun.'" ". nc"SS (1.1" ...~jon ..Iht "l" " · . 8-1). H.h·rit..·mb of appnm malt·!:o· J X 10..ri.. lht' pmt'('ss is kno wn us l Imo ' s/lA.6 ('m Ihil. <t ral"".• . s thmugh un-mhranes by tliffll.k " "K uf I : uiel k·1 11..720. kiIK~' drawn by \ 1. ...I)ill~ dl'g n-cs.· ( 11 nlt'".. A des<:riplin n o f the qualltatlve feutun-s of lilt' pm(" s<.l n...10·nili..Hair shaft Stratum E pidermis { corneum Sweat gland duet Hair follicle .-ml.hiu "."l'""llI.. ~ I ()!it t1m gs pa.l... 1. kiu.SCf:. .lllar ...I csn (I.. . 0 .l11 In tilt' c"l' ilJarit"1 of tilt' Ink'rll" n. art' examples. ...l:.. inlt"'" <Til .. C:. . l>nult' ro rnl." 1I 1 "'. FllIll... .. di' i"'n<. It is th is (·'Ulllp lt·li.Papillarylayer .· 11 IIJt'mhnm.. In the skin... ('On ... 1 tI.I im 'J1..J.. I S ir.i... ...itt' of impt'(!a lll't·.' I · ll1Ulhn -lI"L..cap illa ry Dermis lIf:7f-::::::::I=:::::-= Nerve gland Sebaceous ". ..... lll.. S.I)I.

Chargt· is lilt' tllin1 major const raint to trausuu-mbraue !).r \i n> IUMI -3 ' 00 200 L • c.p of Ilt'lIt1roltio ll is flullntital i\'t'!y ...(11ItS. variation in lilt' illlllt'llanl"l' o f t1ifTt'n' nt memb ran es to d mrgt'(llllolt.· m ll·.l lIK'mhr. . ..loilily.... For SO IlW membranes . 10 cross tln. ...ult' 1 a drug an' 0 lI1ol"'('nlar sin'. Hen. III(' pro hahi lil)' of collision with tilt' membran e and tllt 'n '''y ill('n 'aw s tl.. ..1 n il 1II0\ "t'II lt'nt Ihn MIRI..of penetr ati on is Nel rete o f penetration ..10 "----4--~-~ -8 hl"'l'hihdt. ". " II ..Jot.... H-2. bul ' tI. -4 -s -6 .. wit h ft'\" t'x('('pl ions (t -. .. TIlt' tlrh ing force for d m g tran sli'r is Ihl' ("Illwt'nlra!ioll of tilt' d j fTu si ll ~ Spt't.hihr...... " ".·1 of tilt' dlarg.J.t' is important. '(.alt' lilt' pm p.1rnm' Puth . lt't· an'a dou hlt. This tendency and Illl' d T t"C! of IIlOk-cular Si7....-xprt-sv -d ill !t' f11I S of 11..lnnl/wa " 'r f"' r1i...lllt'Sfluitt· rapidly hilt is almost totally IIna"I.... lipo pllilid ly.. tkM I ·ffit.. in t'adl of tilt' e unp u m rt ents on t'itlw r sitlt' of tilt' mt'lllhr'lllW... tltluhli ll ~ lilt ... S-2 for transdennal pas.·Iit.' . moh-oular ~ i7. . Smallhpid-solubk.... IIlt·lI1h r..21 Conc entrati on di fference 111t' im portan('(' of lIlt' surface urs-a of til(' membrane is n 'lillily ap(litrl.SSilKt'.s) 'SIl"1ll ill w!lidl a IIlt'l1Ihra rw 'W 'llarall's I\...'II: ( :.li"'i. tilt' n 'lati\"t'ly looSt·ly I. /'\ 1' 1 .ilgOlin.i i" o t·l ~. r.. LiI"'l'h ll ll: ity i.CHAf'IH a '" T n app rt'(.UIUl'lIIlS l'(lmpartmeuts.nty.Ilth! b" l t1 ilT nr hIM ..'n l. " . '.m l~ JIIs itll'r a »ruplc.. ~ o!t· th at lilt' p roduct r · SA has till' un its I)"pil~.o.ll of How. th en' is ('(msidt 'rahlt.... ca pillary 1lI"'lIlbmnt 's). I<"('1 .l~ an' shapt' and dmrgt' of tln.. is ofh 'n d l<lr'lI('lt' ri/J'l1 hy pa rtitio n ht'I\\"t'(' u oil and water.lIlolt'('\II.. lall'l l tn lilt· struct ure of membram-s... H.. E.-s. anti d largt'...' an' shown ill Fi~. For t'Xilmplt" oxytocin...lhd t. T Ilt' tlm't' lIlajur ....o...lllr ..('\. wah·r ·solublt· materials mu\'(' pamt"l'lIularly tI ln m~11 narrow channels Ilt..L..\1·u lIlt'm hr.Iwi lh ['I'" " i. Ill' '1I'f. lilJt' " 'P""""nb ..un-loubr-d tl m~s tend 10 Ilt'lIdratt' bpid nu-mhrane s with ea. a (....more IiRhtly kn it g'oLstmi nlt'st hml IIIt'lIl' brutu-s. distance/time.~J Lo. paml'(· lIl1lar ly (·ms. Molec Weight ular (Ol olej m .~ Ii<'finK .n it nasa...1Il0lIUllt'plitit'. I' I"•.has unu s of . For example. \Iolt'('ular size has lilt1t' imp'1l1 till d ifTusion of stlhstalln 's in '\11 h UI l ias a majo r d T..dmgs n ·at lily (lilSS I hnm~h a uu-mbram-.lI·stim'll . Slln. "'MI Guy. 9:ffi~. lillt'philid ly...ge of a variety o f IIllcha~l'(IIII()I · t'('IlI. ( ~I .. ..io" or PL'nllm 1'1. 111is tHfft'n'n('(' in t·. rt rm.. (log sea!!) 6 OctanoVNalerParlrtiOO Coetllcient ... lW-l..w.. }wnlll'fJbility... M ~li tl of " 1I..lIln '(·s of variatiuu ill pt 'nllt'ilbilil>' of a "''.) " o :2 .· Ls. 'I'I.. TIll' li d r an...... a1wuys la~t" '~ ll ll mt'/l i lll "..li fM . The second sonrre o f variation.'<.lIlt'S. "0..... !It'nd rollioll rah ' hmfold ..... lC.......: r . \ IO"'lIlt'lIt of \\1111' r thn mgh tilt' pa racellulur channels (a ('(JIl\t'(1h1.. I't'nnt'ahilil)' then-fon..I'.lm I"·rmo. ...'rtil"s of p.·n l.u \tl.p' ."I lll tll:"· S o r Ihl' Sin n/.. P Permea bility SA Scrfoce c rec . A ~ain ..·...' p r ocess) aids in li lt' trallSport of suhs lall('('s hy th is rout e. r"'.tssi\"l' d ifT nsi.ht't't'!l cells . Soun.~ u~ "" 600 800 ~! E- -7 -. others tin lint. 1 - C....·ITt".... 111 is 1t'r is pn 's ulll ahl~' n...g.

~ ) .'iali/. Al hiRh pl.itl".( Irall' I" >t1 .:uIUt'(lLIs p !JiL'>l' S o n hoth skh-s ll( till' membmne. when then.. hI' 11I011'(.. ~It' lll l mul('s are 11 inert barm-rs: lilt ....-ith low illJ!.t sonn.·lt1!:-· . p. tht' mit' of t nlll sport of ~1ll('11st. n'sptlll'iihlt" TIll' subs trates a rt' oftt'li ('II(II ~t'nOlis comp ounds .lt:I('risl il'S of p.'(' ntml iolls.. h.Ss.1).observation of a ltnnn-d mtl' of t ran sport a t inl'rt'<l.112 OWTEI!8 Thus. ana- the. when all tln. til(" slowI'r is its ~lt)\l' Il1 I' nl is lIlUH'lllt ' ul <l(.coucentratiuns o[ lilt' difTlisill~ speci es a rt..'t.ms s 1I1("llllmu ws.o...J.po lar a moh-cule.. rat e o f t r. I~l\si\l' fildlilillt'( l d iffu \ ioll uml ad in' tmmport .n Ii.'1.lllt' . T\\u 1)1 o f slx"i. · AuolhN determinant o f jlenJwahilily is memhram.mat e rials and 'it"lIIlI'SIN ounds a n ' po la r. I that ra te o f dm~ transport is t1in'(:tl~" pmportionul to ronce-ntrut km (Fi~. I l. of tilt' lIlt'lllbr. nI r"liun .. I nil W M " u{.""".\'('f. "li. Of st'lt"i. (...rrio·r .lIIsport contin ues toward equihb n um."". This d istan t't ' cau va ry Irmu a ho ul ' 0.th~ l lr""'l'un . ~I any of tilt'S(' comp · ·ip' lip id sn luh ili!)" )'t'l Illl'y pene-t rate membranes IlUll.mllil Rlul'l)s(' ('1 J1ll..1:in'!y n'l ai ll ill ~ \i la l substances.movement of ~h l{'I)s(' intu ('l)t lln x..·pt of a carrier stems from tln.lfold when conccnr rancu of dm~ is dlluhlt'll.11( is 1·lIa~I'(I . " f:l\h' r than anl i{ llt'l l fnr fl<l\sin' diffmion I hml1~h a u Inert lilX)itlal barrier. limiting Rate Carrier-Mediated Transpon Concentration .. With P'-" r. D nl~ Ir.thlckm-ss. and tilt' sph 'lII c umot lit.!t'I IiS 'tl appt'ar 10 lit. ·mh. Sta h'!.n h I l i~hly pt 'mwahl( ' t!nlj. n . a condt tfon ill whit-Ii tln..1 tiM' .lt' .. n.K't" area o f contact \\i th tlw me-mbra ne.ilQ' \lt ~... han ' a s!x'!.~ >rM~..~ . a n' small. to and From wlJidl til(' dm~ is transported.. " >"t~'''t ralic>" •.('. of l'l llll!X'li tio n III'tW('t'lI 11I01· t'1-'lIl('S alit ! Iaok of soll uml io n a n ' t'ha r. s aturated.\("(! suhs l mll' concentrations ( Fi~. S-3)... Fi~.. tilt' last stat euu-ut a l ~ l a ppls-s wln-n th e uther lIlo lt'{'ul(· is a diff(' fl'nt dOl~.('(1 transport P"It'('sS('S x's i have IIt'('1l pmlx)S('(1.twI'1-'1\ n-W0 lIs still continues a t I"<lllilihrilllll.ltll'lISt' mee r-s { Il)\\ ll a eonc ent rution W'-ulit> \\i tl. TIlt' l. tht' {'1 )l\('('llt ml io lls in ami surmtl lJ( li ll~ Iht' n 'll hlolltl ('I'lls an ' t"lpml... lowN fi~ur(' ) .t r. Initiall)'.. ~I O'''(' III{'ll t of dmg IIt... t t's. PaHln' ! nciJitntnl d iffinl'IIl is l·x(·mpH fit..lifT".. slIrf. ~. Unk-es a dm~ a ltl'rs tlw nature (If tilt' mc-mhrau e. IO.' the ~ lllt' in tln.! difTt'n'utly.. a nd a t ("(Illilib rilllll... am! Whl'lI tilt> \lllllll W S of tilt' ll:J1 l1 pa rt lllt' lIts .l tfampurt S~'!.... '\"l'1I m ort' if . Will.o lll t'!Ilpt'llll ih m ' ' nl of ('Ill'fK\·. tiM h i ~l lt'r is tht'l'N'nlll'ahi lity.1 by tln. Spt'l.. it slowr-d ..Internalcellular environment hy II ~S .. it fnllllws from Ell .I un .. IIt1'\\"(.... t he la~N an d mon. tI r.is i l liI ~I' ry. . bUI tilt' lid flux is i'. Both ahS('II('t. each lllolt'{'u !t' dHTuS('S iudl 'lx ' udelll l)"o f th e otl u-r.L sin ' di ffus io ll.li''.('(! function. Fur I' Xample . 1.. \ Carrier·Med"lCIIod T porI ...liun n{ tlnll': I>I.. . Passive Diffusion til .In'l: Ir""'l'urt P 1'~ Jl "'t 1 It(. tilt" di slalll't' 1IIoll'('ult' IllL to Ird\" " ("J'W from t ill" sill" o f int t' n 'st «-..· .I' m " EClllilibrilllll is ac:h it'\l'(l lIlon' mp i<1ly ..ilh ..Pl'.• a n absorpuon SUrf<lI't·) to a h louo:l l"ltpill:ll)" . TIll ' s!lurk r the d istalll.. tI. ..lIISpo rt is i lll'rt"L~'(Il\\.... Of d ost...dnl ~ is placed Oil Ollt' sid t. /01-3.i a li/A I·arrit·r-mt'tliah ."" ~ II 1illlitjn~ .lllt's maint ain 01 l'ld \l{ li ll~ or n 'llIo\"iuj.•.1 of 11'lU"1">t1 itlO.nl I1I1l (for o -llmcmbmnes) to S('w ml milliuw lt·rs (ill SUl Il(' skill sin-s. ~It'lIIhr.'1 ll1('t.·.1105 to n . It is a passive pml...

tin'" II..e.". Blood ""'III of ....dipt·p tit lt· trun... tim): in II.. t· " a limiti lll!: value or tmnsport m ' axinnnn. it..rium . Iht' tissue (Fi..· I" (-h.. l..('1')1I1nll. via tln..~a'il rui ll lt'st i ll:u t"pi111t'Iium .Il3 into tlu.....r. nnt in tlt·lin·ring:tl m g to .~·Iat1alll ant ibiotics and all wo!t'l\sin -<"'()!l\'{:rtin l!: e nzy me illh ihi · Io n. This ill(' n 'aw in n.. Thus..~ ) Tissue B Permeability-Rate Limitation ..-pli]. a nd its rate.. Thr. M:I".l-ish'(' fad lital('(1 ' di rrll ~illn an' ~I t llr. n -sistance increases wit h i nc n·a..'l l nn I>..".....' U'It'..~ a.liah 't! S)'SIt'IIIS. k--t ..In l!' "'-.\ s n ll'lIIh r. which ran he la~t·. t ilt' ml "" ll\t'lIt o f d Ol)!. Acnw trallSlx lrt is d ist ill e !-lli~ llt'( l From p'l-\ ~i w f"d lil" h'( l d i fTlI~ illn hy th e Iwt movemen t of su bs ta u(:t· a~ai llsl a r u lIIu: n t ra tio ll !-'T..II~· 1. . 11 01 IX"Olll'ah ilily. Imuspo rt ac ro ss tilt' j<'j Il Il UIU is SIOW N fo r nh uel and llIa ny nit' A.I. and competitiv iuhihition..e..limit in)!.. ·"' I> n.•• (n)fl' hI.1 I. II.ly F " rom U III ' (If pt· rfllSion to 0 1\( ' o f pt'nllt'ahility ..... rm-mhram-s o f int·n ·'L i n~ thiekm-ss: t·.. a.~i ll~ sii'e a nd .1 IT"'''' nl~' t. Furthermore.. If II.II.. E\il mpll's (If (J(1in' t n"'-~IH 'r1 ahound am i ind ude renal ami hili. ('''''I'''rl· !l....... I't'rfllSio ll is usually expressed in un its o f m l /m in IX' r \1llt lllW (o r Jl\o lSS) o f lissut·..·()S(· !rdmport is n-asonably sj>t'(:i fle ami is inlrilutccl "~' ulliN slIll!olrah·s.. \\i lh illt·n ·......• . l' mnlmlh. dr-llvr-rs a lld n'llIon's substa nces.. tI.ill> 1h. "10.. t1:lI la~1._1 R< n.I h. T ritiated water mo.. ... ~I II(.t· o f et hanol and lIIillly small dmw.e.p<l"~.1 It.1 h' " w ".... lirnil....". .l( -h ..... II. hlt. pt · rfllS i n~ tissllt·s. 11-4."I:''' ill . Perfusion-RateLimitation Fi lt .. al.l 1M"""' I.·S aw.• •iIi.h~· . h tl" if n.· 0'(1"""""..10 .. p erfusion. · lIlay ari !'(' for lIlt· sanlt' tim!?: t'mssin)!. l... 11m ' " m... This pt·rfusiou limitat ion is exemplified ill F ig. I I~· tI.. t1lOm.1. polarity o f tilt' molecule.. than is tilt' singlt· t't·ll la~l...uM' (llTt'n T .e. ilt virtu. . ..... for t ilt' !lil\S. at'nlSS Iht· small hllt'st int' is simila rly !X'rfusicm rate-limited. I'i---J B).."' ·lnt·"1 tw· i.') . see n-non o f certain ad tls 0 111 of til(" central 1ll'I'\ U lIS svs tem .. 11 1t maintenance of tllis Wadit"lIt requires · mt't aho lit' t·l\t·rl{ At1iV >tran sport m il tl lt'n ' fo n ' b impeded hy lIlt"tahol it' inh ih itu r'i.): r..thilir:o·.e....... ti ..g... . 1 . ' ..e.po rt sySh' lll...lloin h ·..ul it'lIt.In llt i. v.".o f pas~.·n o f thr.. ..ul(" n ·si ~ t allt't· til dm. problem now litos in pt'fl(·t ralill~ tilt' membrane...non of IIlllll~' adds ami !JoN 'S. ~p(·(. or n 'mtl\ing tt From...! nl"ilil..u) ' seen.Ii"'i1.isla ut . 8-. t ilt· ratellmttatton 1ll "\1. sk p is IX·rfllSio ll...· r u f tilt' ea pi lbl')' t"p ilhd illlll.. lr rit·r-ml'i.hriurn " .. 'it""i ng any tissu e :l\ a wholr-.r"' .' in lt 1 Ii 1M' i..'1 of . h.·"h .1 .limililllt .e.....· 11"".transport o f vitamin B12 ilt'ruSS tln...epide-rmis an' 1(·" p eruu-uble to a tl m g.....' 'Mh l.1 "....e. t e BLOOD flOW Blond . \ \ 11('11 Illt' l1I hnlll tOS o fTt>r \irtually no barner.'" ...l\ill .t.. An exampk- is tln.. " . increases. n.)11· TPill.e u f certain sub stances across th e jcj unal nu-mlmmes o f a mi . At'{'(mli ngly. For tilt' sa me membrane....It. sllO\\1l ill Fi. tilt' slowtost o r ral c.rfll.. Tissue .e. C llamt1t'ristks in eonuuon wit h p...mhr-ll.ts IlIl<!t''W' Il<l-..... FI" WdmJ..l. and int estinal absorption of sonu.amino.ouio:".. ...• ''It''mhr-.i\l· fadlitalt"t! diffusion . ill commOll wit h otln-r (.". From lu me n to hlood .. es fn >t·ly thn m.....• tilt' lIlulti ple . " ' · Itl tlml{ i ·" ... o .... ~ hil(h... hlt l aI.•• ( ~~~..it 'lI" I.h ti lt· 1IIt'III Im lllt'.. IIf II..• 1>1<... .l' Increases ..h nu-mbram-s cauuot II(' divorced fr om fIt·rfu sioll t' J1l~ide ralinll\ . ·.ifk it>'.

II~· nM'II. 1>.O. tl...tw('('u .'1rati u" .l H '!"St.. J. ' . El ~'wht'f(' ill ' lin.:.. irn'slx'l1iw of p ll . whkh results ill illS('ns ili\.m. only un-kmized uoupolar dru ~ pe-net rates till' lIl('mlmuw.Lu nll.ilil. Pham. " "'t h~l' lritiat.L\tril: fluid varies lx-rween 1..-sli".....Io"l'Ult.."' III()VE MENT fHI1QUGH MfoYBiANES orhe r larger polar com pounds than for ethanol or water.5.1 ... lill1i li n~.·"'hroll.ul"la'. linal hl..:t ed is ('(IntO/I1('l1by IXlih the I' l l and tht. urine pI! fluctuat es I)(.·lit". TIle majo rity of evi dence s llppo rt i ll ~ tlu ..o."... likt· urea.... At h i ~hl'r hlunt! flow rate-s. IrlI...r ' lIl"'liU IITS.lh.taIKTS. WI" ".tr " I' apP'·lIl'll..: I" lr ."lrin~ ih r.1"11 o f g. .. TIlt' un -ionized fonn is assumed to 1)(' s u ffi<:i('1Jt l~' l i pop'l i lil' to traverse membmm-s. II....·m. 8. J.1.hilul..' body. .""Il'"" bIo:. r1. lncn-ased aeeutuulatkm o f d m g uri till' sk!. luwnsttlve 10 blood IInw (lo"i ~.p H fa\'Ors greate r i(Jll i7~lti nll o f d m~ !IlLS led to the I' ll parlltul/i 11I.'fllllt 'S lilt" !"llll o lim iting step..t1 .• . membrane 1N.1 lI"w 11...1.. Ii~r tl...~ i...ort li n~ to Iht' II('udt' rson.5 an d i .. not Io~' 101 . ly to changes in pe rfusion (Flg. n ! ".1 n il' P". At low h l(XM! flow mit's.. . ·· . 111 fmdioll UIl(' iOIl...... .J I~' Irolll...I1H It1lt. o UrHOtIized concenlrolion and fo r I"L 'it'S 20 .." l y.' tln- membrane so that pe rfusion lx-c omes ml e.• of a Illt'lillmu l(' when.0 t- Ribitol o 1.J K.. renal exerenon. .k"l'U lo:' ...Jtioli 1"'''('(lIIlt'S rdilliw l~' ..1"11 of blood..is fl O rrans fi-r. If it is not ..ocl w .-a..) Tritiated Water 6 Ethanol Urea o • • 1. i atio ll Frmu tln."".-. till' compound h a~ su lli dt'1I1 time 10 Ir.rm . Ilr. ' ..'5 a nd i .llff" i" int....M I.1....><1 lI""' . !ltl\\1" "er..' 1'M of the d m ~ al'(-. i A .t..11t I!l--S. Wit" I"" '"YI"·".. and ~iLst riC se-cret ion of d n l ~s ..O. and a t eqnilihrtum ..sd lmlch equation.'S tlo " .M .p I! p artition h)lx)t1l1'sb slt'IllS F rom stud ies of gd-st nl intl's ti nal ebso rp non.'1lti.. IR.lraw" fm . fo r acids . The.] \ TT 'OUS ' .. Ha. TIM ""•• of I"'L~' "I' a .. "" ·..'·ak bases and exist in solunou as an r-quilihruun hdwt 't'li lln-iou i7.·om·ahility !JI.. chan ges in I'll ten d 10 he much smaller and to show h-ss dt'..S). K ( Ioni zed concentration ) pH '"' p a + Iog.. T hlls.."~ III limitt"<. an d abs(J'l.n uf 1. .....bl.~ .. 22:f>.'1'·m 'i. II... have inte-rmediate pt'mlt'ahility charactensncs aenl'is tilt' jt'jllllll lll . IONIZATION Most d m gs are weak adds o r .l't! and Ionlzed forms .I.. S-S).. Some co mpounds...ter . l". jo 'junllm of ."d Rl'miw'h..0 Intestinal Blood Flow (mUmin/g tissue) . the concen trat ions of til(" un-Ionized sp ecies are equal Oil b oth sitlt's..'<. AcL''Un l i ll~ to thi s hypothesis. p.f"oc'~' p"'m d ..bnuM po · '''. th('()!)' predicts tha t tln-n....

1 forms an ' 9 and 9 1. Ca lT t'illt.l.. SoI1M· .ionized at all p i I values .of Iranspo rt wi th p i I is I'Xpt't1t'(l and has 11('('1\ ohst' I'\'l'lI.. sudl iLS ph en )10in and Ulan y b uturan-s.u to S.'t1.'t! is so 111\\' thilt Imn sport across tilt' ~Il t 1I1t'1ll " milt's mav IN.. Consider....]..l. Ko + log (Un-ioniZed concenlTOliOn) P 10 Ionized concentration P 2b As h ~ lt l(l ) = 0. W arl IIOs(' I' M values an' gn.H.{\\'t'l' n 3. . .ak. • ---. '1--6....alltil11.K 'idie conditions. For tllt'se ild d s d mg tmnsp0rt should II(' rapid and Independent o[ pll . .'t1 form .l.8.uKI " a' K: Strong Weak ::1: V ..' AcidS Bases pKa . \ \'arfarin is all add with I'M -1 .e. ..· rUll<1i..1t' IOn' "mph"t.r and an.iudl'lN.. Fi rst. {I' M (Ui ) is all l'Xitmp!t' of a hlL that is rapidly trans<it.t'xe lllplillt'i.-'.!l. Sl'UJIld . Oii' • .'nl. I'M less than 5.' slow eveu untlt' r tilt' most .8.IK· "'Ill 1 .'ndt'lIt of I' ll. IllO wi lh 1'M values Ilo tha n 2.5.pltunn luglu-r.t-.' att'r than ...gl's ill till' ioui 7J'i. At Ollt' p l l uult IOWN than tilt' I'M ... should thl'()ft'lit-a lly also dt'pt'nd UpOIl pll . [or ('''Imp]t'. \.~ (Fig.IKlllall i w' lrfari n. Sllll\\~ d langt's in tilt' I)('n '('ul of IIn·iolli7. Fif. 10 out of II tot al parts or 9111 of till' dnlg now exists ill Ill(' ioni7..l. tln.Imlt' ' '''Y wiclo·!:-·. n. IK· . Stal!'(1 d ilT t'n'ntl)". 11 roltin is to to I 1(' ill [a\ur of li lt' ioni7.'(1 form is perua-eblc. St'\"('ml t'(JIlsidt 'mtiolis an' ill onk.S.Ot'n('lmlp asses values seen in th e ga.1 d mg: i. equintolar conre-nt rutions of un.t' fradillll 111l -iulli7. "n ' '). S-6). 5 .. ti ll' fr. in pmd it-t' tl.\"I..e' . -"'- • • -- -c..> hnth "d. 3..5 art" l'sst'lIlially un. 1:"'''1'' .mgt' l . T Ilt' I' M is a characn-ristic of tilt' dn. .'l1 limg witll p I! for .'rk. i. \"( 't)" \\"('ak adds . anti o nly 9'1 is IIn·ioni7. Ilupt·n.l. till' pl\n of a compound is til(' pI! at which tilt' uu-iouized and iOlli7J't1 romx-ut rutions an' equal.lt'tion un-i onized only dliUl~('S dramatit'<llIy for adtl..l hy transport . Weak '-' ...1 illlll lln -ioni7J'i..Ki tls of tlif· ' 1M \"allit's. :\ si\lli"~r ana lYliis indicates thut a hiL must ht' \'t'I')' w. alt llO lI~h transpo rt of s(' SS ' still sln mgt' r add.. " ..l.).0 and .troinlestinal [l'n'nt 1 Irat1 <l1lt1 till' n-nal 111111I1('. At one. for transport 'i<' tolx. uud for these compounds a ('h il n ~t' in rate.'i. I'M .CHAl'TE P8 I1S H ."....K'ross tilt' gastrotntes nna l harrie r.-... lhc h. 111t' p ll r. == ~ Strong .Ionbr-d am! ioni 7J't1 dmg exist in solution at p ll -I.ln.R.~..~ n( .. it..1 ·y . Third. 50<J u fl h(' d m ~ is uu-iouized at th is pll. i.I. provick-d IIII' ulI-ioni 7."<lhlt's 11(. -. tilt' l'l 'II\'l'r~-' of those ill pH S. with 111\/1 .

.1 ." nll·i...."tIUl.iun i /~ '(1 form ) ('apa M(· of Ira \"l' n>in. p n spuntln-liue. All l"\id('iIl'(' suppu rts 11l('M" ('\)'It"('taliUlls.ml~· (.(('m s. Only \\. "in. ! (IJ(lum h and t1hSfIt'iall "t1 (ullho llm l) for ms of tlndm ~ {'..s .· with l1Nl \t m lut"!i h..· fr ·· l Ii"" n".1I.1 .' t'(luilihriu III lit's. . ...!!:l. tI..m l t'Clllilih riu lIl. CUIISf.1dlil/'Jo:I~ ill II. t1 I(~' h.1l1t' is )x'n1lt'ahlt' un l~' to ull -iuni .~ .(. is unlik r-lv 10 II(' accurate.ionized [or rn. u..l'i('s slllmlt! hI.. ~l 't it has b eu appli('tlmusl \\i ddy to pn -ds-t tilt' illllu('IR' >u f pll Oil tI u.. Anunul slud i('S '11M ' ludknn.."l n)i " l l's l i ll. . lilt' \. hid l lioll s..1 .....~ "It.1 .Il• • ..n.. ·"1... ah hougl. 111 "Im ng.!!:l..r('t i tim !!:..' unsre. ~· .m lit. hindin!!: ts R"\'c 'n>ih l(. lllt'lIlhmll('S and.- "·"wi"... tl.t to II(' J?.. I' M ...... I. "' 1. => s ... c!i\MIt'i"lioll (If lIlt' ........ i\'l'II o mll.....\-" llml of .'il!... rlu..r~lh l(.1111I t. tho....I . . appn).'dt"tl.i" II. A" ori Wllally proposed.ult' s..l!:ly. I'll " .~M''' ..... himl in~ allt! ion i /~lt i oll a n ' . ami Ilsu ally SCI rapid Ihal an e-quililmurn is c<>.. .1 1 n n 1II('ml mll)(..I~I' of theM' I). . :' fll " . · inlh ll' nl't' of p H 011 a mIl. "'ill.l!. · "'il!... III )\\l '\ x-r. insla lll. Iimila lioll is ill !)('rfUSioll. \\i lh uuly 11I11' Sl'lt"l'i" s (UUho lilltl . Ill'spill' its ..(('I.'(" mls...• fr.l\lIla pm!t'ills and tissllt' t. ..lIJ('s occurs.I .. \ \ 'hen.. !. Ill )... PROT!lN BINDING ~ Iany d n l~s hillt lln pl.~ .· r Il<L ·S.!!:t'!lt'ml aplx'al . ~a.116 CHAPTER 8 t "llit. ..Ilt'n1. -11u.!!: UII lIlt' ra lt' o f I1IU\'l'lIIl'lI1 tlm ltl~h il IlIt'm lmuw t'. on wln-ntilt' ralt ' lim itatiun lit'S.· . !l'1 idt s. in. I..rapid F rom a k-ss addit' r-nvinunm-ut.1 " ssill..1 ..(lInp(IIIC'IIts (d ist'IISSI'(1 ill C hap.. '< 1 fun " .· r""!(t' of : .hrr uuuh-] "..110 1.. ~sl's t " mu ~" meutbrum-s..""..inllul 'IIt" uf p ml( 'in hilltlill.·. ' 1lI0 'lIIt'lIi of clm j. .It' m il' ('IT ("(1s when j. tim !!: . .".'t tilt' dt strt IJllliun (If all iClll i. I' ll .J'M· lit" . O nl. at'mss ..!!: h ltl lal"J?:t' 10 do MI.IY lilt' inllu('''('' of p l l u u tltt' IIIO\'l'III('nl o f wt'.r-udelll ah'oll rp liull. pll fur ... An :onlill.d for t1WM xis '. at a slo'" and ('ffal it' m it'.pmlt'in -Iltllllltl for m IIt'ill.!!:" nlt'lIllmu l('s....t'lw mll.'Ill (If wlMI pnlt''ss rute1hl' mit ' p n It"{'ss.J I Ii" d ".o l almos l r-xd ll si \"t'I~· ill 11ll' iOlli.(I III( ' lIl hr..~s M I('i alt... pKa 2 pKa 5 pKa B .l\t ·S .l"S.111 ... lilt' p l l partition h'llC )lllt'sis fails to expluiu certain OhM'f\'allCmllds (t'...It ·r ~ ../'/' "d .. pI! is p n-dicn-d tn aITt'<.<1 ~. 1)...tweeu S am i I I.' pmt" "s dt' llt'lItk hO\\'I'\'I'r... " 60 .. ... 1"1Vo1"'" 1.·inlli...~ lril' transp ort should hI' sluw. \1 0\'1'11I('111u f III('M t'(lmllClIlnd..1 't.1 . m1 'In' alwa.~l lt ...l lo lit.i...r 20 2 3 4 pH 5 6 7 B ptll1("(] and sl.. al l'(luilihrium al ulIlinw s 'Ultl lllltl('r \i rt"all.penetration of tilt' iOlli /~'l1 form o f ma ny adds ami I ).....!!: nlt'mhr.s r ' Ihnll.Olo \ ....'lJlly. O nly if rln..lk adds allt ll ).\' .it . is p ll-(I"pt·lltlt·ul tra nspo rt (·xrll.11I" W ...I n 'fl~·r "" .. Ihou~h al a Sll)\\"('f mit' than lilt' uu.1 nu-mbram. ~ . unbound d m~ is Iholl. If tI.11"".~t1n 'l:t ·" .·• " . "-7. is iml('1 limits II.!!:. 1e ."i. \ '1'1'.uws lin p l! -tlep.1 111 u f p'L !!: 11m ".lI'Y . :\ \"ll ridy of fl" ..."".run-s IIf abM)'1)lioll e and di strillllliun .uwolls n 'atiiulIs.0 . TIl(' Iilt. ~h IIII' ~a.. AI Iht' usually low p H of l ilt' ~asl ri(' fluid . l'..r.s iuni.. Ilmlll.d i.IhI.... problem is nul OIW of movr-nu-nt of dnl~ . \il'\\l"t l ill mllt'l. If t"t' n ' is a IlC 'r fusinll Iimilalioll .tahli slll"ti wit hin milliSf. all t'ift'lllll"I'U1t'(·S.al ('fluil ihriu III ill all ('<LM'S ill wh it'h tilt' nwmhr. 100 80 pKa 10 1' oI". ~ 40 · . in OlU'll('(' of p ll on 11. t()\\-.. tllt'rt'fllft" any variation ill pll is 1I 11 I ikl 'I~' to ha \'{' much t'lTt'( on :1 )('m il.m lx ' ..Iilllitatiun is in 1 )('fIIwahility is an t'lTI't'1 nf p H 011 mh l'xpl't'tt '(l. 11)(' .tl.i rt llall.1111I11011. Hul l. 1"f '"f''' . (·.. I. TI lt'S(' observanons sll ~t's l tllal 'llianlitalin ' pft'llidiUIl u f lilt.fl. s"d."" .lSSllllll. tilt' p ll partitioll IIn )()lh('sis n-lan-s 10 ("\l'nts ut equilihriutn.

tin.o f tra nsport is loward blood in mesenteric ca pillam-s. tlu-se concepts are mccrporated \\i th ot he r p rind pll's tlt. e.lsslige of drugs a cross me mbranes art' iIIlIM. gol~t mi n !t's .uw s. ~1 ()l t'l·t1 lar siZt. within . How accurate art' ('<teh of rlu. so is its Ix' m lt'ah ility.ump lt·tt· d istributiollof charcoal.s.1 o f ' p llt'lloha rhi lal fnml tht' lxx ly.1 1.('tl l'(llllpnt llltk USill~ the fl ~ul"l'. t 1'\o nnally.aHllg ' \\i tb d mg absorption.:t'r un-a. phenylbutazone. 11ll1s. Brit·flr d iM. c. for the ~ast mi Jlft'sti nal lra(1 as betng unidin-c lonal. passtcc factlttatcd diffusion. is \irtllall)' one at all times. I'.. till' terms: pol siw d iffusion. 3. tinal tract . distribut lou. nwmbmll(' uf tilt' tis. all alt eration in p rolt'i ll conten t is not expected to alTtl1: rate at a gi\"t'lll'O Jll'('nlraliuJI . tilt' lu nn-n of tilt' ga.t'S al'nlS~ I1\t'lIlh nult'.CI-tAPTH 8 117 hu um l d m g am i di ffusion uf lin.unbound d r u lh mll ~h tilt' membran e mus t occu r so g raptdlythat ra tes of dd h·t'l)· and transport are t'<{IJa1. whether till' ove rall tran sfer Irorn hlo(xl to ~ I t luuu-n is p~. with \"t' r:' higll coucontrunons o f d rug placed int o Ibe ga. and \ pt. 10 think of d n ll{ absorption in STUDY PROBLIMS (An ~wer~ 1 Study Problems ore in Appendix II.ga. dt 'st: rillt· tilt. active tran sport. As prt'\iuusly statecl.~t roi ll t t'st i llal l rad .l\ si\'t. Pmn-in h ind ing in th e '\(ltlt'l)lJS phase-s dum nlshes Ih l' IX'n1lt'ah ilily of IIwlll hr.stm in< tesrinul tract ads as a sin k for removal o f d m g fnnn blood . . \\1lt'1l11lt' surf'll" an-a of a nu-m hraue is doubled . t' ~ l1I pl t'.lfio ll of ild i\'alt'llehart:oal Oil rt'lllo\ 1I.~s lilt' l"lpi lla r~.'us."('n rate o f delivery. Om.~dlt. l low eve r.T!tw.l1 of o rdl ad ministr. all t'(llIal to 2 ).l'lllar wt'ight O il Illl' pt'nnt'abilil)' for a S( rit'S o f ' . E\'('II with t. important applil"ltiolls ca n be mmle of transpo rt in the oppos it e dtn-c ion . diffusion across a uu-mbrane stops when tilt' concentrations Oil hnt h sid('s art' tilt' same. lilt' concepts o f th is chapte-ron p. Carrit 'r-Illt't lialt'll tnlllsport is Ollt' in which t' I1t'rg)' is 1J("t"tlt'l! to tran sfe r dmg across a rm-mhruue. t For e-xample. \\"{'II a. am! out of the b(xl)". d.ltISl' o f extenstw ad." Oil blond fluw to ti lt' S(' various silt's. phenobarbital. and digitoxin in cases tlf dmg U\l' n IUSl'. In this case.. now intlueuces lb e rate o f transpo rt . Iollo\sing ora l udnunistration .(llllflt llllld s of ('(fual lilltlp hilil'il)' (od anolM" . littlt ' ' uf tilt' d rug p rt'sl'Il!t'l1 IlIUW S into lilt' tissue .tends. t'fft'l1: of t1ollblill~ lllolt. 2. d!t'r part ition l'(x'flk i t' nts o n I t~ M. For a ~. is all importallt ddt' n nina lll of pemwa bility. In lilt' next th n-e chapters .tll)' lndin-ctioual.net ran. th e site o f tmn sft'T may 1M. lIt.· art' t.rq )('ah 'l! oral administratio n of charcoal can hast en removal Irom ti lt' hod)' o f d m gs sueh us tligoxin. Tilhlt' 8-1 shows til(' ('1Tt. If p -rmeabihty ts ratt'-lillliling. the ratio of concem rutums al'm.stmintest inal trlll1: or Illlly apply to a milch lary. " ls. Dt'fillt. 5 .sorp tiun uf d m g to charcoal.' n-strict ed to oll l~' a small regi on of the. 4.followill l' statements? a. TIlt' rest rict ion depends Oil th e dist ribut ion o f charcoal alo ng tlit. \\'ht'll dls trihutlon is perfusio n-ra te lim ited.J 0 I. F igu n ' &-2 sUllllllari7A' s tilt' n 'sults of skin pt'ul'lmtion for a \1I.Jrtalit to all undcrstandill ~ of moee ment of drugs into. am i elimination.s tIlt' roll' of ioniza lion in tht' 1Il0\l'lIlt'nt tlf \\'('uk udds anti weak l"lo. RIVIRS IBII NATU RI OF TRANSPORT It is importan t tu n-mcmber th at dmg transport is gl'm'r. h~' <I lTt'l1: i n~ tilt' unbound couce-utrutmu .ility. altered pr otein I )i fl(!i ll ~.' rfusi oll rute -lhmted or 1I0t depe-nds on the pt'nm'ab ility of tilt' various ti mdion alll1 t' lIIlmul(' s along tilt' It'n gth of Ihl' gnt a.rit'I)' o f tlll-ioui7. Ut'l'.

Itw. &(th.. 70 .lah' tllC' clearance o f phenobarbnul into til(' alinw llllll)' canal during t reatmen t with d Mrt'tl..".. tww</' a """O!P'"'" ... H_H.. h..small inll ·slillt· as iI sillJ?.~'j I A~. cJ M ooob«lI ..lt' l11 lllpartlllt'llt . 111t' ck-uruncc value delefmillt'(l in ~UM should apply us wdl to lIIo n ' lIIt'II1 o f dmg Irom the hmwu o f t ht· ~a:~I ".'\(K all't1 wit h abso rption wln-n IU L of lIuid is in th l' small mtc sunc..~ .11.5 M ('JI"..JD ..._ ..' ... ...h((JlM n -'lIn. (d uring In 'a l lllt' lll ) "" C L (no frt'af llw lI l ) + C I.lIG ~"""'<J"'_<J ~.. concetve rlu.*. <I Iv . .. ..111 CHAPrER 8 .'i. lIinl: C I. KIllMing tha t tilt' \'o IUII II" of d istri butio ll o f ph t'IlOha rb ital is I).11fe (Heunl 36:l: 13 03 :!...~.......<>"'IT""'i... 7 """""I .hiM·lifc· g .-. 25/ 31000l-3 10ll 1QS4 . a.".. . a... (hy d lan:: oal ). Fo r th is i pr o bk-m.W""""....i lltt-st i llal l m<:t into tln. Iffect ...179 d ~ . Teltle "'1.. ..... ~ ' ..."*""._~doMocio<~ etoooa:d jNM. CII. ('ak1. If til(" llIajori l~' of lsl d r u rt'1Il1M11 and ahso rptlon O{'(1 Irs i ll Ill(' small inlt'stint> es timah ' the.

' IIU' lafJtt'f lilt. Ilt'i ug a complex struct u re.tlly. tis! the Ioebs Influencing d. however. am i dll rali ull of t·fTt>(i . maL. Till' gnuli('lIt is Iwulltai ll("C. (x>('1 l ni n~ al this lim! other sites of ahsorpt km . l1lis is lIul only h(>("lllst. Distinguish between diuoluhon and pelmeability .(.111lt"C. li· lators]. Descnbe ibe inlluence 01 decrecsed permeability and surface oreo along !he i~lf101IfOCI on the pedcercoce of ool COflslanl"fole release 5~5 in vr.1 depict s 11ll' mnm-mus slt' ps il\\l ll\l'd in the " hso lVtiull of a llmg g1wu nT:. that abscrp non is conskh-n -dlu-n.· absor bed. us 1I sou rce of va riahilily ill systemic T espm lst' am i a.1 the ove-rall mit' and extent of dnlJt abstJ'11tiuII Fnnn till' gil.1 (·xt r. that ('\ '('11 for IlJost ' d nags jnte-nded to act IOC'lllly ( '.' 9. hut a]S(1 lx-c ause it iIIustmh's lIlallY sou rces (If variallilil)' t'Il<'1 1 1I1ltt' R11 ill dmg allSorp lillll. JtI~· ads 1I. l' lJIpha~i s is placed 011 ahstllV ' lion follfMi ng oral atlminislmliun .. ul't'asiuna ll)'.g.l of tht· (" .n-mainder o f the hook II should I. Ahsorption is fanJR"C. It is primarily in thts e urn-xt.l lolIgl' f.'nls . ahsn rp tilJlI is a p n > rt"Clu isitl' fnr ad h it)'..t llt.ote-limilalioo!i in ob!orption .'(IIlt·lltly ad minish·n . k('P1 in mind. 6 .. Fi~u rt..-nt ra nou Wadi t·nl is pn·st. dllrill ~ abs o rpnon may cont ribut e to . with pCJIlIcular relereoce to !he ~lCochemicol pt'op9fll8S of !he drug and its dc»oge lam. 1lI ( l\'('IlW IlI o f d m~ F rom till' sih' of app!i<"lIlioll lo tilt' s)"sk mil' ci rculanou inllut'Ill1' S tillw of onset. Drugs an' m os t fn.()II ~IJ abso rp tion fmm olher sitt' s is di scu ssed.and th mll gl. 1 119 . 5 . 3 AntiCipate !he influence 01 ~iCOChemicol prope!tie!i of a drug on .oouhon rale of a dll'9 . 11lis chapte-r <leals' .. lo cal am-sthcncs ...i ll~ a pR >(1s(' IjUlllllitllli\'1' pn'llid iull tliffk llit . Anlicipole!he role 01 goslric en"plying and intestinal trom.·ul arly. A I I I.ABSORPTION OBJICTIVIS The reader win be able 10: 1 Describe !he sepsinvolved in !he ceclabsorption of a drug 2 .oul tln.of dmg tlll·rapy .1 in thego!Jl'oinll»llnol absorption of a drug. topi ("11 lI~('n ts .111 until \i l111all. tilt" gt'ut' ra l p rindpl t'S gm'l'm iug mil' and extent of d m !?: ahsorption . Tilt' majority a rt" Intended to ali S)"Stt' lIlk'l. XOIwt!1('ll'ss. 4 . o m l llKMlt· o f ad m inislrat inll is tilt' mo st prevalent for sysh 'rnil"llly a(i iu ~ d n'gs. .llly. .! .uiahilil)' ill d n l~ rt'sl")(lIlst· and. and for these. \'(1 11 111(' of di st rilmt iull of III(' d nJ ~.i ll.s tminlt'sl illal lmd . L m <. IIlL~al d (>(1J1lgt'slallt s.s a means of (111ltm lling the conceut rat ion-time p m fil(' of d m g in the b ody.. and .I{M lIlid appn"C.no dm ~ re mains 10 I.!l'mso l Immd ll. Dd ar s or los ses o f 11m ".! h(>('llUSt' tilt' I .. mydrialil's . much can lx' IIIJ(!l·n. intensuv. lIIallY uuatmnic and ph~'SioloW(' fadOl'S afT("C. m ay result in fajlun..S a b ~l' sillk.o. A cone.ts ob5orplion from diffetenlsile5 of odminislfolioo.

COIllIIIOIl e xamples art' 1.. 1. movement of dnll{ tlmlll gli membrum-s han ' ht'('11 t1iS("l.. ali(I pll .\ bso rp tioll of adds...of the uu-mhraue.. ha~ lx-cn calculated to he alx llli 20l} ~ 1 2.. ..{'ton.l... i.II ..absorption sln .I" h"" or " .. h loc ltl flow an.. These f. 1II t! oth ers are 1I0W {'ollsidt'n"{l \\.1 ..lCh minute. l11111post 'll lal).\:ail..I I" " n tit I.' ·II... hO\\'t..lid.. tI. :\ ....-~ ...l1I. weak adds an' 111 0 rt' ah~orh('l l rap idly From lilt' stomach at pi 1 t ... " 'K'(M ll h' n ...imp o t determinants o f tilt' rapidity o f absorption.. Ihl' uatun.1... "I .' . the p O'l li{1ion of ti lt' p i t partition h}]x) tlJesis.iI" hility.l-SS through membranes..I . llml an t'slima! l'{l I L of blood p'L 'iseS t hrull~h the intes tina] l'llpillarit'S l'. r " .Otha n at p H H. 111t'S(' llppan'nll)' l.rrirn ..oL'ln'illlt"Ii " .... TIll' (1Irn' sl...t· of d mg fm m a solid phanll <lt't'uticaJ fonnulanou..-. T he tot al ah sorpti\l' urea of tilt' ll small illh·sl ilw.~ thnmgh tln.120 CHAPTERQ P.ag(' (If dn .Inol:"" il fin ' p. .Ii. Surfact· an-a ... r rurtl. t. Gastrointestinal Absorption In al'(unl.a h11'15 am i ca psules..IliOIlS run lit· n'l'(JlIl. is always much f'l\ ft'r from the I('!is acidic small Intestillt· (p ll 6.II I \( ' so lid IMrtid l's cannot p .. . '<ttT" I lltu m _ p\t1" t".. ' " " MM·" . Bes ( '..hlood is a pn-n-quisite for a!Jsc)'lltioll to o ccur. Til <In sn . a d nJg IIIl1 s l disso!n 'lo he absorbed.the physicochemica l properties of tilt' molecule."'.from thr.·r.... permeability.l l.. III(' dnlg must b in solution.. ...6 to 7.)(l1It1 i ll ~ c sttma tes for tl.Iv· .D. solid preparanous. \. TIle pt-' nllt'llhilil)' Gut Wall Portal liver Vein To Site of Measurement Metabolism Metabolism To Feces t 'IK' ". . 9-2 ). \I any factors in fluelll'(' tile rdt"L<..KI Sl iM uf 10-"..... I. li.lw n lltlCl'f l tiC is a compreln-usive tenu tlt'fluting the study uf the in fluellt't' of phannnceu.u ln ' witl. is fa\u n 'l l o n a accounts.f tical fo nnulanou variah h-s nil III(' pt ' n o n llann ' of a d mg in dr·o. rtan l's lx'l'ially tln. in ito .II is ..t' stOlllad l art" nnl)' I ~l i: ami 150 JIl l Imin . JI:Ill "'all ..y '''U::-' 'M ill tiM' ~.. and tilt' co nw J"S(' holtL~ for weak haw-s.li' m in d"' lt\. TI ll' intestine. lt'l l. .small mtesnne. Ihr" ujtl....5 ) than from tilt' stomach (Fig..i lli.Imjl. .hilir:-'. S.:t'ly of nucru.lsst'(l ~t'lle rall}' iu Chap. '' 11I-11I"' oJ " r .." ..] ItMM"" .I"'''l lt i''fI. . 1'. ABSORPTION FROM SOLUTION St'\l'ml ph~"li i(Jl()¢c am i ph)'sim l factors that dt'l t'nllillt.. 1>i." I". 110. perfusion... Most drugs e art' adm illbh'n"(! a.1111. Ih respect tn drug eleorptlon..(lTlfli{1 inR obser\" .1.h llillit l jl. lncluded a mo ll~ t1WIII an. l' n·""'llIi'i' . " r I" " '" tno.. and for perfusio n rate-l tmued absorptlou.r-r.....'1>....l. ' .... Hi..mem branes di\itling tlu..I"h"u..

J. HIlI"I'" S F..~ ~..Ir..K!'· of " " _jo . ... h. rt.·" . !It>rplit. Bt"t'all sc' absorption is J.. it" .. I'<.tsl ric muco sa.·rmt'ahility.1onoll)'. ...•'.".t sh'P ill III(' SIW o f dOl ~ ahsorptiou...ran .......i od"I' ra"'itlt· olt par· at..t<.....~' .".. o 2 Hours 3 5 T< lnll... hil i usually 111(' majority of d m~ is still absorl Jol: 'l1 t1 JnJtl ~il ti lt· int estiual t·l' illlt'litlllt..'" " '" IIt~.. oi I'n'P"'nll". .l1nitl. l>itT..I t. I'tu.. I ~ I'.. II. "bllt... pH3 i Mo. ... whil-l. Intt"sliu al Ah o.t.fit.at i" it.. ...percentage o f a d ose ahso rlJol:'l1 t1Jnltt~h tl ll' g..(' J.m. suiOl".m !.""''1' frunt tI.i'''' (3111 "'K i . Slo..Irit. ........ pH6 o 15 20 40 Minutes 60 80 . 1'."'i ""I'I".."' . J. . slows l:'l\ l rit· (· lIljll}i ll~. 1>" ' l' il (".. expl.· ""'I't~i"lo\ I~' pn. ../. M•. the ahscl'l.• "' . 01 (.. ('l1 Gast ric E m pt)·i n~. llit· "II1I~l"~ 1 It·". ro" "'1' 1I1 f~. .1I 1·. lI. "''1ltio...C:..1frum I> ol."l/. It.... Dmgs that inHUt'II(....CHAPTERQ 121 of lilt' illh'siinal llll' mh nlllt"s 10 dm~s lIlay aisc i lJol: ' fi!:n'ah'r than tlMI nf till' stulllat.'i1S J 100-1 199.II· tI( a1... i"" "f 110.w than [rmn th e slo tllad l... ~ .. I.I...t' ..ptood ·il l... Hr .. Hdt'ltliort o f dOl!! in Iht' stomach i n(·n" t~·s tln..~ a1..lruK. 9-. I ~.·r. ' l1. or neutral compound s.. • 6 .."IlI..rt'll!t'r po·n...." ) al..x-ro-onh-r.... .10· \( ./...) .. F..1.. tl. 1I. !RI... .".. whk l.stalsis onto the absorption sil('s in ti lt· smal l inl t'slinl·. l>4Illl.... 11Hi1l.. ~ .l ~1) .. M... ..." "Ol/.'{"(' ..) Intestine.. I X .-l.' Eff.tiult of all ("( I m pounds...". ..." IIl ~i. in tilt' maxim um p r.'»\.r Ii.. more than t'llllpl'IlSllh! fur tludt"t'n·:t\t "ll fr.li'''' ".·. .(1.. 4 t·la .. i"" (·····1 (" "'1 . 22.". jI.: I>".. '. . ' than [r um llJol: ' .. 1 0 .' iucn-ases ill surfat" un-a. is F aster From lilt' (small) inh·sti. . tltt· illh'sti ll(' va ries ill its lltllltif<ll't·ft'l i pmperties and luminal compoouon.2 . . lilt' stu llIad l lIlay 1 ." .... .". . hav-s.<.10." (---I ( I "..r-<oltl " ."". m "..t1t. Food.1 s".. lit litis Hog..lkt·1l nil an r-tuptv stomach when a rapi d ouset of at1inll is desired.(I I.. .... It. ..h.. Stomach...01.J tI . ... cspl'l'ially fat . n 'p~' ril':h l ... Indee-d... 9-1).." ~ illlmo. 1-. u~.......' pulw s of t1 nl ~ an' ('jt"( 1I'l1 h}· lw ri...6 1..11 \ -...bnll.oTtit'" II"S..) .It. -.n rn.....dus why t1m~ an' Frequently n "t'OlIlllw nd t"(l 10 Iw t. 1'<"" . f 'l..1..I It.·lot" 'l: n-."".( I ll 1I1~ h '. lud " ../.~·.. .).I... !>l. : 11.\u alTt"t1 tilt" mh' of lIhscllVlinli of urln-r dnt ~S ( FiV.t./iI.11·" ."l>t io.. hU " "' I<otic . I. p.. of 1I. .. m..~. ..\1 <ot...·" (15C1O "'K) lnriuh'r" .·. Ihi..... I" " ..I..lifM... .nn>Ol. it'WI'l1 as a rt. ""•.. .of ~..~ ..': rl' alt"f in the small inl l·stim·.. rmi.>t ~-.1I'll fo (0).':asl ric ('lI1 pt}i n~ al..I>">tp! it.I. tln .)..( . a "..... 111t' int estine lila)' Ill' bn><ldl)' d hidt'll into tilt' sma ll t·l p:.n o( Ol/.. 'l~lrit· t' lI1pt)i ll~ of liqui ds is app mximall'iy . ill ." it•... Th ruu ghuut its It·ll~h .lt1illn of un -iollizt"ll add ill the Inu-sttm-. ml' H'>ho·" i.1. in . I ~ \\' .. J T.. 11wSl..10"(... Hli3 ....I"np h ...i . I"n~. ' M 3) I..ti.• h\\7."[Xl'iitory o rga ll From \\~I kh >1.1 (al... l rah " n "' HI . "rl'tlm. Iw tltl')" adds... Sd ...·n.. ti"I' . 9 . ami blood flo..i .oJ"p lin u ... -I." I.• ( . .'ori ....' " t " . ~nt 1t. H e.t\ t ril' t'lllpt}in~ is a l"l llltmllin). . ill I'll 3 (.. ( ..

... -.'50 Wmo !.( r"'''I. II..l\l· nii ll ~ tiM' ill h .d l . 1 hy tlw ih-oc ecal j llll(:tinU. !I ".·1lI 1l 11 tn ('O ll. " .I"':" i.r....... " · 11 ...U6 . j~wr in 11. limit :lh'"0'l)ltun fn llll an oral \Olutiun. n'rbn .l.. a 1Il(·ll... t" til . Pt·nrwa hili l)· ."~I "li """' lrwl . . ."'.S ill IIII' It"nnilla! ik·lIll1.·r-IIM'!li..••11 .. lllt"l. • . 1 ' 11.·nl ~·ll i~1 0.· n_n pLoo. n J. .in..·fun· ll llall~' rhilll: In 7. in Ihr .'" .. ...0 in Ill(" d.t-"l""'" IIf .lilll· ~·par...' .<Iuudt"Uliln In tilt" rect um .10..:.'lla.t ..11. < km :u alltMlIld.itt· alu lIJ....'(·m ling ('okm . w{.." " 01 '" t & 1.1 (p .lr. Snrf'K't· an-a Ill" umt It·IIJ.....llt.' H. It ... -III1..1I as ... (mill the. tl. Ek-ctn cal rrsisl all('t' .. \ ' I'I·m w..J .tuw alltl (n )ln 10 In 24 hr or eve-n lun ~t'r ill tlll· la~l· huw.Iar . lu app lies to all (1m " T k'Ctll.Ii<. I' "I1>1. I.~ lU' 1' .i II.ms it ti llK' of lilah-rial s is an"lm l3 to -I lir in tll(· slII.\. ~"Ii. l tr..· " loI.· pn"d !\(' (I" antita ti\"t' pwdif:tiull u f inh"'tilloJ dm!: ah\ol'r ptiun di f· fK'llt. W...L...... ". dlolh in " \t . lP· S.II.......6 ill t he' pn":illlal s mal l in h"lOt ilU' rhiuJ...'..•.>1_... 500 400 Stomach Jejunum Cecum 100 o o 4 8 Hours 12 1-lJ:. .r.i n¢'1.J >tpIi<"." i~ !lot'!"n d.· and utllN l'Ulllplt ''\iti... ~II.. n...l ..· of liJ:llln(.tKIIIS. H.h".4 at lh..·n·nl pa rt s of the .rman.~un· (If Ilu.. .(n 'lIl II....It.. at an)" UIlI' . p ...'t ilNl\ Iot·t\lol " ·III-pitlM·lial ('1·Il...ti(' a nd nwtaholi<... \0 110 ..' I..-<."10"'''....k'(Tt.. Ilolt" ""..Tt·it....w. II .. MI If.'II: 1.-s Ir. ) p". .." ....• pn.. .. l h .nl'h lho· \t l.... ' II'" . 1·IIlIlt)i lll.'" l6 "'I. J "t.UIJ(. . \:.· mwalt' mo n' fn '!' ly tha n L... S-5. TIlt" IllFoUl p i I.·.«1.rgl·r (11M.. '. IIf 'an.....i. n M"5ot" \ lIlntillK' ''' IIM 1 I\1' l. pt.. 1ar . ) h'TKl~ In . i" l" II 1""..'w· pn~"5~i\l· I. . i lIp101t~ 1 Lot IF .. ill this (""d-~' tilt' jejun um . P mt(" ol.0 tl ldl <Io1~ u]>ti( "' Irom tilt' 111 1111'11 i.q:.... •• -. 11".. pI. fro m lluUI.-I'I" ph-l"'" 3 hr hm lM...• ..122 amlla~t' i ll{l . falls !iharpl~' to 6.. n"l.~· important for pol ar d m lt'. . I'''i ~ h 10... .J' ~ I . n ". illustrated in FiJ.It'<... tI....I"'''J'f''''' ~"".. ti IM l'{Jitlwl ilim no ' I ~' IMMI c... S..-In.K' (""a II hot' ~lI ffici.."... P'""'. ...-<... and fcKi litaft'C."Ia...(.i ' "1101". 'I. ~maIl ( M.."t>clillt· I...e.... lioILrn '~" (" 01•• j ".mal l mnk"l. T.1.\ n. S-S ..· " 11... i .t " 'Mlk l ra te.tlt'tht.· " "larl~· \ia thl ' ti"ht fUIJ(...ti.. " tl.. II ..r \\loj ~flb a1 1\1' 3.. " .~ o f tilt' jum:tinlis bv-tWt"l'1l lilt" t' llit hd ial < :t·!ls..K1i\.l...1 11.· r tlK'!\(· c.· Ih.." .l· ha. wtth an al'A )"i...lil.: mic·T1Jflnnt..... li .. .11..·. .">lm.. . .'i>~ J_>tpIi<II' .r \ l.lI'pu rt s~"'h"ms an' di stTiIJlltt-d altlll~ th t • illft"!Ot iul' ...I. Jy.a the transeellular nr poardl"t'lIl1w reete..'1h tit·· (·n 'a. . ..>1"'. "I~i ..llilit)" ill ti M \111all inh. nit· i\'SII(' (If In(tk'(... TI .~ 11I...>start of ti M 1"('( ' 11111 I....~. ~ . ... ~ for r........' ni In (Imp n IT shotT I)-' with flM..1 .rj "n. ralll"b I. S.. As shown in Fi ~.L\t ric..tirM·..I_n.......".. .c' n7. .. Sl t-.. t:..· ('0&'11I than in ti ll" ' lIIilll inh'stillt".... n il' po·mll·ithili t~·' ~lIrfan· area p mdlK.'I>di · o:-fTf'(·ti ·~'I't'"..In l( ..\ a (k'<._ (in Irnni dt.tllpl' ..I!t·c1 pnx. -. I... 11wrm.. "''''lI: tl.. v-veral ""Iwral fl"<Iotlln~ l·IIl(·l"gt·. t. . 1 11 .o . 'o f ft'll in n-.. tl l . a.wll i.I ". Tr.. .:: 10 7. Io...1 Wnll"') I"oLu "". IIf n ~""-.I~ 1.. (.1I inh. fl\"t'r.1.. W ..tlt1-'Tt't..50 "'It ..."S"'f"S... po'rfll!>ilill mlt-·limi h-d ( Fi~.m itil lint' . \lolt'(. I" ft.tze is (Mrtic....lri ttin· ftl. .J1 ~. druil.<.·. is 11I11(·1.hil~·-Rlrf >IR".· " Io"ll ltwt tI.•• 1. 6 ...:..orrt" MI .. ' of ...it.. t ..i ll h'lotillt~. Ahhuu gfa th('!\t... not "".: 11M' inlt..-ry .. flIIYlI-I IY-t ..01 ("111I w .'ullflihul1\. II...) (.. Il..(.... Y-t ....... it.1\lI .. 11M" ( "''{' n'i(\(' in p .· ".· .t' in tI ~ IJ nt-til-s uf ainurptiull wl M dnl ~ <Io n' pt Kffi '1I ill (!IIT. 1 sb.

of tilt' ?:a'ilmin lcostinaltmd. .·(·11 if the)' art' mt't alMllkally stablt" lIult'sS til(')' can lit' processed by OIl(' of tilt' specialized sysle ms that traffic vi tal materials.. EWIl if SOUlt' t1m~ Wt'rt' 10 t'lIh'r till' la~(' 1l inlt'sfi1lt lilt' pt'flllt'ahility tllt're wOllld ~ti ll he snffidl'lIll)' h i ~!J to ellSlln:' Ihat all Ilud " ('Illl'n'ti W.I\1u lahil i ~· o f the d n lg..l~t mi n lt'!i ti naI tract. Fe. llOWt'H 111l1S.t'.1mintt'slinal tis~ t1t'S d rains into tilt' hn'r via tilt' ht'patic po rtal will. mn lit.lpid am i l prohahly IUlIlplt.1)(' rIllt . 111t'd n lgs shan:' tli€'t'()1Il1ll0!l pml)('rti('s of I)('ing l'M l!ar .t'y may ol. Fo r !ll'mwahlt' (Im/{S.mcnt 11t'('iUlst .ment . \\ith calculation bused 0 on measureme nt of dn. ahSl I!'] tion is r. C ouseque-ut[v.p ortal vein 10 Ff · ' Fe.3 to -1 hr % ' afh 'r atiministratillll (Fil!:..::L'iioTlally lit.l\'a ilahi!ily. tln-n the hitJa\'ailahililYis less than nne and the cc rnph.' is an anatornit' n' tIIIin.liver t'st:~\lll'S extruct hm the re. 9-1). The ' ultimate limit 10 pt' rIlwahility is Si7...'i pt'nnt'. from the apical to the ha. dearly is then k-ss of all ('Ired HII Fur t'\1IlIIplt'. n 'ad ling the. ·. ra nitidi nt' is ah'iorllt't l fmlll tilt' la~t' in!l'sti nt' ("'l'n l hou~h d m /.ul~· all g.L' S st'f lut 'lI tiiln~· Imm the ga't mi nlt~tin ai l u lllt'll ... Of Ihis 1'M' m l('lIti ll~ drug. 11 ll'\\' IlUlI·II of Ihis d rop is tim ' to a dccn-ase in p(' rlllt'ahihl)' and how much 10 a dec rease ill surface an-a between small and largl' illit'slim' is not kIl0\\11 for certain. 111 is is not always so.10 -1-llr tr. Ah:'>ll!']lti un t)f 1I's.\itlt'lIlly.bio. Causes of IA)"" Oral Hioa millibilil.g in ft'('('s IJIll'han. tlm g mu st p.ntll~· l'M l]. \\1lt'n W\"t'll o mll)".hil it~· fur lipoph ilic d mWi' which lr. proteins .5 X 0. F..a) Ill'mll'ah ilit)· \ti lll nU1'i 1 of that ahSllr!)('1! ha\i nl!: ' (It"('ufrt 'fl \\i thill . E\idt'II("(' SIlPl'M lrl illg this lIolioll is pn " idt'(! \\ith tilt' 1I 1 -a ll ta~olli st ran itid im'.. J11II'MIst'l! ill till' lumen.1 intt"slin{'.lS V('Nt' ImnMf. f. D m ~ lIIay .5%.Il(' small inlt'slim'.ulllosl totally I'xert'It'(l lIlldm ngt'l l wllt'll ¢ \"t'll ill'ran 'Il(l1 l s l~·.?. would lit' 0. 6U is ahSllrllt"d hilt all \\i thin the first .' l'Omplt'l(. es pecially wllt'll d rugs are placed into the ~.uuin BIz.. Thh rd alin 'ly I'M lIar slahlt' l'IIlll'M llilld i ~ .l\'aibbilil)· is n'f)' !ow (0.. \\i thi n tilt' limilt'll 2. If lilt' a ni)" cause of loss is incomplete lillie for "hso!'])l ioll. if51I'l o f lilt' d n lg is Insl at {' . \ \11t'1l a d r u is given in solution and p<L <.hi oa\11ilahil i ~·. hi llt Itl [X 'rfusing \i rtll.\. d mlt" slill primarily t)("('lIrs \\i lhin tilt' sma ll illh'stint' bllt is unlikel)' to bl.1 10 14%).tr.5 or 12. only a ' fml'tio ll 1II:1) ' C' SCil pt' tlt'sln _dioll wi thlnthe wall. most likt'iy dill' 10 1M lor inlt'sti n.llt'fon' t' lllt'ri n~ tilt' gl"lw ral ci rculation (Fig.5 X 0. Tln.. w ry littlt. t1lnmgh tilt' ~ut wall.. s ) \\i lll movement fmm lilt' small mn-stiue to (. f"F' is then tile fract ion m-it lu-r 1 1 ~1 ill rlu. an important site of r-limiuanon.msil Ill'ritM!.J :l~ a standard 1 measun.llld{'1! from the foregoing consideratlnus of hifJa\w lahilil)' t'\'( ' 1J though s tl. ah smplioll from most sib 'S of ad rnini strution is com plete. f'1I' o f thai n' adlinF: Ihe. IIlt':L'illfl'l l owrall systemic. ami tllwugh IIIP li\'t'r. 9--1).('S.tt' \\i thin tht' slll.uso ht' Insl hy dt't'lmpns ilioll in lilt' 11I1Il1'n: ti ll' fml'lioll 1'IIlt'rill~ lilt. la~(' polypt' ptid('S.L\ ahSllrIM'II. measured syslt' mali('ally.il surf. tissue s.t'S g 'i. and ot he r ·r.'it is Il'(' '''t'f('t l lllll'hallgtoc i in ft'l. Tahle 9.' If (Img is also l'Iimil1alt 'll ill tilt' lin 'r. Ihl' hit li. macmmok-cular drugs an ' \i rtllall~' un able to p<l~S t h ftlll ~" tilt" int('stint' wall (.IIt.('11 not be cousiden-c l.\n'nollsly am i omlly admiu istt'n 'tl t1 n1F:.1 lists repn'st'lltalin' t1 rt1~S for whieh om l hi(li. the-reby reducing till' Iractto» of (kist. Bolh illtr.~ al a peripheral venous site . SA term for drug appc'ars tn drop sha!'] I.hlt" W . lU I "ddilional fmction . at any 11111' o f Iln -se sIt1)s. pl'a riu.'i IIII1St Ilrst POl'iS througl) the lungs to n 'adl rlns site of measurement. 111 i ~ st"(l"t'II('(. As t1is('us''i(·t! in Chap.g is a measure of luminal n-tenti ou.. the fr a on apcti t'(l. Tilt. Xote that the d rug can lit' n-nden-d totally nn<L\'ailahlt.l. dnl ~ ~n' lI intrawllollsly is IIst.1011. tht' n '.'lIu!arly.IUllg an' {'u. -1 . ' mtllfficielll Time fo ro AbflOrp'iOl I_The P .llatt'r. lilt' t·fT('(1 o f tilt' IlIllp 0 11 tilt' meas ure ment o f hi(la\ 'ililahili~' I1t. n' adily al' ro~s lJI(' TIl h rallt~ .ft'('('s nor dt'l.K' -' of lilt' t'pit lld iill cr -ll. then' fo r up to 2-1 hr. such as vit.I('" sltop.

largt' bowel..OOt. and a d m~ WH'n ft"d ally is nol al wa~'S n -tatned for '(' a sufficient Icnl-...ve ompi<:illin formed pl\/OmplCl\l.. Finally.t" 1l orally for t'lTl' ..\/. is sumdt'lIl1y hi~h to n-nch-r them useful ~\'l'n o rally. 1Il 1J('(llr ".s al.i tlJiu lilt' a ~st mi ll i esti nal 11'. .ocin Co..!!.ct 11Hrt Comple><ohOfl Conl"'9CJlIQll --"'" Hyd'~$ k~ SuIlocOfllugohOfl Glucu'Ofl.\/.._.. E nzym es in tilt" in testinal cptthehum and wit hin IllI' inh'stinal microtloru...st other stte s wirhin tlu.on LOM 01 och\/lly: pl'oducllnocti\/e LOM 01 ocrl\/Ily product inoc~ve toM 01 OCrl\/lly gIven wllh 0 penpbercl dopa deca rboxylo~ Inh. Tahh.ben.oiIoml ccd ocnve Ad loOfplion 10 choieslyf mlne: cdsobed morenol not c bsobed o ... o..!!.1. As with ramtidtne."l .n (e~) 1 IflOC11ve $ Lo» 01 ocrl\/IIy: producllnoc 1ive LO$$ 01 ocr. Amil..- Dew.lar wt' i~h l ~rt'aft>r than .. 11Hrt I. ~ TIlt" reaction products an' oftell Inactiw or less p otent than til{' pa n 'n t moh-cuh.1l1 .tI_1 P 9-1.-r ..1T.. and utcnolol.Iy: ceodcct..~ III.. til{' fes ult may 1)(' low d n ._1"1 Lew 0-1 ...1('(! into muscle. mn.124 and.p. of tlme 10 ensure complete abso rption. h)l lmd lOmthiazidt·.'j() WIIIO]t' . P.. lllt'tal )(llilJ:' SClIIll' drtlh .tI .ly absc)rl)('f.n Neomyc... tht· small inf('slillt' is Iikl'1)' to ht' the predonunant sitt' of ab sorptmn.'('Urs 1)(' ... dm~ injt'<.lClorlQll ~ed uction Imi(:.' IllI" l oral hiOiI\1ulahili ty of a 11m.n Ce!omondole Ce!orol.]. For example.me Voncomycin . :-':0 lillie limitatioll exist s filf a rtt.1 TetrocycJine .too W mo1d.lun-rac tions "'i lh <. Genlomi(:ln Owe .(... subcutaneous tissue.. ~"" '''''''00 '''''' wl _ I. (.. t'll~l n..Iy product Ie» ccn-e Insended /of cccr (. wlaieh uormully rt'side in tln. 111..CIII. Hcact tons can he ho tl..K un -a.nresr'nol) on'~mflommolOfy OCIIQll: poreer drug may have someocr. 11Il'S(' include'<:inw titlilll'. ahsorptiou. with tilt' exception of pyri t!oslig milll'. ~t.'tmslih wllts o f lilt' ~'lsi roi ll l ('st i nai ll uid.( ' U silt· o f ad ministm lion ami S)-'S!l' mie d n 11lulion. ".'('ur . ~t ()sl o f the compounds lislet! in T able 9--1 cannot he ~i\. the n. I'yridustigmi llt· is a quate rnary ammonium ('('lIlpound.l<"yd iIW is in('ulIlpli't{. complete absorp tion is anticipated unles s des truct ion 11I.D-.("11 {1 parenterally.n Pyricbt'gmine 5rreplOlT¥:: l n T~opIon. 5-omiflO$Qkyli(: Enzymatic o..an ' small molecular wt' igIJI......so tll.11..'ompt't irag RpCJcl imlll.hody..cylic cod formed.11ve LOM 01 ocrMIy product iflOC~ve Prcdccrs (d>g11OX1ool have ecucbe OCf1\/rly Sol..... c. ranitkliue-...9-2 lists v rious reac tions Ihal 1'.1.bolOf 10 'educe go$llOmleSllnol rneIOboIl$II'\ LO<\$ 01 OC~\/IIy : ptcduc1lnoc..-ptl_ .I . which Illil~' explain its low hioa\~lilabilit)' dt·spilt· its smallmolecular wt'i ~hl ( 18 1 Wlllo!e)..zid. Any react ion thai ('f lll l p '''tc ' S \\i lh a!Jsc)'l liulI lllay f{"( IUI'f. AIt. potu dn l ~s fIJ r wllk !. t h(lll~h . 2(X) 10 .. IT-Iatin·ly lar~t· (mo](. alt h()ll~h Inco mp lete (50 to ~}% ) . hiull\"ailabi lity.n CeIotoxlme Ceha.:o. 11-2...1 when coadnuntste red with milk and wi th certain antacid s is that this antibiotil' For ms Sp<lf' '.We1. i\'l' s)ost('mic atti' il)': they mustlx.. '.llie and lJUll{'Il ~'ll\at il-. cce-e onrl~nflommotorycompound Acr. Add hydmlysis ' is a com mon nonenzymatic react ion.gh..... and IIII).reason why tt"l l'.._tl_...... TIlt' rect um has a small SUrf.

('(III('ntly was aspirin shown to he pharmacologically adiw." 1)OII-:S tllat showa suhs tautra l first-pass ('ff£'ct d uo to Ilt'p.. . salk .dudl' accurate prt'1lictioll of tilt' contri lmt iou of a ('flmp('tin ~ n '. It was lIlarkl'l ('11 at the tu m o f tlu. lu-patic extraction is so hi~h us to ('Sst'lIliall)' precludo tl\(' o rul m utt'.l\ pivampicillin. Ind(.rt('11 to salk)'!i{' aoid in a si n~I(' pa~sa!-. n's ultill~ in a substantial "first -p ass d T('('I .ne N. an. dlly 1If'I Kltic Extract ion... ~ . • . particularly hy ('..Iv.' deri vath"t"!> an ' made. lltewl~ Lew 0-1 al_v-IJ.ph arnlill'fllc'¢lM inacti ve.lie add.. nn amount of pbunuaceuucal fonllu latioll he lps. \\1 It'l1 tilt' llwlaho lih' (S) formed durr ng tilt' first pas s tIlrtm g:h the lin 'r is les s po ten t th all the parent t1m~.~(. TI lt' eo mp l('xities th at O l"('ur ill d w prt. I)('ing des igned to b rapidly h)"tlmIF '('l1 wi lhi n the hndy to e salit"!i{' add. ilion ' !)('rnll'abl.lhlt' fraction of aspirin is {1111\l.v. inn-stmal wall is so rapid that ulll~' ampicillin is t1('h'(1('11 in tht' l'i rt'ulatiun . I I. For example.S It' fi N'S in the hw r.~ occurs for lIlallYof tilt" t1m ~ listed ill Tahlt' 9--3.lie add) is om. PI)S"l·s. Vero pom. aspirin. I N f .Am."1'or<j Naloxone 5 M ..t::e through the intes tinal wall.25.ne De~ltopropo~ I$o$orbode d.."..( '1I.'l('r-dlly refem-d to as 1Jmd"...!ed'p. tile 0 . t' .l{1ion to d''1: r('lL''l'11 bioa\lIi1abi lif)'. lc Ilf . is r. on <>-o}O f '''doped<>'''<le ~"". polar anti hiot k amp idllill is illl'fllllplt'f(" Its sys temic dd i\l'f)' is Improved substa ntially by adlII in ish'riTl~ a ilion ' lipophilit. am i an ' llwtaholiJ".eldonocol ~ Cl..fluorOUIOCil O ..(11Il' within th e body.lSS ('ff('11 is diS{'lI~S('11 in Chap..n'"o'" Nico/cI.-... TIll'" are of d iw I'Sl' chemical structu re ...• C a 2+.mne ~ida". dost... Only slll)'. to euhauce absorpncn. CON..:(' th rough th e liver..('.lIlty"'" I...'rrptyliroe Chlormeth'ozole Chlorpto.n' Alpteoolol . D.of till' first Sp ltllt'lk prodrugs.lat ioli. Euher till' dnlg mu st ht· gh '('11 by a parenteral mute. Aspirin ( a{1:tyl sal k~. n-quln-d to aclik-ve tilt' .~..1.roe T""""... }-'l.....t:: passa. 10 8<1 . oftI'll du rin.lble deri vati\"('. pivampiedliu. . ' lS t1l1'y an.a1 dose is la~ef than the i.11111' tlu-rape-uttc effect . S o i mes tilt' problem of Incomplete met absorption rnn h(' l'in'u lIl\'('nll"(1hy physit-ally pron-cnng the d rug from destmctlou in Ihe slollla{'h (s('t · enteric (Uatill~ di scussion...1!. Tluh~ 'tlrol ys i s o f tlris ('StN wit hin tht. Apart [n uu th is feature. ::wroe o Cy1o'obine Desiptom..lylIine Me«:aplop."... and permeable inactive este r prtK1m~. Similarly.. or t.._· Hydrobzllle Imip<amiroe 1$Op"~enoI NaltteXOlle ~mi ne . lilt" poljvak-ut cation {e .". absorption of Iht.t'l1 via a num b of ' er pat hways. '('n'RS(' in oral h ina\"ailahi lit\' due to this firstp...sl. 05 ~ "'. Ih-n-. 11 1 i. Ilt'patk lJytl mlysis is so rapid that a siJ"..t::. 36 ) or I» ' syn thesta ng a mon.. a labile es te r.n PenklZocine Pento.t'lI. Aspi rin W1l~ o ri¢ nally thought to hI' inadin'..ltiozem Do.t::ly su!uh l(' ('fllllp!('X('S will. 5.pre H v. In ~ l lll(. i~lp mlen'nol... Drve.O'vbicin Enco jnide EWodioi Meloprolol Morph ine Nolb.1l'JIO" ..j ea.o ine ph PrOptonolol ScopoIam. """'_ _ 0 1.~ tliffe l't llt pharmacologic act ivitie s.:.. .pine NiGQI.hyd'oe<gotom'ne D... tlll'y have httle in common.3+ and :\.. p .. upon ingt'stioll.1..ell. • .tpid l)' h)'tlml)·J'. Elimi.ne K elomine tobelolol lidoca'ne lorca inide D. instances .("('lItUl)' to overcome the unpl easant taste and tilt' gast rotn tes nual irritation ass ociated with lilt' pan-n l d rug.... which are mpidly ("()JIvlrt('1 ' 110 Ill(' adin' molecule. 9-3. o r it must 1 discarded in favor of another drug {'illld icl"tt" )(· A method of l'stimaling tilt' mlll..ne Niltogfyce<in POpc:M:!<. such . which is couwrtcd to tilt' uct ive 1I101 (.CHAPTU 9 '25 in...ltk elimination art' listed in T ah lt' 9--. Do...imumlikeh· d. Y(Ot tilt" ori¢nal dt'sign wor k('11.e .m. .· ..1 1+) conta nu-d in tlll' st' prepar ation s.epin f'henoxet. D r-n vativr-s.

<tilahlc .dat a in Tahl. Part o f 111I' n -otal hlund sll pp l~" ' Jlilrt il·ular ly Ih.Ipplit's III dm ~s.'. conside-r tln.C IIlIpl" ld y absorbed from an intramuscular site.'d as it P'L\ st'S Ih mll~1J 111l' her-r..'( 1 to till' .L\st·s tln.l'. III 1.\ lIt· .1\'01.. .k~ .(lIllr.· impt'( lam'(' to till' movement u f . and d la~I' pUst· a pa rt il'ular p mhlt'lIl for adm inistralioll (If prnlt·in.1(>- in' hut umk-r nvt tv.l-sln t­ illh's tiual lrat..l$ Suborachnoid Svtxutoneov~ 1 46 120 1 18 007 053 0 •• 035 w ~70-m "'_""'"c""""" 8e l'In-oo:d. " l'h i. rln. PlAA fV&M wcx:.c.·I.d 1Q84 1'In-oo:d-.· hl'1Il0ITI.....'ll c1 m~~ .ts ~(('ilt c!iffit. and il\(l('.L~ S t h n l\l~h tilt" liverpnlhallly {"plains mos t (If tilt. fllacl .N: CONCt N'~"" liO" (""'9/ 1( Coudal lvrnbor ep. I m~s inln bllM even for po la r lll. ... dl"~r. ad ivily of lI i t n ~l~l"t'ri li adrn inislNI.<In¢ nal attac k. 1I1 i1~' 1)(· d ifT kult .' 9-4 for lilt' loea1 iUlt'stllt'lic lit!u('ain t'. how.is adminish .s i n~ til(" 1 11ll'(.. 0. hll'(('ilS" S in hloud flow havn-u ahsorptiou... Thi s ksw illllx 'ilanl'(' by thc' l'ilpillary ' \\1111 in llIust·lt' alltl S. SC. For . Absorption from Intramyscvlar ond SuIK"toneous Sites Tile G ent.(('(1al difT "(('u t sift's in tlu.of rlnharriN (the.. (If lidocairu. TIlt' n-ctal mlllt' hils a (I{'fi n ite atl\1U1ta~t ' over lilt' oral mult · for d m j.<1 s ll hl i ll~lIally fur all acu n. In I"l m l l'll-~ t tu slllall m" I' "l'IlI..'t~dll .S Iissll" is pl·rfllsinll m!t'-Iim ilt'il.12. 3 .."udy. im!t'!x 'm!c'nl of IINI..·ill l"l\it~· bypasses rhe liver and ente rs di n ·(:t1y inlo tht' supt. ~ I acrumol n:uhlr a nti LJTn p llatic Tnm spo rt... '''lectI_ Ce_ _ tr. alltl Illoll'('ular sin' III" In llppmximatl'l)' 5(MK} WIllO\t·.~. tissue-.' s..oidai vein s. of injl"l"tillll (inie rslitial llllic! l alit! hluoc!.may illsu pa rtially (t'(ltll.o.' p erfusion.IIIY d nl j. l""laril.wh couceutrations hi~h {'l1011~h nut svs te-ruicallv il.'.n. h~ 11. il uun-h IlIlIrt· I(M )S(' I~' knit snuctun.am ! sllhl' ul'I!l.u<J~ EdOO<lb-o C """~ond C C ""':l '000 '"'9fl . a m ) .. CHAPl£ ~ Q A\'ni di ll~ first P. si. 1""__••' Site . I.wI. ~c 'n lilm id u .ti_ Inle<cmlOl Po.II'" \\1111. SllllStl l un rlu. Fo r examp h-. I'nh·ntially. This l~lp i ll.( first-pas s Ilt'patit. !I.·Ilti((· !-t<lslmintestinaltrurt..·- .silt.'11 is t't·rt.a tg' · diffcn-nc cs ill speed o f ah sorptmu ure d. fo r a gi\"('u dose.... and latgl' pol)llt'ptitlc' c1m~ : t1ll'ir lransport across lUauy lllC rs 'mhram 's is him!c.. pula I' llit'it' of mok-culur t\'t" i~llI -Iii WlIlOIt·..than 11.UIIl'('nlm!iulls "hst'rv. oIloxd~.p" ilk pl'l\mil t." " pitl lt' liili l i n i n~ uf till' ~. .. 1.tslf'(l i n lt'sl il lill IlIUI'(lSil h UI is m pitlly · lind t..a. lix.'ra l Ca. n.. illnil..(' o f ahso rpli'lIl on rwrfusiull llIay he t'xplailll"li h~' lilt' uatun. loss.Io... nllll l(I I )( · rfll. Ih...· h i~l lt' r tilt' JX'ak couce-nt ratton. ill !!: a (('p mdul'ihle biua vuilability. 111is d"p"nd"lll.t sw a llo\\l.. Tlu s <lntian ¢ nal d n l~ is almost ('o m p ll' tdy nWla!lu ]i7J... S in tht· illh -stillal wall and m il ' m lill m . 't· o f io ui.()..a mpl.It....~1 the P_k v •••• • Ud__I_ 1 00-_. ill lin" \ti th a t1 c'(' (('. whic h is Imp ortant in dm ~ IIll'mpy."g.. . 1.l'apillary wall) b ctwr-en tlu.'s.-..in d n..L\1 10 Ihl' small intes tim-. l1 J11 l ri i lll lt · III overall .· Iufenor and midd l.·l llTl~tmll't~ may n'. Fu rtllC'rlllllrt·.·. '(! when Ihe Sllllll' dost.·"rl~' l·\1d" II1.'\ "('r. III\' fasn-r is c1 m ~ ahsorp tion.. The lI lt'taholih' s M't'll ' i ll h!ood an ' link weuklv ad Ie..lectI . o ffe rs Iitt l. ionize-d.'t 'tl d' '('(('il\ ill!!: fm lll Inn-rcostal mu scle to s.rt't1ill mnte.a tinll.. 11 ll' sp. l\in~ fissu. silll'(' h io<lt' lilah ility slro u!-tly d" lx' mls flll till' sitt· o f absorpti ull wi thiu tilt' rect um.Ilt'patil' portal circulnnon amI dUlllp s di (('t11~' into ti lt' inferior vena l'u\.durol Brachial p1eXI.·Ull. abso rp tion of mo st drugs ill solutiou fm m musch. a wute-r -soluble.' l ric ad tlity or hy ('1I1)111(... dt-slmyt'(l hy 'S ~'I.(('tl. lllty Jlt ' lIt'1 mti n~ tln.t·.·rim vena ('.

Tilt' II) d nl~ 11..i.w >t. Fu r tlu' s. ... {' ... tl( I.inhlmlit. d rug n-acln-s ti lt' s)~lt' m ic t:iR:lIlatioll I') ' Iwu m echanisms: d ifTlISioli thm uj...·.. (.. ">li< IIi . than appru\i JlJa lt'l~· .lM Wlnoll' ).... T hc'y han .mtinllC' for lIIallY hOllrs... ....ultll (x. Those of t' ~n 'atc' r than allll ilit : U.. . m ill afh'r i.•Ii"'''L.'} for ~1~t.. mu rt· ('rt'iltin ' IIwthcllls to o 6 12 18 24 Hours 30 36 42 (. ad 1l1 inistr'llticm ltitS hl.!. s..l pll.t.'l'lIl~ 1. 'wJ:' ·nM"n~' .·..£MM.• • ... .tioll..nJ: . .: C\init... wi th a r ate of tLx 'lim' illdi{"ltin~ (ullt i lll l ill~ input..v.alsc l 111'('11 ShC l\\11 to lill' a bsorlx'(l a('rn ss 1Ilt'.. "..·""." Io.1".. hilt f()lIo\\i n~ S. alltl ft·!It'stmticlIls ill till.tT"n'lll il...ol".·>. ill. l'olyp{'ptidt'Ji cf II's.I Sio n.. IllC'rt....oo. eli. ~L"~ I n·o. ( . t'Sll~t' acros s the capilla ry eudothcllum ... h.uhninistrution..\ IN If]Jtin n li m'li{'S Irmn IlIlth i.. 1! .·" ..tll tilt' Inn. .nl D ..1 a half-lifl' of fl. IIi . to trnverse tilt' edpi llary wall . 1. tIlt' ' plasma l11l1l't'nl ratioll is p mI Oll~t 'l l for at It'a.t\ l mi nlt.sysn-rmc l'in'u lalioll fr om the silt.Ullll'k ~ l oll'(1 Ittr si:l..U 1" :1!i" t·ll(...."-' 1.. Bt'C'a uSl' of t lu . .. ~ l c )S t Hf tilt' Infonnanon on tlww kiml.J recombiuaut lnnnan /-..lr. un.J. has 'S 11Il'C '1l ohlailll'li fo ll(lwi ll~ lIOTI" lwu!ar p an-uterul ad minis trat ion.. •uu ] s.1 .lM I WIIllllt. J. S ..-'~ tt·­ r n lil(:OJpha~t ' (Ulolly ...( a .~·mJlII IInw is slow ami {'aIlSl'SallSllf]ltion fm m nonvascular pa n-nte-rul sitt·s to l.".. is d t'arly a IIt'('(1 for tilt' dl '\·j·lllpu wut of 1ln\ 'l. (.\ mai n (1111l1'01 Iwr't. l.1~1i(' t·1l0'lllt·s ill til(' g'ol...lpilb rit"S and by n lllH'(1in' Ho o f lilt' lnterstittalH u ids through lytll phat il' d.""""!:l.i....... routr. to 3 -l.·) I.<. 9 ..I)l'lt'ptidt's Imn ' hl'('n tl'sh'(l in connulled-n-h-use (rnil'n ll'nea ps ulalt'l!l illjt '(·tahlt· 'ysll' lIls.. . 1 42 hr .ntt·r..\Ill" fo r p.(' llllpOsilioll hy pml t'l.1<.m. It'mpt'mtllTt'. It T .r-. '1111" 1I0n \1Isc :llbr pa n-ute-rul m ule's "fT('r lilt' lId\'alll a~t' o f pm"'dill~ pmlnll~c'(l input fur short Ilalf-lift· peon-ius.shnrt ha lf-lift' nflt'll UhSC: I'Yl'(l anti d("(11111!'It)Siticm in tilt" ~..oj IlWl< ~..~1 rnn" 1l' ''Jo:..d ..u) · illlpo rt."'J.h-ss ah lt.c.· . 1l'"1\11\C:11t lT part'lItt' roll u dminlstrution allows fur Il"Ss frt.1i"" "f . t'o'" . tl1t' p rimaril y 2 M Y 1'lItN tIlt' hh lll via tilt' I~lll phat ie path way.ll.. S odlif" '.·u. is w of p rim. ~'j .. i lljt II .. t£.. n M' n~ults.CHAPTE Q l! 127 (11lN ' IIf t1t.t. 1 1.' l illin ~ o f tll(' \':l-"l'1llar ('. ..I'..·n s1ul\\l1 to hl· lt i ~l. am! illtrapentoneul m utt's. a' shown in f ij..l'" th rt)ll~h lite ca pillar)' pathway. t:" m.olmUot......"Slir lill tnn-t.tm illh"Stinal tra<:t. tilial f1l1 itl.1".K s.".I m l!:s.>II<..1 t. Thu s. of tl m /-.sti lllu la l i ll~ f"(1o r (mok -cnlar wC'i~ht .lIl l In"'. the-ir o ral all so rp tion h t·\trt ·lIw ly low ami errat ic.al u WIll IJr'OUlC's . 1 1i~l lt' r lIIolt'{'ular wt'i ~h t pol~lll-ptidt's anti proteins may rt'l l"i rt. L'I". ly dl1x 'ndc'll t on tl.· of ad ministration. .I.m..ic" 1in .( II... Lic '" .)( 11 11 1 wmn1 p rimaril y p.'l lut'nt ild rniuisl mlioll than tllC' L\'. ti~J....It'1i\'l'I)' s)'St<'ms for pmt t'ill t. lIhta..usyl ah..(· silt· o f injc'C. ~ :4.1 U ".. ...-1it· ~ 'Klit .. \I " rt..·" I. Smnlh-r 1 'It.~ I ·CSF.. r." " ". ad ministrat ion...Ino~ f. i.'.K " .c.. I S. am i c1q~rt '(' of mbbin ~ al tilt" injection sitr-. relates to tllC' n 'p md ud hility IIf tlurt'1l'<t~t ' int« rln.' l(r."i"J: j .id k J:n ".t...Io~J" ~l>1ry II.. "Ii< "" " ( ¢:."...

i--6.'t isfadory and un Sillisfaetol)· for' Illulaliolls.ltt'.'lllil·al prope-rties o f ti ll' d m~ ilst. IlnIactors i n fl uellcill~ abso rpuon fro m IheS( sites art' li kd~· to ht' till.'in~ ' ubsorptfon from tilt.f. III rt'1. to facihtate ma nufal1un..'<Im g. p. lut km.lIISI. is 0111.l.'S('Il!.h'L> ill"t·.' dosage fnn n. 1I 1'1Il'l.· and maintain iUkgrity (If rlu. ami s.lIl l'stllt'lk~ .\"(' r('('('i\"('t! parti cular ..S'Ul1l' dn S( nf drug hl'1 m\i ll ~ difft' rt'lIlly i" t· it~J . difference s ill absorpuou ( .·lopnlt'1I1 of 1II0 rt' SPl'1.' of dilT' rt'IK'('s in abso rp tion o f a t lm~ from various products is <IiSstll. vtucb ofh-n depe-nds 0 11 thr.'M1II why d isstl!ulioll is st) impo rtalll lIlay ht' ~aillt 'l.1 fil' meth ods for ( Iel i\"t'ri ll~ t1wS(' dnl ~s to tilt' sil t" of act tou.'s in drug absorpuon a lllon~ p roduct s.'il.d m ~ .dl'~rt'(' of uccumulatlou that O( '(1 Irs un multi ple t1n<..' first..'<l.lly.lll lt't· {'flua lity u f dlk~I{·Y .i. and 10 fatili!. :'\OIlI.III illlllll'Il('l. n-leuse o f dm ~ foll(l\.t'UTll p ll·te hina\'ai bhi l i l~' or Illil}' rt'fillin' til(" dl ·\l.o f tilt" ' les s conwution al ...c.rc.lf. t1elayl..I.121 CHAPTHQ ('nslln' {'Unsbh' nl and mon.ollliioll n'( plirl' II\('llfs fOf an illen.utent tou. TIll. pote llt molecules that n-qutrelcw Input rates 10 a(. thl' p rimal)· nwans of l'\-a!lIating dm~ p mtlm1s am I di s(:rilllillill i ll~ 1)("tw' ''(11 .in-s.'. t!loS(' i n llllt'lll. o llwlimt's contr ol..'t'1I1 years then. tlt'pit1ed in ri ~.1in ' tln-rupy. On (X '(·llSioll. 111t' major (·.'mlly.. considerarion hit. ami bucca l (w i t)" . 45 ). 11'('>:11 lOil\...ionally.' n-sult is it largl.llion o f till. 1J(1\'·"V ill d im d isstllutioll ksts fail 10 t1lITl'Ialt' {'f. 111 {. In all cases. Of otherwi se-.' prt'S('IIt1. ill14 Illlml){'r of s important d m~ pm(llIt'ts.lkully abso rbed when ~h'(' 11 UrdU)' h. Th is is cr-rtamlv trm. Tr ausdr-rmul allpltcauon ha. as can the manll faduri ng p n x'l. t'al. l'()IJsi<!t'rJ.ilk'. . suc h 1t'> li lt' 11I1l ~. become popular for systemic dd i\l. Sometimes .and rln. n.' in whid l dism .·ry of small.' u dministe n xl to vtrtnallv unv sih.'l.. or susnunr-d. to hl' ~H'II to the particular p roperties o f 11Il' sin. ~(·Ilt ·I1lIl)' !ipoIlI. pm longed.'t!I(']t'ss.ss of the phy~il'(x·lll.. Iht' primary conce-rn is \\illl till.' l1'ITt-lall'(l wit h differenc ill dissoilitioll m{'.hle i!lien-st ill ('\plllitill'~ sonn. Gt'lll. T Ill.i n~ \ adminislr.. At pn.JIltillllt·S 10 ht.l<. 1111.'hie\"t' d Te(. Absorption From Other Sites DOl ~S mav hI.t.'(lit'lI ls list'll to s stabili7. Indeed.> a IIw ans of .. Ot:l ot<.' iuum-dinte. s) ""Slt·lllk-. variations ill ah stl'l'ticlll mit' may h{' impo rta nt.df lsa~t' fonn dllrill~ lJandlill~ and stura~t'.'SM lIlay rt'snlt in 'S dnsagt· forms l1mtaining rlu. oral.of local . 9--6A. lSi). Staudanb exist for content and pu rity o f lilt' mum-reus iniU:IiH' i n ~rc. h in~n'l.-ganllt.' u f diff i-n-nt excipients (iIlWt'tlit'llts in addition to t1 m~) alld lllimll fill1llri ll~ pmf. body T\\1J siluations 1 ' IInw (1msidt·n'l.n IIt'W P(JI~"Pt·plidt· and pmt r-iu d m~s that an' poo rly mid (·rr..(1.' extent of absorption . Lm.. o r . l hy fo!lo\\i ng atlministmtinll (If 1I so lid is a tW()ostl'p pn)(1'ss: Drug in product Di ~5f)/ution n'al izill~ Ihal ahsorption Entry into .' same .ing (F ig. ddi \'('rill~ dmj...' Iln' n-ason for It'slin~ for hioe quivu leuce of preparations of a d m~ iutended to bc' switd lilh!(' (p . . \\i th abstl'1Jtioll.' are dis.S lint ~uar.t' till. .' : tilt' mit' o f d isstl]lltiOIl o f Iht' d m~. a large '~l rit'ly of df ~l~e forms of d m gs are mark eted in whic h release Illay he.'ss. 111 he.st'SSlllellt in humans ('I.t. I ntended.'lln"(l es ill all ill rUn' apl" lmllls.' po le ntial for tliffen 'n('I.t. Dissolution 11ll' ff.lit'lJ l (".of til(' bodv. TIlt' ~ ABSORPTION FROM SOLIO OOSAGE fORMS formulation Ecpmlil)"of d m~ content (lot. sites.

.stmin lt·slillalt·p itllt'­ hmn.d"". .1li"d .t· t1i <.·: .is rlu.· '" ..IllY faster.. ~_ X.' .ts tmi lllt' ''l i nal t'pi tlll.... So. g.. III this cast'.1"" '1" "..." . pe-rnu-ability rather th an dissolution rate-lunus absorption.I " f tI. \\ 1"'11 .". An ccunpk...I"..t".rtid t·s is 11ll.ll~" r'''llltllll till" r..spt't'tl of absorptinn of this t1 m ~ .. III t1isso llltiull filtt·-lilllilt't i absllI-plillll.tt··!i"' i"." ./ Drug in Solution o 1 2 2 3 4 t·iK 9-6...1 >rI".. .uu l s t i r ri n ~ .. .abo so rpttou silt. Differenc s in rates of dise solutiou of lll.1 m:.t.u-t with watr-r an d 11ll.• fr.· H..rillal [itn. .11.UIU l. "oI>..d.t..o lll!ion rate-limited.11 i> 1 .." . Permeability Rate-limited Absorption B.SlJ! utiol\ pml't'l. '-"r.' t'1l11" solution. Evidence sup port i ll ~ dissolution ratt·· limilt'l.. 9--6B. Ht't l ll lil\~ Iht· sin ' o f ' tln. pl l..l ..1 i. l1li\t is.0...'t1 dm~ mpidly enters Iln.· thai Ih.Iuti...·r.1i"l1 h I.h ti lt' d m !!: tlissn ln ·s.. l in ~ the..1." tl. !.s than Ir om a sim ple... i.l absorption cume fmm the Ilntit't'a hly s It""'t·r ahsOlvtion of s mosl t1 m ~s from so litl t1os<lK fnnll. a . liult· is absorbed.. Factors (ontromng Dissolvtion \l allY factors inllllt·nl't· Ihl' dissolution of a dr u AlIlon ~ the se an' surface are-a.'tls rt·latiwly "low ly'... than the rate at whi<... Ex palll.".'1I 10 di sint l....·" .'i.~ .. 111is jXJlar ..1..' lill lll . aho.tml( i> in ..Ii .~.l.I.It"! in . tlu.· "h''''l'tic. ii i.s dim<:ulty P"!" t·tl":ltill~ tlu.Ii"..'g mlt· into gnmulcs that finally tI{'a~rt-galt' inlo tilt' tIIiJ.lal.Iutio. DiS O S lution Bate-limited Absorption 100 Absorbed Drug Drug in Solution 100 / Solid Drug Absorbed Drug " "- 50 _ Solid Drug .\ )..tr t ..."" "" .. tliS.li"" nl lt·· !im ih .d m ~ partick-s.' lI IltlClll cont.. '!lld an y (lisso ln'1! d m~ rt'ild ily traverses tilt' ~a.h.dri\ ill ~ fort't· llly. "'" ..· t1m~ I"" <li...SIln. " C.". man-rials ( di " i n lt '~ra n t " ) art' tncorporan-d into tablet s thut {·aIlSt· tln-m to SWl... Ct mSt"(llIt·ntly..~..1(ml.: n.t1 (c • .solid p. in . · "'..· .t... 1It"n". .Is h' pt low ht'1·..so t\'l.... shown ill Fi~... .second and much mon. o f t1m~ absorption.'\ . mos t of tilt" t1 m~ is di ssoln'1l la-fon.. solubility.ga..tI II.·s rapidly hUI ha. · . r ...d"" rptio" l ((::.lm Ca. il.110. absorplion is d is<..concentration of t1 nl~ ill solution at thr. "..IM Tln.m lih iolic tlissol n. ........ In t... howeve r.ih ~ r. ..' Illost conunnu uu-aus of ach i{'\in~ this ~l.·.(HA P1H Q 129 so lutioll is a llllldl faster p nll't"SS than is t'llIT)' o f drug into the hotly. Il"t· t'xjlC lSt1l to IllXly fluid s hastens t1iSStllulioll .' il . for t1i"Slllutioll is tli rt'l"'l ly n-latr-d to the Stlillhilily of the dnl~ at the surface o f till' disSt)hill~ A.·u lII~~·ill [rom (Iillt'n 'nt tllblt·t" ha\'t' little or llo l·llt'1:"'l 0 11 tlu. for t·. linllti"l: . .ri ~ ..·) I.-.' ''sorp tion cannot proo-ed ...<1I111l11011 situutiou... ( n.s tmin!t'stinal a bs orption of IIt'tlrnyt'in ¢\"t'll ax a ta h!t. Iilll.. anti sometimes lilt' exten t..IU<. dm ll~t"S ill dissolution profoundlyaff ect Ihe rail' .. .. In tlu. ".-..'1'1 .. To this l' lT t'l1..muplt· ..all appn'dahlt' amount is ab"orht'tl. "·n.

\\'illl l"{lIl\'{'n tifln:11 tllblds.ldl anti small iutes trm. ~ to 12 mtn ill diameter]...trti al tli~l'sl illll .h an' ~t' I \{'r.. In this state. .lr "htllIS i t. hOUri of til(' (lay. This 'lI11p!....lilllililll?. tlll'n 'hy limiting furt her di ss(liu lion. illdllding s(Jli( l~ illmml im'spl'ti h·t' of Si7 intn tilt' sma ll inlesti llt".t\\"t't'n 0.. wit h a mean transtt tilllt' of around l hr.so luhll' salt than for the fn'(' add o r base.ltu ralt't l solnnon at til(' abso rp tion silt' l:ou ld Ix· llI. and tilt' stah' of tilt" p atien t each inllllt ·lll't·s ti lt" st i rri n~ rate am un d til(-' d i s" . As mentioned previously. tilt' " h f)II S(·kt'l·pi n ~ \\~ln' : ' th at prnpl'l.low <I(III \.. 111t' situalio ll is \'('f)' d iffel"t'1I1 aftt'r t·<ll i ll~. ste p and N it s. l . 111is ine rt' aS(' is ~rt'.. 9. gas tric l'lIIpl)illg of bUlh small alltl liltge S( .lIlS who t'a l tlm't· ~lJotl llll'ills:l tla.('. h~' lll' l pi nJt to ma int ain such con dttlous around tln.Lst ril' l'{JIIIt"n ls.s ad lil'\'l'" 11. this i. Fo r ('xa mpll'.·lillt' prt'('ipilatl's onto 1l1idisS(II\'('(1part icles 1'1\· tl'ring tilt' illh"Sliul'. 011 . In tln. is mi nimal l.s all ~. o nly S(llid.:tnit' . whil'l l('I lIltillllllllsly m ix anti trilu nl!I' til(" gas tril' l.7 mm hy 9 I1IIIl or tablets. T his explai ns why tablets.s lril· 1'lIlpt~i ll g Oil ah s0'1)tion o f d nl gs ¢ \'t' ll us solids. o.l'{lIItmt1 io ll of \':If)i ng fn 'tlllt'ILl')'. capsules. E\"('II if dissolutiou W t' 1I0! tln."ll lu till" rt't juisite Si7'(' hy t rilu r. :2.rate.u llid sti ll II(' low . As sht)'.'kl't'p illg wan"s" i1n' 1It)'.'Pi.. 10 Ill' mpitl.di ssuhill ~ man-rial.dmgs.O!t'ri(' au tibiotic. littl e d nJg is ~t'll e mlly ahsofhetl from til(' sto lTladl. wht'll takl'n Oil a fl'l l sto m.s 1II0 of til(' \\~I ki ll)!. As lou ~ llS thl' SlllllllU:'" relll ains ill II fl'll sta lt'. ~l hi ll ~ ill lilt' ant rum can he Ijui lt' \i~nr()lIs ..l li ~ht 0111"anti is mlleh ~n'ah' r for a 1 1I. food. a!t ho u)!. T he disilltt~r. Slll)'. Stirrill~ is gt'lwmlly su ffid t'nt to ('IlSIlTl' ('IllItp!t'h" and rdpid dmg ahsClIlltioll from solid tlosagt' for ms l'l lll tai ll i n~ solu bk.i nl?. Tlns conceutratton is mud.of small noll\!isintegmling pdlt. then.U l" Illt'n'fon' lI('IlI'ud.3 aJl(I I . \\i th SOIllI' of t11t'1II still in tilt" sto ma l'll I ) hr af!t'r iugt·stioll .of abso rption IIf tlU'S(' dmh .. TIlt" I'XlIli ..{lIIte llts.l\t riC Inlllsil tilll!' of soli(ls is illln"a. thl' l'l llld iliulIS a bo\'{' pn '\ <lil.is luns idt·m hlt· individual variabihty.di S('II.t~('f fflotl p:trtid t's an' f('l aillt'tl u ntil f('II"l'I.t tl' r afh' r a Iwa\'y ' mt 'i1) ttHm aftl'r . 9--:.u: iou of a fl"(1 Slfllll.ol\in~ p1ll1idt".l!N·I'\·lItions an' I'X' p lailll. tbt' mt'an g:lstriC Irdnsi! timl' fOf largl' sing le unit sys!t'llls is 1I0W alultlst "j' h r.~ mill ) am i o f latgt" singlt· lIom !isinh~raling umt s k itlw r capsules. di ssol ution in the gas trk fluid is a p n'n'tluisite to ti ll" absorption o f s(lllll" (Inl J. cn Pt' ristaltil' IIIUn'IIl t'lIts in the sto llmt.O IlS so luh ilit)". '" For . alltl \~triahlp.!. Only Iha t which di ss(llvt's in lIlt' · stomach is appa rently absorbed.·S(' I."l"S. a p H t~11it... an un pn'tlkiahle pt.( . st sider til(-' iufonnalillll pn )'.utidt.. s ('lIhn illalillg ill an illt£'Ils(' l'lllllnU:iinll.130 solid. couFi~.ssillg the nlll' of ga.lIltl even sus pen sions of sll.' \\i th ~:lst ril· lI l1 i( 1. During fa..n l in Fi~. tlt'a~Tl1!:ation m it' . \\ilh t1iall l('lt'ri I I's~ tlmn -: 10 10 111111 an' allo\\"l'll to fIllSS into Ihl' small illtl'Stilll. nhjl"li i\"('...i dl'tl in .l('1. Ihl' stomach d isp lays a compk-s temporal pattern of motor alii\ity with "ltt' m ating p erio d of'lu it"S("{'nt"{' alltl modr-run.\tJ <I n ' thl' uu-nu transi t thues in 1111" ~tnlll .\ .l\ l' m~I'. "t' Gastric Emptying and Inttsta Transit Befo n . I'jl"liioll time of a S(llid Il.'riod \'a f)i l\~ fnlllt 20 min to a f(. tilt" mit' of d issolution can ma rkedly mcn-ased hy mill Ka salt forrn . This "". Adj usting p H of Ihl' medium also i U{'T('lL\t'S dissolution of we ak adds and bases. locatfon o f til(' dosagt· form in the stomach.ltioll alltl )). hours .. For thoS(' !lI'fSl.u lllaillt'<l.sling.ukalillt· solutions. not as effc vc as IlSill~ a salt form . tilt' nth. Xom-theles s.ts (diauu-tr-rs h(.lillt" h)'tln x·hlori dt". si n~I(' IInit th :w fo r ~ lIlali pl. llw g. · soluble at p H .tt i c)ll rate. TI II.. d i si nh~rdlioll and SUhs('t !lll'nt dt'aWt~at ioll into finl' p. Tllt' i m.rgt.'ti hy tilt' sil'\ i ng .lill~ is ~'t'1I .u:h.\\.l ri ll~ly soluhle dnl ~s an' prOlIl' to absorption problems. however..t1 of till' Iutes nuul lInid . point is wel l iIIustmtt'tl hy h'tml')1. Furtllt'flll of{'. Perhap s the sp aringly solubll' It't rd(')l.'~ll l. lngher for the muchmon.s (III whl'lI lilt' S(llid is lakt'n duri ng tilt' 1id mot or adi \i ':-' l')'d l' .'lIt'ts.{llltrae tioIlS. rt'plill't't l h~' n 'gil lar amlmtlfe gl'ntle t.i . This is ~t·n · e rally. TIll" explanatlou hes ln the diffi-n-nt ('lllll 't ' lIl mtiI IIl S ill tln-surface of tilt' di ss(J"in ~ so lid.'it'li..'(·ak adds um] ha.tJly ft't·hlt. fn 'dy soluble ill b oth s lf(lIl~l)' <ld dk und .

·.lSt ri< ('1111 ' >~irl g: an d inn-stiual traus it on tlu... li. IIi<! . al .'s !it) rupi tlly that most is in su iutiu ll IlI.i"ltl..tlK' ..\i ll ~. "" 'a" 1 . I ll(' transit unu.""rtlt"brJ:.1 Fan•.1.1 ill '"·.( II. ti.. y •• •• lIP • • • • • Q ~ •6 • • • • • • • • • • ••• •• • • • J • • • • • •• •• Fasted t 0III • •• • • • ...'ill..".ineither tht' large Iltl\\'t'l ur n-cnuu ..· .· till '" ~ i'K I.· tur...... .CHAl'YH Q AB5OIIPTION 131 I n routruxt tUl'q 'lIh ill Ilw stomach.a.lil·..t~ lri l' and small tntesnnal tra nsit ti llll~ indkllh' that." .> h·riak Th' p"in" will. i 'lt-n''''''~ lilt· ):". ( .ts l ril' t' lll pl~i llg: dt'arly in l1m'Il("t' s the mit! of dmg: ahsorptiou..'"I<. i"l: ...= ~ • • • .l\t rit· t'lIlpt~i ll~..lpidly hut h disS()Ives anti pa.. ' ..m · i. i" .• •elut io n in Slo macb . Ihl'S(' llala 0 11 ~.1.' . U " r laru.' a I." "".' tlm ll' rstol ltl..~ ) alld ..• "r II... ~~ 1..L"kl"aI po >l nl•.· "'...Lw. " n . a 1 tiuu..1 .. ~O . (If thi s snuancu.absorpuon of drugs gwen ill so lid dOS<Ig:(' forms can Ill.. wllt'fl'. II .tllly slUII1.h· tiK .~ .. tic·. Hapid Di ..ly li lt ll' Illi....·lld' (I." nlf . till in It.... ... 111 ts tilt' ("'(1I1H1IOIi situation S('l'U with mall)' conh \'l' lll iunal tablds an d 1' lpSnlt's . y..· pI1~. Ught Breakfast Heavy Breakfast Light Breakfast r.. an... .lr to rnovc down till' small iuh'slilll' .uf sol i t l~ " it hint lll' small inh'sl i l\(' va ries liu ll ' among: sllhjt'{ appears 10 1 Independent of either tilt' sin' of a su lid or till' 1s... ...1' 1<.1cl'Wt)«' f"mlS .--7).UIJ is n 'lllark.t. . ~>l.. . for tln.anus transit .Irk>Irall" ll1 ml' "I' .. In co"lr.7..\ • • ••• • • • • Heavy Breakfast rin·....allp..· ..'fun ' " nlUd l has r-ute-n-d till' inh ·slilll'.. Hapkl Dissolution in Intest ine .d tt. 1 10:..sim ilar to Ihat foun d fo r till' truusit o f liquids.... quickens drug abso rpnou from solutio n..In'I:'(''''' ".llicoJ ... Constder lilt' fullou illg: situations .· .tl wall. lJ.... d rug dot's 110 1 tlis. lJI\l.. (A. J.n' ".."h''''. J G. 1. • • • ...".in" .i'·..1ri"·l.· .. app m 'dlllatd )' . unabsorbcdmatr-nuls an . "t.'i.Il.. il "f l" mn.. D m g: t1is..lsl rit' l ' l ll pl~i ll ~ tln-n t1r.ai.• • • I •• }." .. 1)..stom\ ach. . (l"..-. .~S('S across tilt' inlt'slill . S.lt h~· ~... all. ~ . 1tI. II... Bo tll solids andhqeids app<>.· n"ih (" ..: T n.·1 .. n n·"~..'(1' S E.1r... )(' pn'St'Hl't' o f fotltl in t ill' slt ll ll ad i ..S. ." " 4 • 2 • o Fi". I F asted F.1.· lasl ....<j.0. :!:....' Iutlu.majority of this tiuu-.d. lI 'l\h'ning: ~..l\ in lilt' illlt'sli lw il r...lJI\l.·.... As the mouth-to... " I' . ".· t. 11r ( F iK 0.ull ati (~llly atTt'ti s tilt' time and perhaps till ' mt l' of t1 nl ~ absorption.~ ).1 "rr Ih. . 1.. .tS a p lll~ wi th n-1 n .. " .Ll'h .". II N I' . . for example.1a"I: ..". 1. .. - -Q D .tli tiUll' h t~vka lly 1 to 2 days... ~ .... " KI"i" h1U"tinlt ... I... All t'lllt' ril"('(MI('(1 pnltlnl1 is an t' xln'lIlt' t' ~lln p lt.. l u tlus situation.. •. ~.I.. I.1 ."all i"h·. El)1hnllnyl'i ll a lit! pl' n· Stomach 10 II • • I • • It • • • Smalllntestine 8 Eo 6 -cE ~ ~ • 0 • • . i1Ii " . I'rm i dl '(l with till' ph)'siolt~l' illfu nnation above-. 11. IllI" pos sihle mil' u f g.. .

delays ~. tt htn.· t'lIlJl t~i lll?: of slld l p r oduct s p rnloll~s 11 totu l period for d rtlg n-leuse and absorption .<.'('ss. do sal?:(' fon ns.(' singl(· un tts takeu Oil ."t.ng 1 ll('(Iit'a lions.solid dosal?:c' form Illay lx.. In Slid .lsl ri(' Plll pl~i n~.·ry of the grauuk-s 10 III(' int est ine is t'Xjlt'l1t'1l 1 Ix' mo n . hnwt. Om' ' d.(JIltinuuusly PlJlpl i('11 with Ill(' g' lstri<.iutestnu-. ~ lallY slI(.l}' ill the.(! by a dc·li\"(·ry dt '\i et · RS I OIl~ llS rd t'.l"l rit. T his "lt'Y 1 wOlllcl S(·\'t·rdy limit tilt" dt'si~ l of <'.. As !lU'lltiHl\('11. M. alltl ujl til 12 IIr or ('\ '('11 mort ' wln-u taken (Ill it fed stomach.132 c-wttec icdliu G art' mp idly I l~llrul~·/.: tln.of tln-se an' tUiltt'(l "'ilk or contamed ..!.. Release Produc ts. \ Vilh till' I' .pt'nl1t'n t o f IM I' ll and a~t'l lioll . 0 P(MJr D isso)uti o n. Evt-n t!loul?:h tln. r-un-ric-coated product s an' lIlIt til II(' 1ISl.d m~" ma~' also apply Itl certain ('(mlmllt'1l-n'lt'ilst. tl l rdati\"dy polar lIlol("t.llh'rillJ.l'i('S the tillw for dnl~ 10 di s. O il 1lI0\"l'llIt'nt into Ill(' ('(1 011.dm ~s \\. A p n l(Inl1 {'u lllp'JSt'tlof ('nle!ie-l u illt'(l ~m ll ll l('S is an impmn. I lt' i n~ h-ss t1qx ·mle·nl em a s i n~lt ' e-vent am i o n food.11 these. 111 it material n -sistunt to add hul 110 1 In tilt" intestinal Ihuds.. tll(· noslllt ill~ I1lmll.:al aK ('nl J. 110\\"(. dala fo r SOUlt" d mg·dd i\"(·I)" sysh' llls indit1lh' th ai rt·liahl(· 1Iml slI_taillt'(l ahsUl ltioll for lip to 22 hr <'1111 1M' a('h i('\"('(I.lslri(· t'lll pl~i nl?: hax litt l(· (.\("S.l)"'· h('fo rt' (. Co n ln)lIed.and Iute-sttnul Hukls.sp'lrin ~ly soluble in both ~.l f('11st(lIllilt'!l. Sub s("fjll('lItly. Any c1c·l. \l' this dda~' is mo st likc'ly 10 1)(' SI. tlu ' n'hy fa\uring inert'.St·.rtit's of Ih(' drtl g itM f. \ Ind l o:IqM'Il(L s 011 Ihl' n·latiH' impt'1hlll(.'(! \\'11("11 a rapid am l n-habh. thc' pmpt.lge for ms o f d m ). V. slid .\-s for dm~ lllll\"('llleuf ill lilt' dl'\.l\(' fm lll Ill(' c1e'\i l't· is tilt' mh'. the re llIay aln'ady ht' insufficient limp for compk-te d issolutioll am i 'I h~ lrpt i(l l\ . 'l Ganging Rate Control n it' mit' of abso rp tion is ('C llitm lll.1 . n-teution in the' slo mae h inen '..·rllli'ability .of d m g is indt. ('(mtrtl l of dmg inpul is losl..o f d e!in.111 fats.. It \\lIUld lit.!T('11 011 lih tilt" rate o f drug ahso rp tion ..:riS('oful\in.I."~III . su mt' <'llll('('m m ll. into tln. for whit'h 1 1 M.. S \\ilh sho rt ha lf· "' Iiw s inlt'm)('11for oll("('. fOCI(I. in whid ll'iN'.I')!.\"(·r. A so lution to hoth f)pt·s of pr olih-ms h iLs Ilt'('11 to (. 9-H )..11.· fluid into lilt' dU(I(I(·nUIIl mid i~ il\'uilahl(· fur allSl'''ltiuli . So\ lIlay <Imp (' Ilnu~h so tlmt til(' mlt·1 lim itin g slt·p 1 '(IIll(OS p. SA is at its h i ~I ll'sl ilnd ('olltrtll may t1lt'1l wdl lie \\.·ult's.· likt'ly to ()(.(lJX' aJl(l limilaticlIls o f th(· appm.1ion in Ih(' la~t· intt'stinl' may pro:·dude rt'!iahll' input of d m~ 1 Olltl I2 10 16 hr.(~ JRli ll~I>'.in t('sli lW \'a ric'S IIl1 p rt't lit1ilh ly Ir mn 20 min til S('\1'ml lio llf'S s when taken Oil all {'Illpty s tll lll ad .t<.c . TIlis silu ation is Il\urt.lS 1I0W dist'lIsS('1I. Th is dday Illily lit· 011(' of tln.'t.('\' and ill ti lt" intt'st ina l \\11 III 11.r \\.a.'1'1I " . an.ltienls' ('atill~ hahits ami tl wir ~t'l lC'ml la(·k of tUllip lillll<'.. ( " (. IIIm.limiting sho in ti ll" ahsu rp tiull pn )(.l.explanations for 111(' ohS( . For n '.l in-ry dc'\ict·. wtth a fiwd short tilll(' within tlu.lsoIlS diso:'uss('11 alxl\"t'. us tilt" inh 'stin al fluid and contents 1ll0\t' inlo tilt" largt' tnte sttue am i \\111('1' is reabsorb ed.(' ill ta".sl t'xisl Ihal ll lllll.. Scum.itstri<. .l"sa~t' at'rtlss th t. nit' conclusions d rawn for sll. Salil) 1k add is a ~ilst ril' irri tant. til(" n ·I(·.\. J' .day ad minislr:l!io ll. p .coated products an' la~(' s i ll~l(' tablets.. SA Ie I'm fCl r drtl ~s d("t.{'(1 to illadi\1. \\l len 111('5(' t1m ~s an' adminislt'n'1l us a sohd. a Il ondi sinh~rdtill~ material throug h w!lid l the n-h-ase r an. Ihe mle limit ution ('(mid dlanl?:(' fmlll tilt' 11(. tIlt' slllall inh·stil\('..rt'la illC'(l ill til(' stomuc h.n ·lialllt·.hiua\'aibhilily o f ~ris('ofllhi n whcu tuken wit h a fatty meal o r \\. AI.l" Ihe dt'\ i e(' IIlO\"('S0:10\\11Ih(· inlt'slilw ( Fi~.1' to th t· inttoslinallll("mhmll e . Th at said . such as tilt' oral an tifun J. fll rtlll'nlluro:' .\·t'r. to dl·!lt'llll too 11lI1l'h oni llis do:ola)' lo .·n·ilsi n~ p alm lR tilt" l e'll ~ h o f t!w in lesti nal tm<.lellie\"(· a pm lolll?:l'(l ahsurplioll profil(' gin 'n tilt' wo:oll· "·ll(l\\1l unp n '1lit'lahilil)' o f !l. Ih I. . ami tilt' tillie' taken for an illi ad tabk-t tel ll<l S [rom tln.·llwllt lx-cause tilt' run.' Jlr( lt llld ~ i ll tilt' addie envt ronment of thr.rate of abso rp tion is required.1I enteric. SOliI(' d Ol~S . Ih Ill(' dc..Sl ll lllil(. Fuluro:' s l \\llrk in Ihis an 'u is 1ll1'(!c'(l to IIllclerlitam llhe S(..lst'1 l drtl ~ is (.lringly soluhlr.w aibbilily. and fat ill pa rtk-ular .l'i('(1hio.sma ll intes tin e.stom ach.cd ion o f Ihl" so lid content s lIlay S('\"('rt'ly limit fu rthe r di sso lution ami ht'Ill'(' abso rpl ioll of d mg.rYt'1l im 'rt'ilS(' in tln.(lIllm llt'1l· rdeil'i(' do s. lim itation m n lit.

...<.·' '' .·a-'. "" h."...·. .. In I ..1nf 1'·1.-a...r .'·"l!)..lol' i.I:(J. d.." I.. 1 . Ih.. n·. · " t...· I.· \~"..'vl"t1 I )( '~und li lt' small inh'stilw ...1wilh .... The Iln'1l "".l \..r ..". t" II.~.. I.· of \~ "" I....' ....· . . Ii " ..n l.... C'l '''''''' n·L.· ral. ~..m " ..." l .1 dl" n~.· fr :t ..::::: o 6 12 18 24 Hours TI. a.. Il f 11M· ~q n>i"Io~ill....". I\....! ".>ri". tnr..f.hi hl~" TI.an)(.s:thaI i~ IlI"...j a1""'1J1itIlL D..' n.o. .Inl\: "..hr..rI 1virtllally.1tin .1 I.· l("'l ruil1l lilwl lr...rpti<>u ..'\I i". a \ .._.ol!l".7 ). ("1' . 1I.u.f 1 ..h.l li .aI f·lif. \ 'a i~ tI. fmm .t<' .. .·. 1 n·I.r.......II. I).· r41.. of ..... TI....needs to he k 1lU\\11 abo ut the rdation sh ip h d W t ' t' 1i tilt' pllysit( ldll'lIl it'.. p' . k .· ...· d.· (~II (6 1 i.o\I\·" is II.t n·It~.i<I"'1( in tI.· .1 lo I"·n..1 fnr .. "".. dnlll: ...o I ~"".· mr...".IIl nr.. C ..• Il..l ruinlnlinal lr. 1 ""·..·mhr '. Io-M 1>"1 . .· ill lI"·'''''''I''''il.1 .. "'J III .l tI.pn-dict iou of tlmst· dnl ~ fur which coutmlled d mg rk-lin 'I')' run hI' adli..1l'l"'''l-:o' nf f dm i( ..In.. in 1I .ri.~ . _ 01." '1) ' ' ".. n-" ·a" .2 c o a w & !i..• ~"..~ . compounds is !'''' 'nt ially n 's tridt"tl to t i lt ' small in lt' slillt' (t·. " y "1 in II... an' ~.. " ""lal in II.·1'· . of tI.. ' I"i<-kl~ . ..1" .. C urrently.I.1"""111.t Ii.... I<"" 'r Ihan tI' 41 III II.~o\ \ '<1 .. it is " ·It ~ 1 . I " ..I ·n·"·a. t. a A j_ '" a ~ ~ 0.. an ' unk"..... TI... TI.· I.. .11 i"I.1 pnlpNtit·s of a mok-cuk.o\I\'" i•• "m':. lit(' . R... f n'It·... 'rpti"" makhin~ rat. I. ~ al" . it is N difficult to make any quunt itativr ..· rall' nf 4h"'''l'linll " 'L dino In 11K· ral..." . i.· 'I''''''.· . ..11"1( i • •h ~l nIJt'I'''1. " " ....... 1 d lilt" r""'-(''' 'ln. ·n.". iii 04 0.ol 24-lor ~"~I. I""·.... "M' 'Ii " . i. Thel'nlllll':1 fail.· . ...."·d i.· hIt '"~ fltT Ih.133 may Ill. _ 1< ' . some of th e d m g is likt'ly to he TI'II'.. '... r · s.011 lim..." A...l i"'I.. IIUWt>\" .In~ fnm......· r....·.Io"'i<~' ". L-----+--=:::====.....1. tI..:..1.111.· of ah..•.".. tiM' rod...al l 1n" ....".· Sl" "'L<IIr" " l...and Intestinal pe r n walnfuy..-\" i\ a" .... ah sorption of tllt'st. ...l !i....· l(a.".· Iln~'" 1M· '''I< It'r li lt· n·I. A. uM'ml..1 \ '" willt ti ".n fnr IIJm)(" ill.. Rut dea rly..1"'...f ... ill p . · n ·! . " . wln-m-u-r n ']l'lN' of t1mg 1 )(')1111\ 1 t he stomach ('onti lllll'S for 4 hr or ilion'. 1I ......• Fig... U. ral... ~. 0 " "'hr..6 ~ a. ~ ..' I. '''-'n. tilt' Ollly "'('OliN' is 10 ('\" lualt· Ilw dm g tlt·lin -r)' s-yslt'l1I ill r . ·.. ~...1..'''' ' ... Mon....." . noll.-..<.. s..Ia~(· iu!t'sti rw ( F ig.. S. kh 11.g.' .. TI.· ill lI"· I"" lil1..1. .:l" Forms.o\I\'Q _ n. ("<"I"lalll li>r I. "nlin*.r) .. ·rti<. Cum-nrly...tltr. i" · .•..\... p • •0. II....· 111.11..1 I" ... 9--1\.' a problem.. 1"·m..In. I"" n .".... ' .... ·r lIull'l II.· . In (..'h .' "'tl.!!: " ..·) I .kl ..i . r · s.0\..al.10·1...1.". an .....0\1\'" b IUlor .......'" Il .k. 1 Ira.l'it'11 i ll tlu.. ·n· nth' (. 1. . hfM·.. "ilil~'l. \1.I" . ln linl. iu r... 9--1 ).'m . ".... tI.' li ""linl:.1 iul..ho... of n'''~''''''' . .11 iU i.It'r .. ..hly " m"d..J sll"..· i.·n u.1..' i " ral..tit· ...' II. (' " . f ' n ·. hna! 1""'1 II . En -II wi th rapkl-rt-h-ase dO Sllj..tI Jo. in 1"""' 11 Roll' nf ah•.r .'..Tl·a.1 .. IiI.".. f" " I"'r ' ~"'1' 11.tll • R Kalo ..... alw"~...."..I.\0\1\'" will.1: '..1" 11'" of 100min.In . "". p . " "' Ltl ' .". "..'i<~' In It.....· f"I......" ...· " f3 1..·".8 8 0. o Fi ~.ito:i. ·nlilJ (h.II.

a (.t· p n.sprt·ad in. sin-...M lir. lwrfusioll.l: lIlt· Sill! o f a s l m n~ add a nd a wt'ak lli(s(' (.'linll.1 ·!'lt lxidl· llilSf... .1 9j-l H o • .O('. when {·a psll)t·s of d llllrtli'l7 )oxitll' h)l ln)(.. .".t..t.. To a('!lit·\. M. For t·\l..dose . hot h wat erlIlisdh lt· ma terials tlml peruut a gn'atl' r soillbilily o f tln.111"'1<.ll fnlln <:".ihlt· solve nt . largt· do st·s somennu-s appc'ilr til Ix' ponrly (·IT t"(1i\l' or im. IIIl" filial p I! is low . u f all allUt'tllls vehicle.(·j'ltlsitll· "~'ti mf:l l le lrid(· ..1. III the st udy refN t'II('('t1 ill Fi ~..v.. 1111' raft>of a bsorp tio n IJ(J\\' he{'tllll es lim ilt't l by di sSlJllItiem of Il.d m j!. is sparill~I~' so illblt' .gt· m:lSS u f tl m g is depos ih 't l amullll tllt' iujt't1:iu lJ sln-..ratlua lly n-ston-s lilt' p ll al the.h· "'fl>l kM.llI.1.. f .Oj..1:ion site 1)('{'l11'5 wtth Ililutiun a m i abSlI'lltiun of t his wa l(·f -Illilit..ITt"<.c.1..v.'iulut ioll deJ\\ll .I ~ ".k I"' K I Io'I. its a111lt't IllS sol uh ility is appmxillliltdy 2 IIlWm l. The result is p m t ral1:I't! ah Slllll lioll 11\'1 '1' mall)' h01l1'5 or even days . I R.ra il' o f tlis..'In. Upo n illjt't."(· t his hi ~h concent runou of 50 m~ of e hlortl i.."". .lrl-:t'r volunn. I'. A < ~.'t·ipilah'tl d m g..t illg a solutton uf a ~t1t of (' i tl lt' f a spariugly snillbll' add ur ha. 1to "~M'U .1. -u 1(i\1'n ' in lram ll"" ' ["~' l ... le . 1 .lOh". 9-9. Chlonliiv.1 10.· nr. .).q involves cousldr-mnonof pi I. till' sllla ll surface un-a.... al".3 1i ~U. ahsmp lion is I"\"{'II slosH'r limn Irom . ·nt.5 ). Indeed.· to prt't·ipifillt· o uil if SlIJUIiOIl._ '1Irinl. Precipitation at tilt' injt't. snlubilitY. a b r.t.nlia7.mh.: s t. h~.S s olution of a d m ~.. ..tio.latl. 291 : 1 1 1 A."d " W. .. «leorpuon follfJ\\i ng ural ad mi ni'itra tioll is rt·la!i\l·ly rap id . <llld stirri ll~.l n "..... n{ d ... am l m inim al sti rri ng n-ml 10 keep tln. As 11111\'('111('111 a nd lu-ne.. . a dnl ~ tlrat is sp r mgly soluble a nd slowly ah smhl 'tl when injl't'!I't! lnt ramuse t'ulady..l& 4. limited perfu sion... t. For reas ons aln ·ad y d ilit.lliis riM ill p ll a mi lilt' ah so rpt ioll u f illt" injt't1:('t1 wa ter a mi w ate-r' misdhlt· materials (..(·pox idt· lwd rochlonchvm l . a ".1>11".lia.nlr.lr.. or s..an.{·u1· pfiollS. Then.ltIo-.m.n.1( I ..adnnmsn-n-d (Fig. ehlo ridt ..1f]'" I~Ml fn MII II.l I(i. ."... 50 111 ~ of chlo n li:v. IfJ\\' so luhilit)'. In contrast.. d l!l.n "nrJl~. IIIIw('W I'. 9-9.. AIIIlll ll'f (·sa mple is diazepam . 111is t'sSt'nlially m-utra] d m ~ is kept ill Slliulioll wi th lilt' ait! of Pnlpyll·l\t· glyt.rilalioll. J.. 9-.('IXlXidt· !lyti m... 1st.IritIo· ".imaldy 3.('lxlxidt· hydrochloride.· Ihan {min III<' 1lJ-. ' d llortli..lI nplt" illt lluugh.J O n I"llh . till' \"{.1 .hI' gastmin lt·sti nill tnIl1 .·. Bein.'lJIoridt· a n . do". H...ni<...1h"t.. kM ..u.IIk-It· contaius 21)ll p m pylt'IJ(' .i"".(Illlplt·tt'ly ahso rlx'(l.K . was adminb tNt'tl bv hot!l rll uh's. app n n. SI~Io" ...... . is {'wlltually (.rll"Ki<l••• wh.site.~ )xitlt..'Sl l 1tIf( " f t"'t.s ( Fi ~. 111(' t.. '("lI. ll nl). CHAPT[ i Q Absorption is llo n nally l11Illptd (' within I Of 2 h r u f i.1 t.'M" .n..injt d ioll silt· to 'A. 2 cO--OJ. rrt'a am i a hil{llt'T nih' ofhluot l ll' l\\' til tilt' Wlsl nl inh 'sti nal lrad pnllno h ' uu m .rapid t1isSlllution uud ahSllrp lioll fulleJ\\i ng ingl'slio n of d llnrtli.of fluid at tlu.. nl(.1 En!:!.~ • 20 Hours o 40 60 . uduuuistrunnn of au ' U l lll "iJ II.. . in sohr tion .\7..5) alld when t ill~"(. 1~·I"'nni . v l. TI lt' cxplauatton . il \ S1't'1l wi th p rutr-iu d m j.' \\1lS d issol\'l'tl ill I TIll. ubso rpnon is slnw from til(" l. ". R I...e). :. niWl ..... h' r t1t'gn 't' of a".m. K " "K '''llr...glyl'ul am l 4lk polp orbatt· .' 34 Precipitation and Redinol. II llwl'\l·r..l:is minim al.mU'I' lla.l l l~. til(' huff er ca p acuy of bo th tilt' tissue and tilt' blood pt·rfusillg it j!.1 al.onli""'1"».-.. I."1. th e sann.1..Io". . .) d ..·lIsSt.

01l1 1111'nt Oil Ihe stah'llll'lIt: D m gs udnunisten-d ill so lution . \ \ 'ln-n ati mi nislt ' rt'(l o rally ill so lu tio n..ullust. whe n adm inislt'n"l:j e intr. c.ytln x:hlorid(' ~1 1t of Drug 8 should d issolve muc1. I ' .] h.m. admillistmtion ) than fmm tilt' small intestim. (O the r factors. \\'. " yd mclllmide salt. Tln.conven tional sing!l' doS(' uf hoth Dm g A and D m ~ H is IOn 1lI~ and thai IM Il h drugs an' slah l" ill 11U' gastromtesnn al fluids. oYoIe<:ulo ' _g~ r pI(o 327 8' • 273 eeoc 78 ceco C ooo o 378 Oucle<nc'Yammon ium PoIa"j. 1'tQl'f 11l'Y ce Ig/molel C~ "C If I1lS"C """ • [Acid) Nee polo.. circle the IIImt appro priate tim ).t ioll ) than ( il~) in it pa li('nt \\i th normal ~a.~tomllc!" d. in diddn l llm rs dllrill~ the . of untrr. such ax surfal" an'a and su mng. foJloy. S.lilllP p rofile.ilel't1r. Lo ).000 WllIole> protein d mw.p h sm<l t"lllJ('l:'lltmtion.:t· lIt1l1disilltl').tln.i ll~ state ments: a. 9-. fint. ~rt'iltt'r than 100. U sl four factors that can illllul'Ul'(' tilt' rate of di.'_w'lItitllly the . ed 111t' hioa\"ai lahit i~' of thi s drug should 1M.l'it' (in Italtes ] that completes the foll'J\\i n~ statements..' p rilll ari l~' ahsorlwtl Imm tilt' small intt'stin(' via lIlt' rranse-llnlar route.1 Imm 1ll1l <. 6.1t.agl' form .rt. U st six <I m ). Wll(. Abso rp lioll pr oldcn» an' Ii kt'I~' to b grea ter witli [)m~ A.(. Wlslrit> ('lIlp l)in ~ mW-Jjlllils th e absorptiou of srnall lil)lJpllilil' t1m~ . milch slow er.! tIlt' Aue . A substantial Fract ion o f hio<\\'.11Iitrly il'i un a{IU("l:)us solution of the .~sol \l t ioll of a dmg fr om a solid d os. . List OIl It ".in'n tlla! rlu.Iow art.0 tha n (as) dot's tilt' fn. I)m~ A is poo rly absorb wln-n taken orally as the fn -e add \. or phr. 'S h.'\ltltioll via tlulymphatic m lllt' for Iargt· ( ~ I .'5 art ' four dr u tng:dllt'r with some of tln-ir ph poit':ll prope-rties . r.~'" ti(llJy thl' n il//(' m t" .lg coutrolled-n-lc ase dosa~e fo rms ('IlIllllu nly n-maln ill tilt' u stomach for 6 hr wlu-n takt'll ju st ufh-r a Iwit\) . · o f til(' fullo".. 1 . B .ing its ddh"l'lJ' ( 100 mg) in solution to vari OliS region s o f . 13 ISO (.~f)di lml. in the stomach of a patient with acblorhydrie [uo ~ll'it riC " illid ~"l. d .illl lUI) mL o f water. 2.'5 in rates nf d issointioll lllarkt'tlly afTI' tln.. U slt'tl ill Tah lt..I. milch . c.. (..Iay .:.U.lSI three reasons for rt'tlul't"tlo ral bio'l\'uilahility of a d m~. Ioflx ". (It . The su d ium salt of Dmg A di sso h't's milch [aster. llifTl'rt'1lt't. an.:rati.:s for which oral hioi\\'ailah ility is low <111(' to a suhstautial first-pass lU'pat k loss.same. 2(XJ ml. In T nbh.'.t. (It rs.) I.11 in te stin al pt·T1Ilt·ahility is tilt' d rat {'-l i lll it i ll ~ sleJl. on an empty . wo rd .r. a.wH/1I' mt.1t'. . gs . Fur rapidly t1hsoh..' siK'lifieantly incn ·il'K.1 hy taki n~ tilt' dmg Id O.(ura l administrat ion].m ' more slowly ahso rllt.'j .·alm's of dpmRoxadll.STUD YPROBllMS (Answers to Study Prob lems ore in Appendix II. admlnistl'rt 't l lntranu rscularlv. 01 UIl1Qflil ed form SoIub< 'Iy 01 UIl1Ol'\'l ed !OIm Img/U (Aminel Neepolo. !islt.I" [i. Polar d rugs an.9-5. in a so lution o f p ll 3.~tri l' funct ion. 11\{1il'a lt· tjn. 315 _0' coepcced Pd." add ill a solution of p H . a d m g \\itll a hm:atl ill\timil' m hial al1i\ity. 1Il('i\1.tilab!e dnlg enters the syslt' l1lit: d rt.ll ~ pr oducts of a d m g.9-6 1It.

booooc 1Od. 9-6. For d m l?:s tha i l'xhihi! a bsClllltioll palkms sim ilar to that of d p m Rux. SIlAAI'sl 11 JXIs. f ".' i n all (lOlrt !'i of thl" ~. 03 8 _ _ v.lb.iIIct·s o f SIIC(-'( 'ssfull)' ad l it. "H 0 2.05 .. Bil. e. . o r large... smal l ililt -stint'...fi nill l m(·I . From w!Jit.o:. .--.to~ cJ" 0 . lm­ inte-stinal t ract ..·lo q )lio ll o f dpmflo xadll. 1 48 _ ~..\ UG values follo\\i ll ~ dt·liH·l)· inlo lht' stomach ami " jt·jUIlIIIIl. "".. . "".. AU(' Vl.h silt' of the ~ll' l mi ll t t's li na' trac-t. ~ . dIIoo.ill..ill . 0 s-b.-.ih 't · pri lllill)' .. ~ OQCI ~ _ *. stomach..·I")· sysh· m .4 008 cop<. ....tinal Tract'" AUC(mg-{/h'l ~A... Regions of the Gash'otnte.1h.l-..Iluel of CiproRoJlacin after Delivery of 180 "'9 to Va rio.. Cipru flu Xild ll aplll'ars In ht· stahle..~ 9</ On JItooowxol JO))-30 IQQO a....t'<I IIJI ti l(' diffen-uce... co m ment o n tilt' d .· in tesnne is lilt' Illajo rit) ' o f lipmlluxatin likely 10 Ill' ubsorht'< l follu\\ill~ o m) udmin - tstrauon of t ilt" d m~? h .136 CHAPTf &Q the ~~ l'f nJi ll h-.ad ll."\i n~ a constant syste mic inp ut for u p III 12 hr follo\\'ill~ admi nistr ation uf an oral dnl~-( II ·Ii\l.' .of .

. from oIN'I"\'"lion' ill hle.~'lln'lIl"1l1 ill vartou-. 'r.trihulion in 111111'1 . I~ . S('\t'ral fador' dl'll'rllli .·' ..·r. 10 tlu. the a mount 01 drug in the body. It hl'~in . ·I r. ill dirlkal plla rllla("okindil. Describe the efIecl3 01 perfUSion lim'lOtion. \ Iud l uv -ful information Oil rail ' alll lc"1l'1l1 of di .U1/JIIlj"ll rd. 1 137 . and the o~fenl volume of dislTibvrion when any I'wo 01 these volU8$ ole known. )(1 or pla. 5 .l rihlllioll and its applil'al iuu .1\\' 1"''1'11 "hlaillt'(! in animals.. ill huruauv...Io-I1"... Ifssoe-obood equilibl'ium distribution ratio d Fraction unbound e Pbsmo pt'OIein binding 2 Deenmre lhe plasma co-ceenonoo. Anl'cipole!he effOCl 01 cseed pkwno prOlein binding on the half-life 01 0 dn. 'I11i. ('hapl('r l"plon'.w l ilt' d i'trihlliioll IMI Il'm of a dOlI!. outside the e erocellokn fkJids d bound to plasma proteins e bocod to plasma proleins in the eKlroceilubr fluids I.-ut inllv bd. bccod 10 albumin and with a volume 01 di$lliburion leu Ihon 0.ihl.. k. 3 .f. ·r of dOll!: from OIW location 10 unotln-r \d lhill l ilt' I. 1I0 \\I 'Q ·r . te l anti From blood ...certoin whelhef . t rihlllioll of tlnlg.i" I1IC ' . /Of a given omounl 01 drug in the body. and the li~ equilibrium distribution Iorio on the lime required 101' dr ug dislribulion 10 the nssoes. Dl'fillilin ' illllJrlrlalioll 011 l ilt' c1i' lrilllllioll of a dOll!: n-qmn. \\111 tiuu-.111 ' can l xde'rill 'd . pe!"meobility limitation. lliollS . the unbound plasmacoocenno lion is lilety 10 be sensitive to vorialoon in pcseo prolei n binding when the volume of dislfibulion is known .DISTRIBUTION OBJECTIVES The leader w ill be able to: 1 Define the Ioibw ing lefm~ : a Perfusion limilork>n in dish'iburion b . hill an' . Cokokne the fraction of drug in the body rho! is: a unbound b In the eXlroceilulor flUids c. . t1i.inl!.uu l otlu-r tissm" "{'('urs al \ a rium mil's am ! to \'ariOIl' c·. bound inlfocellulorly (in Of on tissue cellsl from knowledge 01 the volume 01 disrrib"riOn a nd the fraction unbound in plmmo 6 .2 l/kg fJj . li"lI' ·' . Permeability limilolion in distributiOn c . \\ill. ma..'9.ill. Slieh c1"la 11. \\1111 kim·lit· u lll.1m! c'lId. I'e!"ilihrillll i 1'(11 11'('1'''' RATE Of DISTRIBUTION Di. 4 .n ·\l·r.i d.

ru~ . . \ a (C ..5 0 .". r1 IN l.. I... l<JB .. d iITusihll' (lin n hl..."" 0 ...Ts.till~ lllll'it:I(· o r fat. ~ " ''''.· . .I . <''11Ilt"..... u__ ..I._I c. .>. .1o: ill . .I"..025 0 .'00 15 6 08 10 • 750 OO} l~. Ih..03 0 .. II .lalion hd w('('11 ti ssue Ill..· smal l M:' lipllp llilk dm~s di lTlIsi ll ~ across most membranes o f till' hod )" ami. 9 ). ( i'K"'·.I II" Q.1I1·lin ·l} of d Ol ~ tn th \Ii('S by hlo od.071 ...131 CHAPIU 10 IlIdlll ll'(l an.. tilt' p(·rfu"illll rate IIf ti"'~lll'S \'lIn l'" [rmn appnl'\.... ' ..""r""" .' C hap.MlIltI_ I 1"'"... T issue uptake.. fur lu n~ tlO\\11 to values of only 0 .· "r II I<' h."l)" kmt membrum-s...• w ...1 QllJ Qtp• • \I _~ .... ..6 22 " '00 . I't'ffm io ll ts u"ually (' xp rt'S'it'(1 in units of milhliters of h lootl p N min ute P " vnlnun.inmtdy III 1Il l ilnilvml. l>OIIo: i.. 0' 2.r .1 ill .. 0 .. . ....._ ....'1" . C hap..1M h u. PMt." ."". TI K' .""'...1..... likt· ahsorp tio n ( ~'f.lal....Ie .."tw ( '('11 ttssuc ilml h lllOc:l l"lI.. As " x(M'(1('tL t l.... \1·' M '~M" . M_ _- 0Pw-" om 7 '0 25 15COJr 250 02 . j ...ho n .. C..". I i 71Gvlj 050 13001 '6 43 " 03 15= 300 77 50 J.I · " I .o. T.. I.o>.....I" .02 20 20 0" 05 700 200 200 >'00 350 1.... r..to . D 70-k. i.. ca n l)t· mtt·-limilt'(l hy dtllt'r Iwrfusiou o r 1 )('1' Ilw<lhilily. "'KI IIK' '~"''''"''' .( J\l· r...t In III<' rn"t"'1 "r I.d.. 10.... wt·lI-rM.'rfusio!l rate a the lilll(' n-qutred to tlistri huh' a tl nr ~ nd 10 a tis'illt·.-_ ..~. 10-1 .dod . hy almos t all dmj..-j(). A pn jiu jOlI-mtf' limil (/t/ l m prevail s when tilt' tissue._ ?~. SI_ . ' I" " M . ..~ ..h"tl o( C" . . hi lldi ll~ \\11I1i ll hlood am i tissur-s..cl " .Ie. ~."".is condition is likt'1y III 1 IIlt'1 I"..d t· . po ·.'trtil ioll i ll~ Iuto fat.~". 2'5 :\Il ntlw r f"l'fllr-.. ln ·"'r... Perfusion Limitation Di!ol rihuti ou . 1.....·111." ..... ~ "'1P'" ox- Bit.I_ . ...... 11 1l1lilllU'S towurd equilibrium of li lt . ..·rfu'it'( 1 t i_~ "lI t ·S take III" a tl nI~ much more ra pidly li mn tlo poo rly pt'rfu'it'(1 tissue-s.o f fi'i"ut·.. " :6 " . ~.. ' 1 C r.·" \ ) rdl" "( 1'0....""J<: '5 I 500') . slI('h <IS ('. alJ(l l ).uu-mb ram-s.. 11l1ll1llo nJ.tml "uhl'u talll'i IU" th "\ll' ( 'it '( .I....SM"n lia ll)' lUI h arrier 10 dist ribution...l{ 'rulllo lt'('u lt'S di ffllSi l1 ~ across loo s«..1..I ."Ir."w alKI III<' 1i' ''M tlml: . :...' rfll . _ ~ Of'd """"'...tllflew.: 4 5 0 . :\" 'it'('11 in Tahlt· 10.. ~ ). Qt net "'Cl. tilt" "llhst"'-IIlt'"1 all"I~'S i " shows .I. n 'lIl aill i lJ~ equal.{ <. I. a (0:::::::::l (C A Tissue V. ..• '~ "". .. r.>t"'·lIl.. T1_.".l itlll _ .(Ie·.. 100 ·"ldF'>""""..101 1( Ie·. < ~ 't Of'd--..1 extra!"tHtl tjOIl . .. " .. H)Q I2 0 . h"-1. ale...t~. .....I "'.. ability to ('ross tis-an.'.... ('\('('p l ll1. . Ii-. tI" 'l'n >t hK II{ \ . ...h· ' ~ I ' '''' In V ' C....1 t~ ... ~ l o n.1)' m l J milvrnL fur n. a.....i ll ~ it.1 C A _ TI l<' ... In ........ ' .membranes pn' M' nl (... lI11'n ' is a t1irt'('flllrn .. ~ ~'" 101093-1095."lr.....'pill'il)' walls of IIu."~<".. ' h:ldoo "" ... TI l<' II• • .

[n un the who lt. thm-. when the uet mit:' of uprekc.IC\.IIJ(I K. ". 7 1). =0 Cit and C r .693 Kp " IQ/VrJ 5 Thus. may he ft-ganll'1! us a measure of how rapidly d nl~ would leave the tissut' if till' arterial concentration wen. then-IonAmount of drug in ' iuue . kinetics (If tisSllt. Gk i. is ¢\1' 1I h)' It _ r Role of e xil Amoun t in Iiuue Q . 6.. TIll" pa J'itllll"tt'tkr. tha t tilt" urte rial conceut ra tkm is mainla ilic.. Furtherruore .) ill l"<!uilihriulIl wnh that in Ihl' 1i_ISIl t' ..tll the ccncentrunou i n l'IlIt"~t'nl n-II011S blood (C". C. k r . Cy V.a distributio ll rat e n nls l.'I)' hy lIlt" liss\lt' distributkm ha lf-lift" In . when.C" is tl.". Then tissue uptake co nnuues. hut at a dl'l·l"('a. · Kp ' Cv whe n' QI\'r is lilt' perfuslou rate of th e tissue. e t'Ill(' ~I 'nt \'(' 1I0 U S comx-nt ratton. is Ill(' (-"(llIilih riu lIl d ist rilm lioll ratlo (C.\'r is Illl' tiSSlIl' volume . Q ' C A ' Further. ly From tisSllt's Ihal han ' a Il i ~h affini ty (KI') fo . Net rote of uptok. Q ' C\ -.. with no d ft-"(1 i\'(' im pedance to 1II000'(' II1("nl into thetissue. Then-fore. th e approach 10 plat eau is ddt'rlllilll'(l sul..sud den l). p .NO ."i ll~ rate .CHAPTER 1 0 "9 FiWlrt" 10.10 IK' "' ('\1. Ill(-" fm l1ioll a l rate. rhst n button can 1)(' characte-rize-d hv a tissue d istribution half..h p . · C A Tlus stt uatio u is a nillogolls 10 events tX'l'urri ll/.Q . body and.L'IDill' l"Ol1lp.) 6 Thus. 3 when.lul with unit s of n-ciprocal tim e. K. Q. .' puu rly pc'rfUst'1l.Q . ami art erial blood concentrutton..e.is zero. 1111' rate of prt'S('lllal ion 10 til(" tissue is t ill' product of hloud 11m\'.LS tissut' concentrauou rises .'("<1 killt"lk ally . until ('(llIihb rtum is achieved. it an d that an. . to drop 10 7. · Kp ' C. ' Al a ny time -. 0 .lire for which • H IfH o le .e . It is analogous 10 the I'liminalio ll m tl' constant for loss uf dmv.V.).1 shows 111 1(1 perfustug a lisslie ill which disl rih l1tio n is perfusion rate-lhmn-d 01 amino elnninanon Ol'ClI l'5 ..t dll rin~ a constant-rate infusi o n of t1 ntg into ti ll" h' l(l)' (C ha p . C A 111l' Ill'! ra te o f ex travasation is l ilt" <!ilTc'rt'lU'c' 1)('lwI '('1I m hos o f p rt"St'nlatioll and I('a\i llp. hl l)(1(1 and tissue (.. C r . ICA - C~ 2 The maximum initial r ate of upt ake is tilt" rate of pn-sen tancn. with the e-quation dl 'finill~ till" rist' nf tissue corx -entmtkru lu its plateau h('ill~ g1n'Jl II)' < Iissue ccncenncncn w K ' CAl l .<I ('o llstaul "it l.e . drug leaves slov.l rt llll'llt .693 _ 0.. Iht.of exit. Suppose no w. Role of pre$entolio n .. ltkc ehminanou.

C. These simple examples illust rate two l>ilsi<-· principles .. 11 tiM' """ ' rial " .u nl h·-limil. (t·sI1l.' n '.~rt'all'r thl' It'mll' lIe)" to conceutrate in a tissue.I.s 10 deliver to that tlssm.-rfustou rates 10 t]w S('!isSut' S an' .1 1 . Slltl\\1I art' plots of coneentrution in various ttssues \\1111 time d llrill~ tilt' maiun-nauee of it constant art erial concentration of I mWL..and equal to Ollt'. n . ~m llt' ly.'l1l'(·S in ('...tnl. 1.lilT "n'1I1 ii.. "t (1 mKfLl • • 6 00 pt' rf'L< " "'MI ''<llIi lihrilllll . l rillllh.. In th is study.. dilT. t'l lt .03 ~ ~ ~ ~ 0 ~ 0 0 1 3 Minutes 4 5 6 2 3 Hours 4 5 6 <'OIM't.n ill Ih <u. tiSSUl'S : of lo e r perfusion . S oh' II.• .> <. it is 75%. _ I ill all lli"". in whk-h events ill fat are sIJ{l\\1l for dm ~s with w dim'n'n t 10:. n-latl vr .40 and !i() DlSTiIBUTlON CHAPTf l11Q 01)(' half-hf.. ~·.. 1...'3.li.-t. Slatl't l diffNl·llt ly. l A. 10.....· . p' 'C 1i.<1i\"l'ly (Tabl. . ami 115 min. (mUminlmlj 4 B K. not only is tlu. d m~ in li lt' kid ll('p has reached ('/lllilihriulIl wit h Ihat ill blood. "'M rid Ii"'. " will. 'C! "i lih riu ..to that in plasma wate-r (unbound]. l"'n'. X ext consider pauel B. (~MI<t. it follows that till' l'urn-:ipolldj ll~ ha lf-li\'t's for d istributioll art' n . . wlnh... tilt. hruin . 2.lS(' of ('niT)' an' a A Kidneys aN.I . 10-3 for 111(' p.5...IW .sanu. 1I('n ' tln. nanl('l y I. IIf A (min ) .5 ~ ~ ~ 3 c 0 <.... 0 11..> 0 '" u Q ~ ~ 2 2 Fat 0 0 2 0.u:1J d m ~ was un-asun-d in ce reh mspinal iluid . 8.-16. and 0 . and fat a rt" tln.. M>t1'·n lr. till>couceutration of ('.. JrnJ:' "~Ih .lilT -IKl" in li"M' x .n "'it M rut ... .o'S .oh M" "f I .-.". hilt sn an' thl' equilibruuu tissue concentrations . Permeability Umitation A pl:nJleahility-rdtl' limitation arise s particularly for polar dru gs diffll si n~ am ISs li~lltly knit lilXli{llJ memhram-s. as demonstrated in Fi~.2..11(' events dep uted in Fi~.·II.it takes closer to 5 and 75 min for 9Ull of l"(luilibriulll to IN.loss of dm~ frorn a tiSSUl' take lon gl' r tilt' IXlo n ' r lilt' 1 N. and 2. TIllis. hot ll ihe approach towan] equillbruun and tin. til(' Iml~l'r it tak(. !I (l\\"{.K hc"(! ill brai n am i fat. ' 1i ~"M".Illio" i. tim " . To app reciate tilt· f()rt~oi n~. val ue-s. ~II ii..h.. rln. by I min (IIIm t· than -I half· lin'S).l'o rn'spo nd inl: half-liws an ' 2.at. conslder .it.-.. . T he latt e r is contrary to what 0I1l" Illi ~ht iutu iti\1'ly antjcipate.'N . S c 0 ~ ~ 05 Brain S c 0 ~ 5 4 5 E 0 Q ~ g 0.. r. Diffl'n.-n 1. First l'tJllsid N plIl\t'l:\ in whit-I.·.. in two half-hvcs.ati m i" •. Ctll " l'·" lr..rtusioll and Ilw grt'atN lilt' p<lrt i ti{Jn i ll~ of drug into a tissue .. rllr .lnltWM' .lssa~l· u f compounds into till" ce re brosp inal fluid . tilt.........2.l.llW"" wuh hil l(' ill r. 10.." ti lt' tiSSllt' conrent rution is 50% of ils plateau va hn-. K r vahu -s of a d m~ in ki<!llt'. Now.". Ir . Iin M in kid"•.tilt' amount 1J("(11 to n -uch distrihutiou equilibrtum 1'(l am i til(' 1 ()Il~N it takes to n "(lisl riblltl' d m g ou l of th'lt tissue.time taken for dnlg in tissue to n 'adll'flui lih riulIl difTc'n 'ut." ' I . hM Il.].. til lI. n.1 111ill..l o( ti m . 1i ..03 m l Jmin/mL o f tissru-. wuh tillll' roll(J\\i ll~ attaiurucut and maintenance o f a constau t p lasma conccutrarion. and 5.' lin..IKI 8 1llr l.. Z 1 5. .. Gin'lI that till' p.• 10. will. 1). all Incn-ased affin ity for a tissllt' accentuat es an ('K isling limitation illlpt:Is(1! hy perfusion.

' n . " i._loo. 11... . E..ry..-. for examp le. ofh 'n p' ·I1I..un-ionized dm~ penetrates brain...fm:. (ce n -.hlectotll Atltlle c.!p'''-~ p~r ~ ' . MIlt' in .IiIl" " 1llo k'1>ln-LoIi".6). 19fil1...S .p.f . ' 1...." )I .r\OoTl fmln tho.. .. >.IttnrtI...C "' M 11j21~ -2U 1<xe<>..."""".' .. .. pinal Auid..(:Olld llSion to 1 drawn. n.. C )(' onskk-r.... &: Wilkin. """"'" 1......[fjcit' nt and deg rt'(· of kmlzatkm (Tah l(' 10-2).8 . '1 tI...... dOI'Sthe gl'llt'ml anl'stllt"tic thiope-ntal enter the brain much mort ' m pid ly than it d()('s IllIlst. a ~rt'il t l'r frotl1juu of p entobarbital is un-ionized in plasma.· . that only Thiopental 1. tln.... in pt.Jm jt "o' ll"".~ "I_.l'<'d<?pH l 4 ' __ '*"9' J ~ 'Ooo.IN>.li"'i" ..J. m ..!~ ~ II!'" ". it wo uld apl)('a r e III ht.J. Physlc_ .r..~ 0. of FI.... its t'lltr)"inlo both brain ami muscle U ......l ml:' inl.OJ ..Iml:: in II... Thiopental is nonpolur. the follo\\ill Jt question : -\ \ 1IY... ~1. till' pa rtit ion In('ffidl'nts of salicylie add allli pt'nt uha rhital arc similar..F'9 I .lm......b..or t.111:' 10-3. tllt'n·hy si lll pli ~\i n~ the situa tion and allov.. and .... I.. ~ . c...'... pinal Auid "ill... lipop hilit..ronce-ut ratiun..gllll' w('aker ad d ..'I::I.1. ~ or hihty in inf!''''lK'inl::tI._. either of the se two fadors llIay limit till' roth ' of 1'.lin pI.. Co ... particularly ~rdY matter..." ....~u orders n f s ll~est i llg.. • 0 ..~ PH1TO'j Of" "1' .. pi I i A .. ">l.0'1' cosuc . C... .lio" of ." .lr... to a_ch so.."'.) SalicyliC Acid 02 Sulfaguanidine 0. Ill... Oil IIIt'a.4 Barbital ......~IIl· distnbunon of <I d rug... Bidlin"'n' .. r.W '0.lt' lissut' .. II.perti_.I ....I_ ' ..> 70 8 I 06 06 08 SuIIogvanidine 10 0004 10 IQ~ Q 33 005 0002 0 12 0001 0 042 00012 00005 <000 1 27 115 23 1 -S-'" c....*.. )1. ." ef 1". I TS l1.lc... fund ioll of holh lipid-to. B B G"d ~ ....lIllN1u.in!!: souu.. T he ' Willi.. pt.llTtll r.... " li. Cere...l""llh" . J ' ·!tann..uli!y and is perfusion tX....Lota of H.""' ~d-o ~ d ~"""'""_... .. L S.. \\"ith ]arj!t' di!Tt'rt'nl1.6 0..4 d 4 "" 10 "'CH Thiope<1):J1 PenlOborbi):J1 BarbilCl Solqic acid r5 30 . . I()'-JG"d~. !l<odo..I.tr.water p artition t'()(.·s ill p -rtusion and permeability of va rious ttssues ....] AlIitt' llUho'll. pit.. hd nJt a \~1.\ "'" . n.~lIrillg tolal ttssru..n'l'>Oltioll .· {'('n... For example.....N' C< '" '''''' 20 .jb1o "P-..t r.... i"'p'>rt.·nk illill tlll' op posilt' is rrue?" 111l' explanation lit's in th e propertk-s u f tll('S{' dmgs and of tissue membranes...I S o... r........ .. F .' impossihlt' to pn-dlct t i s... .." na).hK~" (R. hc""T1 for .. ..I..tli<'" .\ I1111 n .. only part ially lontzed at ph\llIa p l l .<I"a i. . pa. ar· i. A\ sudl .ICU... .tuilih...·ak add (p Ka 7.3· ' ""-G " : ~.Tij(lrt 1000..lio ... 1':»'20-2. However... f ...'in. ..0 j<2==--_ _ -_~ o 20 40 60 Minutes 80 T.. V..-. . " ~ ' ..li. h.<op:. n. II. for Ill. ra te-limited.hili~· Nt.CHAPTE ~ 10 .. ... 5 ill('(' pt'rfusiu ll n f Iht' brain .·..· ..0 Pentobarbital 0..." the time rt"flu irt't! to n-ach d istri lmliou ('qu ilih ritlnl is far shorter for pentoharbital thau fnr ~tlkyd k uctd bcc ause....It •• 10-2...<g<' of . I s<'-n:lllk. R-'L 10:" "1...·I..1MI TI•• fe. 11..10'1(. is om....""t """I hpMl ... ..

11l1' rt 'slllti n ~ tisSIlt' ('tlnt 't'lIlmtiun is m u<.<Ii1y p il-SS thr ough nn-mbranos.'Ip iltu)" 1 t'\'('1 Ihn t illl llt"tit's movement of dnt~ illto the . TIlt' most likely explanation here is th at thr. aua tomimlly han ' <I pNllIt'ahility limitation at the (.lar molecules.[T ahh.l-.l-~Illa.. 1 ~ l Ql~ p 10] 2"ClEd Vei l f'"'-:ji:'l'I W . r..ly (Tabh."nl.>u rahlt" \\111:'11 thNt' is a hn 'akdm\'tl in llit' blulM.. 11lis llhSl'fyation . tiSSU ("(.1Iovox u!a. If the ."2 CHAPTER 10 lIIa~J1itU(lt · ~n'<ltl'r than t hat of musch. I nt"' lll al i t~· munbound eonce-nt rutjon is frt't !llt'ntly nhst'rvt 'tl in till' t" f1'h rnsp inal fluid ft' lati\'{' 10 plasma for laTKt'llt. hul tht. t1ist..!-si am i lilt..'i.In .. tran sport .. I.o. Another example is Ihal uf till' d istribu tion nf alhumin ill Ihl:' IltM.mit' or fluid forma liun is sllffid t'lIll)' f.lft' is so sltM' ('(Impan'tl to Iht' mit· o f prntlll<.ltl. ~ ' 40 50 43 23 7... tlOt 'S 1101 ((. HI'.... .(:('5S is rak·lilllil i n~. much of the......Hh 1 ). The [.rapid p mc. remains hell J\\' that of lilt' di rrusihle unbound d m g in plasma.tn -aie l' (lo rn sil)' o f IIH1 M: lt · l~d pi llari("S .'1o f a h i ~h t'lju ilihri mll di sl rihu tion ra tio (1\. MUe ~ 5 3 '4 lOlaI body ~~""""~<l <bcJ <JP-.7 'MO Go' "'~'" Skin 40 2 8 110 210 350 s. of whi ch P". J1l iu tisSllt' IM '('tllllt'S till' sauu. F'.(SiN r.!lolt" as OhSl''''t'il with IX'llidllin .I-SOIlS for lack of t'q ua lity indudt. ~ InllOVOXuio.llIy wi th a nlllllh. 11\(' hulk IIm\' n f \\~lkf in the inlef!ililiill II llitl....~ ... applies t'tlually wel l 10 a Ilt'nl lt'" hil ity-fiIft> liuut atiou... . Then...i for t' xamplt' in nlt' nillglt is...I Ot+>e< I.as tluu in plasma. Pt'u id llin. I1t.·h IM ·ltM' Ihal of p l.' littl t' iullllt'lIl'\' 0 11 tjn. hulk How o f Interstttial Hutds tlmlll~h both I~lnphalk dllullwls am i ducts. Alhu min also d ilT s inlo I!le usc {'t'n' hrn spi nai llu itl . t· . atii\'(..lid barriers. lIlaill!t'mll\('t'of sink (. Hecall Irom C ha p ...ls pn)\idt....II uu-mbrune.mtlilio ns hy IIwlalMllislIl.tilt' t'lJuilihrium lit'S is ludependent. It/-' o..l(amplt' . t'\ '1 '1\ 011 slt'ady stan-. rfusioll. E. Scnn-tum-s. for t'.liSSllt' :IS a . 10-3. Other ttssues. alhumin is fo und in tilt' lIuitl a.. however.) Oil lilt' tlnu. u nly a partial impt"tlalll't· to thr. hut in terms of nn-asun-meut of dOl ~ ill Ill(' u:/IO/e tissu e .to :Id lil'\'(' distribunon r-quilihruuu. t'Slx"(. Noo.s a n 'sllit n f an ill('f('aSl't1 ra lt' of t·nt"!)·.. ant i pi 1 ~ratl i t 'llts acros s e-ll nu-mbmm-s.'('ss. (" ~" lllallY an libin lil'S. lllll·.lIlay he a pt'Ollt'ability Iimitatioll at . a rdatiwly b~l' pillar compound. howr-ver. Ihis t't lmllily is uol 01 . ~ " Iho ~ "'- ..uf di ffusioll slllli<..ce nt ral m -rvous system. A p -ruu-ability-rute limitation simp ly t1t'('f(':l-Sl'S till' rate of e t' 1l11) am i ht'III'i' tucn-ascs tilt' ttnu .'i('ni ly slow so that tilt' n -sultiug eouce-n tra tion. n -ganll('ss ) 1' of tlu..l('i' ft'hrns pillal llllid barriN. v(ri ~ .iiun of tilt' fluid tha t thl' t'tlll('('nt ralin ll is \i rt uallv illllllt'.. tl lNt' l' wu uld appt'a r to h.d n lg's physi<'odwllIieal propert k-s. W!L.i mlJ jI.I)..IJrlli" alltllJlood -t o-{'('n'b m ~1 .(' 111'1)' (If d m gs of us ual moh-cular Wt' i ~l l f ( lOCI h I -HM Wmo1 ) illi n til(' int erstitiul lIuitis.s a IIlt'a ns n f rl'lI11 J\ill~ alb um in frnlll Ihe tiSS\lt's.. Albumin sllJ\\'ly diffu ses a('mss ti lt' t'ntlulllt'lial linillh'S !If lilt' ca pillaries . -ri. lilt' uubound eoucentruri.. ('1111)"of thiope ntal int o till' l uuiu is til(" uu m.borh.t'nll)' uf vi tln-r lonlzcd or polar <" 1111Iltlllm k or. 126 ) for mauy tiSSIII'S. mit.-r o f polar n~allie t l~'t's ..urterial t'tllln'utraliol\ is mainl aillt"tl lnl\~ t '1l0l1 ~h. DI. as t~'('Ilr.l!t · of (' utry of peuieilliu Into IIIIISt-I" than into bratu urises From till' /..s alltl lym phati(' \'{'sst.trlltwtI_ ef AII__I.dt " ('Hp ilb ry 1II('mlJrilllPS a p p Ol·ar to 1)(· \'( '1)" pomus and Im'1. U (p. TIlt' t' lT t"(.'USSl't1 prt'\ iollsly for a I)('rfllsiou-Tilh' Hnunnion.('oll("pl (If Mo.10 f('adl di stribution t't lllilih rim ll over tluu of Ill. '. k-d to t jn..

NIII why tln.t... fibrillogt'n .I'lluilibria rxvu r within plasma when' t1n l~ (. that volumes of dislribulion varv wtdclv. fur a IlrtI!-': with It \11 11111(' of d istribution of )(X) L.. '1I('1i . and Ihyrnid-hillliing glohulin. .considered aho\"('. 'd rit· tn nllllllllllk n . . oftt'n hind to a i-add gl~'l'op mlt'i n and to lipop ml t'ins. Add k dmgs (.d gfycopoo!e.ng 10 " \\i dt' \"Irit'~' of subs tances and 1~l rt i l io ll .u f distribution. also.amplt. "d minisl t-rI"t1 alld IIIl' t'.n '. 3 that. tilt' smallt.0 VO'lObie 500-700 '>-23 0 ~1 4 003-007 .L\ lIla cannot .' Iraction uf drug in h. a \111 far in l'X('('SS 1lt. Volume of Distn"bution TIll' t'tJ!lt't'nlrJ. 9i 'J.. "> I'mll'illS.l" y-glolmlill. 11 rt'!aling amount in hod y 10 plasma conce-ntration.S uf which an ' Ih h-t1 ill Table.'f is tln. fraction of drug in body in plasma . Apporen.'"'9 globulm (~on~ortml 67. It' l1t of I. tln.\1l111111t'of distribution is an app rent volume an ti wby its value differs a alltlJ1lg d nl ~s lIlay 1)(' appn-ctan-d by (.l'1I1a protein. .000 35-50 0 4. Ao::.'\idt"lIll hal thl" la~t' f tilt' volume of tlislrihulioll . For lilt' ex nmph.n L . .000 53.1.'a("11 ti S~I W al"': iU\'llln .(lIIn'I"\I ' . and tltt' ( . III hind 10 carious proteins.\t"tl after distrtbutfon is complet e is a n -sult of till' dust.popoQl(>ln~ CortIsol bond.(lllIllllJllly hind 1 alhulllin.L\ma. only 3% n-sldcs in plasma. 111111('.SSIl" di stnlnuiou.2.000 42. lilt' extent of dislrihulioll is dt'fillt"t! by 1II 1 apl~lrt'llt volume of disirilllliioll (\'): v _ A mount in body at equilibrium '" ~ Pla sma drug conc entration C 7 111is Ililmmt·It'r is IIs.000. 1 The n 'm ainin!-.3 EXTENT OF OISTRIBUTION M ulnph. \ '. ~ H'II I~' Froction 01drug in body outside plasma - IV -V V~ 9 lnchnh-s tlnlg ill the. Fur . Therefore. is uulsidt' plasma. and volnuu..000 200. till' most 0 ahundant pl.o l1s i tl ('ri n~ the simple model showu in Fi~. :\ltl u lll~h Al bum..: fmditJII ..)(ly Kllo\\i ug ptl\ l1la \11 ill am i unlsidt' ph sma ('an 1)(> eslimah't l. ~Irihllliflu \\ithin .lSi(' d m j.l ion ill plll\llla udl. 1I1l1!tip ll' l'(lllilihria Ti ~ slll' l tlislrih lltiHll cau ill\'lll\"(' both him!. Hecall [rom Chap. of lulal hutl\' si:tt'.fradiull in pI.CHAPT 10 EI! . til.hlut)(! o -Ils. lIg into fal .OlJ() 1}70 kg 1~)(ly wl:ighl . Tle. al equilibrium . The amount in plasma is \'r ' C: tl.. ((). this fmdillll run 1)(' n 'adily dceenmncd. B. \\i lh iII11slra lin . ~ V 8 It is . \ 'r. C .'. Hc cull.ll ~ . I'Xiullp lt.t' amount in till' 1)( )(ly Is \ ' . bintl ~ p.' \ 11 u " s I mn¢ng F rom :) I J':11 kg hody wt'ighl 10 ~l).n u .'flll .400. transcortin..act ual dislrihution of dmg oUlside p!.

III dilTl"f grt·atl). Heme-mlx-r..In'l: Iha' . Oue of til(" p rilllllr).. Ac cordingl)'. ..I. h)' ('lpandin ~ .. ('>IIl""Ir. I IIIII('S of distribulion of ('IK. in .· r'l~.....lislnl" 'I.. ... it follows.m.J1" ".. The \UIIIIlI(' of distn bunon of II spt'dfk ' d nl ~ ran vary \\idd)' a lllnl1~ p atients.o . o f \U]lI I1W \'. 11M) Iargl'. even when a pl'rfusiull rate limital ion ap plies. . ht. . n it' n-asous fur such d ifT(. If tln.. it is M"('l1 th'll th(· volume of distri hution of a drug is till' \'U I U lIll' of plasma plus the Slim of tlu. As a ('O!lS(-'l IU('Il('t· o f btudtng. 1O-2U)... as folluws : A. lIu'lr.ew('(1 fmm measun-ment of <1m. rl..lfCnl \ l .apl). the equation abow Ii)-' C.llls o f ml'a. Fat..ItI tI". 10-1. ill fal 11 is .dnl/-.. Fo r ease of chemical aualys is. II.. At "'I" ihhri" m !I. Bin din~ WUhin Blood...rMl. volumes of plasmu aud tissue and distribution rat io.. C.i" lt l(i<' . 1i tissue. dm~ ill tilt-' hexl)' is enti n'I)-' aC"(11111lIc'(l for in plasma.. for ('xampl(" occupies appmximall'l)' 20% o £lM Mly \111 111(".(· l'OIlt't'lltmtiulI o f d nt~ ill whole blood (C h ). + Vr · Kp 11 l11t" pr oduct \ 'T ' Kp is the appa rent vulunn.s urillg (1)ll('t'ntnttiou is to n-lantilt' meas un-menr to phanmwulugit: f('S!'lllll5t' and toxkil). which olume of d istribution of some. lil ... I~' f{) f(' doill~ so .".{'(1..'44 CHA lH 10 f In thi s mo d el. til(' p rotet n-bouud form hdll}o1.L\l rih"hnll i\ .~ 1 1Vo'~'" . til(' unbound dmg concentration is IImll)uhl('(lly uum... how('\ '{ a ~('Il Nal po int 'f.doS('ly related to till' adhily of Ihe IIm}o1. 11111s."" " " "m" .o. p rima rily hl'l'alls(' tln.o. n .. h... plasma is tilt" most ('OIllIllUU fl uid analp .. ami Oil(' liSSlI(' com partment... n" Ii". \"i.!!. t11(' 11 this tiSSIW alnll/. it take-s appm ximatd)' i h rs for distrihution ('(luilihriulll 10 occur in fat ( Fi~. G ( Ell. Oil d i\i tli ll.K...In.t III1IM lllln! coueentrution is ollly o ccasionally measured.. Ii . limn is the total plasma conccntranon.I..~.. pla.. tl.rt'lll't'S art' now explored. Vp ' C Amount in pla sma + Vr ' Kp' C Amount 10 in tiuue And sinn' A = \' .\'(' r. oIl1 ltltltli " f .of 1\. th e amount of d rug in e ach lo cation can ht· expressed in terms of plasma concentration. 011 II"."" (p..rtitinn) rolli<•• " . '~I". For S OIll(" lisSIl(>s til(' vahn. .. is laf'KI'.').." . ~o. lack Plasma Tissue Amount Volume Vp 'C Vr' Kp'C V. (..Ii'l ri lo".n . ca n hI' much ~rt'at N than total hody 'S explains why tilt' v slzc . Jn man)' n-sp e-ets this cho iet' is unfortunate. I. ·IJlt. ".i " f !i""..· ... ill plasma (C ) aut! unbound in pillsmil wate-r (C II) ( '.1II('III(MIs for doill ~ S( ) an' ofh-u tedious..If.. o r volume \ . however. Illodt'l ln ('mbmn' all tissues of th e hod)'.tI1t1l·r.~ .n..1-11 Inulh' Kl liryM·. \. V.l!. in plasma. d rug can bint! to umn)' componen ts indlld ill ~ blood cells ami plasma proteins.of a tisslle ." has lin app<ln' nt \'O h l lll( ' of distrihution ('(pml 10 thai of I MMI~' vulunn-. 1I0w(.. . is conside red ."l" "...on' \'.di. Within blo od....tl.odi"'~'.~I I~· . that v- V.IIIt./' ti.. UIlI}' unbound dnl~ can Plt"S Ih ru\l ~" most rellmcmbrancs...T' AI distrib ution ('tluilihriulII . m.· pia. 7).ri.

llIlo{'{:up it't! pmlt'i n.n-nn v l'1 1 d ilT markc"tlly ror a ~\·t 'li drug...• V).. or tln. or course. nt '<. lI i ~h a lfinity. 12. unbound. as tlil' ~fl'al l'r tilt' p rotein concentration for a ~v('n dm~ couceru ranon.1 to its ' -dria hility \\i lhin and alllllll ~ plllic'lllS ill vario us Ill('m pc'lIlk ~ 'ttillg'i . or t1 0l gs with di lTc'ring value-s or \' an' ~'1. 3-2 (p.. th us .or e ha" ~t·s ill unbound dm~ cnucentration. ro .mK. hindi uJ!. The affinit)· is c rat·· :ha v h·ri7J. Oh\i ou "ly.lm 'lIlc·nl or dOl~ in p la..affinil). j u . aud hUlltltl d m~... or uu-asun-nn-nt . the a. l. it rollows from Ect~ .s. 11](' d('~rt't. n r hi ll di ll ~ is rn'tIIlt'lIl ly t'xp n'sSl't 1 as the Iimil ill ~ . im plk-s thut 0 {"Illilihrilllll lh-s fur In Ihc' ri~ht ..1 conceutrunon a ~nod mensun.stani Is total plll-~llI.9 an' sa id 10 ht' hi ~h l~· IIC IUIIt!. As stated previou ~ ly.mm [i. So metimes whole hloocl l'lJlIl"t'lItralio ll is nn-as un-d. Fo r a single bi lltli n~ silt· O il the pron-tu. 8 i nd i ll ~ is a run l1inll of tln. ' and precision. 1Jl. ~U11l't1lt'less . however. )(' Amount in body 01 equilibrium A Concentrotion in whole blood . Appn»unate values o r [u usually lLS~K'iah'tl with Iht'mpy rur repre-se-ntative dmgs un. lA 111t' values or tIW!it· volunn.. 15 is or gn'alt-r utili ly tha n rrat1iUll hnlind . Dmgs with bound-to-total coru-entrution ..l"oslly.CI-W'TE Il to 14' an. Examples a \ 1' . This is a n-latiw statemvut.1O il 1II1' l.Ls . CINI ....fl.ssoc.'alt'r than 0. P fas ma Protein BindinJ. it is helprul to dc·fine an unbound ) \l llu II W ur d i~ lrihll l i(Jn .(IIIl'C'n· tration am i lilt' l'tmn'r. al.. lIlt' ~n'ltl l' r the bound dnl~ t.".'n in Fi ~.". \'" .1 b un ussociut iou constant .'\(·. Cu .11w n· rnn ·. 111is mlio h. . uud an. From 1II1L~ S law conshlc rations. rather tha n b ound. run 1 dd im"tl.iu!-t n -act ion: Drug + Prote in ~ Drug-prolei n complex 16 Equilibrium lila)" lie e ithl' r 10 tjn. Amount in body 01 equilibrium • A Unbound p1osmo concentrolion Co Vo - 12 whk" p ermits 11ll' amount or d m ~ in lilt' hod y 10 he n-latcd to 111l' unbound dnl~ roucentr arion.!)('r or hindin~ silt'S on a protein is lim ite'll.p rotein Ior tht' d m~. .show u in Fig.0 . 22 ). l'(lIll'C'nlration is rn" IIIt'ntly IIInn' important in Ilw mpeulit·s ..) depends on tht' molar t'()llt'{'utmlio ns or bot h dru g and prou-tu.. Ihe [ruct ion o r dm~ ill plasma u nho u nd .jatiull i ~ s i lll pl~' suuuuurized by Iht· foll.miles o r 0 and 1.e . ()m1 ' again au appmpriall' \Ullllllt' u-nu. P."ltll ~· tilt' 1lI1ll. 111(' u-nu must " t'r Ortt" 11 q uotl'tl in the lite-.ri ~h t o r 1 Iht·lert. K. anti 13 thai ~ i lt .l:_11l(' prtucipal eont-eru \\il h plasma protein hincling is n -latt1. onl)" ir j ll is l'tlll. :\alllt'I~·.C b A~ 13 till' amount o r drug ill hody is i1ltIl'IIC'mlt'nt or till' 7.lIio m llll's l-. ture is ba. tht' equilibrium is ('xp n'sSt"t1 in terms o r ti lt· coucent rattons or 1I1lIICIlIIltl-tlm~.

OlST lI1BUTION CHAPTH 10 Percent Unbound (100 fu) Drug Ateoolol..am. 1 5 2 I'rutd" . P. ~ ? .M 1i1I1'. TI N' {r. when. it tln-n-fen.concent ra tkm IJf bi ll( li ll~ p m lt>in is aln...·upit'1 ! prote-in conce nr rut tou depends ClII the tot al protein conceut n mon. Appmpriatt'ly su hstit uting mto E ll_ Ii. tilt" vahn... C · am i l ilt' hOllnd conce-ntration is (I .(: Upil'( l..1 t "l l!:.6 fur lilt" hi lldill~ o f pr opranolol to u l.value of f ll is ~'l' 1I to depe-nd Oil lilt' tot al protein concent r atiOll.mall « U. "n.. re-s.(If f ll ifr/ l wln-n tln.jup is ti lt' Irac tton of lilt' lol al 1II111l1)(' r o f bindi ng sill 's lI1lc)(..._ TIIt·S(· h\1I l'UIlI't' n lm liur ls an' n-lated h'j"fil . gentam iCin Digoxin 100 50 PeniC~ttn G TheoPhyiltne Phenobarbllal 20 10 Carbamazepine QUinidine Verap.. \\ 11t'1i frl is .{ .2 0..folhlw" 111)lm rt'arnUl!{ {'m{'llt thitt 18 From thi.1 Jpmft>i n .. = PIP. lnll( i ll pia. L ' . n -lations hip rlu.. Ell... 10.1de PfoprallOlol Nrttd eplIle Ar modarone OlOlloxm Chlorpromazine Owepam FUlOsemlde Keloprolen o.') is.n -d (P."IJ11 t1ilio ll". Bv laki ll ~ tilt' ra tio o f th is {"( Illatioll for lI on ll al allli ulten-dt...lIltlium Protamamide. add ~1>l. t.).5 Tolmelm Wanann. FurtlwrllloH' .fill ' C . lbcproten Ptlenylbuta:zooe 0.· P.·l~ " : t1 n. it. Dwo. illllsi rall'l i ill Fi~.. ~ . .. l ilt' unbound roncentratfon is I II .1t' "''''''1' I A1tenlanit PhenytOin Tolbutamide.. ...m"m 0. L 19 .1 Naproxen Flurbtprolen 17 'nil" ull( l(-'(. O.IS is a ppm' illla td y Il l1\" ·fil. r><~ IU ll... 1'. ...

·in . . S · \·"rL. nit" [ruc tion IInlMlIIlIl1 is expecn-d to ill(:n 'a\t' to n .: Implk. 20 \\11('11 c(lIlt"t'ph lill i7j ll~ d t.. Ot1¢n.....·riltlt . .." ml"·I1' 'lI:[itl.t..ot uI' l.lth.. ...-..or Plasma Bound Tissue Bound j r _~ Unbound ~ l- 1l Unbound "·IM.-r.oJ .oJ .... ..J tLt . o 1. 1 1(:.... of 1'" '1w" 'M I I. 1 or.n i~ 11[" \il'ur~h'(t til<' mill t ·tllr. mi" . 22.. . o nl. ..1. C 1Sjo"I" . i.1 1i"" M' cnmI"'I1". n li.." ". \1 . In . ~I .):J.uir. En I:I.....I....11n.n..>. DoS( and Time Dt'lx·mlt·" eit's). an' t...Il'd pI..o.· . I. ~ -I. bUI lIIay .li"'·.7.) t.'n prot vin concoutr atton ami imlt' I:M'm!t'lll of <! n l ~ concentranou. J \ 1.. rl.. "" ."""". P".. d r...CHAPTER10 '" Conskk-r.20 0 0. then.·nl.... .or ... F. r ""..lty. " r pl.J..'..·..... " ·I. ..'iSIl I' t'lllllpOIlt'llts .-a lii." t1y h i ~h St l that most of the availah l(· h ind in ~ silt'S are. lII."-•. l r."" .Ul~I .n..10 • ~ 0.. .unbound concentranou.hhy . for exa rnple the change illIII expec ted fur ilmpmf('11 ifll ::: O. n ...·o ll("t 'ntr..nt. n ill 7loi p..· I't.J.\I .1.. mw'J ...1 e:~ t.: ill <li.tio:II..l 1...I. The fract ion o f t1 m~ ill botly IUt....lo>l "itl.0 u 1·Acid Glycoprotein (gil) . •li.l)l).· ' · "1 '.05 ..S . IWo!!. . 1."." 11... I'"" .io:.1 pLo. ""Iy unl""" . I"" ji' ''1 "f .\--~ __ ~_~ T n ·all. a small Iractron (If the llvailah lt. m"'1 lnr. 1in I.7 ".li" :. 1 ~1.·ht·mltlk l..f tu<'..num_ II.... . d nll: IIIit hill tI.1 loy 1 :1 Bt·.I0.". it dmg IM Jllnd primarily to albu min. ami )i l.tt .I.. -a .0 2.\I )...tllll p rol.i" 'li...22.·•· .... >l uuto. m a conce-ntration is uu-asu n-d .. _ S . Usually..·" I.."... "'·f\''1I'lIn.t . 10.()()..llly in Fi ~..c-."'''' .·. III.: I " .-'It.. .. Plasma pmteiu h ill(lin~. I. the Frac t ion unbound Is tln-n rd ativd . "r .. ('(>lnl""" ·III\.. ."t''' f.. th erape uti c co nccut rattons a n ' slIffieit. · Ii". helpfulto n-membcr thai phanuiK. .'lioo " "". Ro1'""Io K I . 0. pt. "K! " f pn 'lmu.I " \"ihl... .'tllil .~ X HJ"! / ".1\1. tillll(· lut'<lh"ll primartly ill tissul' if Iht.·o..-..hip 1'"-1 1f" .t1lt'rllp('ulic t'Ont'C'nt ra tiullS o f most d nJ ~s.....· .. C.. f. p"'l' r....-ML..oll f"'tll To. In ... 10-6.h'..i..n ..u.... ~. I n : 1' I"o.(1.. Cv/ Iv r.1 29!J:I 4. us !'IUI\\11 St. .occupied.." 1.. s ilt'!' 011 h inding pron-ius is occupto (f " I' d "" I ) at tjn.. .". is o ftt'lJ o n l)' of Inten-s t I :M"('<I II ~ Ihl:" total pla..0 3.oJ .... E. a r lldd Iit])·..." 'liI p IMn I>lt..') . I)' .I ~. consta nt at a ¢ \'(.."'Olthll' ti o: Il. Pr' 173. Bt>flo:4. "n hi". '1"'''dll >I" .. .t".·n·.... T.. pi.·al t'l1 ill pla. c ::> B c ~ 0 ~ ~ c 0.a ~ i . Lar·( :t'<..Pot "f . S ..Ii" rih" . wlwll llll' albunuu ceuce-nt runou is t1t'(·rt'l..... ·.L St"l1 fmm 43 W to 2S w L I.... it " i ll 1)(. I..\ ma depe-nds 0 11 its hi ll( lill ~ 10 both plusma a nd ti. t . 1-:'1 III.· n·I"lio ...... lliu '.unbound concentrat ion..".· frd<1'"'' u" I. '11 ".1" n'le i.'.... f ".·. Arthritis 6 Crohn's • Cirrhosis • .. A t1 rt1 ~ lIlay hlt\'l' a ~n'al affiuily for plastnn p rote-in s. II.....m Il..1..lh'l: In I" ot l. .".Jli h~' in It. .... .<lioll"lir "f'I"...~ .. 11' _ i"~ .. th ili equation should no t hI' n-a r· Tbeue Rindin~.· or l l I JIit ( " . ·nh tI.t1ilJll-tlt·I:M'm le nl (we C ha p .lo ~ ....d io-llll III. I. ' In suhst'q U('llt chapters..15 ~ Control Renal .. thru.ill.• .t.II .1hit )· n late-s to tln..... •.r "....1 ~Iy ..·) f.. O('l'<lsiollally. 10-1.n 10 "("CU" " 1 rolf "...lh .10........'Ulngic at. Then hot h )i.. \llI.rm ...·hl. ( I ... pt'udt·IIt')..II C-"-"''''. 11 l(' tota l plasma t'l lII('C'nt ralioli til" s p -nds Oil IMllh lilt' extent o f protein hi fl{lin ~ nnd r!n..... fur D n ' lt 06 0 o . . _ .l l. J"h.. and flllll'tin nalily. III" "".. 1.. R~ .. (I o.. ( )..•'io".c...• C ..t .: .-nl' . Ii. s 0 • • ('('1 ".l 1· .

\ittl: II.alit' . e"..·.... rt's ll lt in~ in Ill(' loss )(' hi lld ill ~ is impm t an t ill dm~ di si rih uliu ll.1 ( of. 11"'n n.I.. di. V· c A mount Vp ' C Amount in plo sma + Vrw ' CT\IV Amou nt 21 in body oo tside plasma ill whi<:h \ '1W is til(' aC lllt'()I!S \1)111111(" o ulside (If p lo slIla into which l ilt' d m ~ drstn bun-s alltl L C rw is tln. (40 "'R) ..)'1'" " · I'ra.l . J."'nh (01 "'~l " clln ln it' hq-.Ii. dll..· " f di"rih"h .. <triM with II.~"'I n ll .1 in 15 pal..).• " . 11176. Snuilarly..•• . "''''' ma. J..~...1..... 3 :U1-249.. are equal..".o llsidN. Gil. {.. and Brill!.. ~' .. '"H..A.Yah.. . .' E.'" (If its inh'Krily.n-lutinuship. und in 1 i..... 24 I-"Ilt... (I>ala fn " " Br.1011: . >1".t:om 'spo nd illg IO!. v Appa rent Vp Volume + V · rw fI»: c Appar ent 22 volume of d islTibu tio n Ih'(~..· .· fr.3 ... "f ( of.. Di \'idiTl ~ hy C... 1.·..vn ~n·ah..II.. J..0 0 0 0 <P .lo· In 6 . EW II !MI..u....Il" .1 n . tisSIlt' hilltli ll~ o f a d m~ cann ot 1 II lt'a~Il H'( 1 dj rt'(11~" Tlu.. ... n ...p"''I'r.. 'it· Ii.. Clin...rinR .11 d m g concent rat ion.. . .) 800 600 0 0 0 0 400 . .1 0..un bo und couceutra tions in ph~Ill.. "..2 Fraction Unbound 0.tiSSllt· must II(' disrupted. ·.It·l dnll: ( of.. " I>jo'(10 Ie.n itt ..· af" 'f"" Lv.' 11 {~ llIi l i b ri m n is adlit"\"{'(1 whr-n 23 whid l Oil ~ ll h~ ti l ll t i n~ int o Eq.".~MI{·S . .). . tissue t·. D1ST PI!llITlON CHAPTER 10 tiss\lt"has an affinit)"{. 00 200 \ • 0 0 0 0..".. tilt' fnllo\\ing mass-b alance.. Unlike ptl~lll a h i lld i ll ~.r than thut of plasma.'.1'" '1 .1'1. T tssue hilltlill~ ma)' II(' inft'm'(! (n JlIl uwasun-nn-ut of d n l~ hi ndill~ in plas ma.. ·.. B.... 10-li.•d i"n u"I u. ! ..n ..I fad.. 1 'Ir.: A 'h " ~' ..01011 ...Jllhat ffl 01 plasma volume of tiu ue = Cu/C. 22 yields v_ V p + V ' -Iv rw lv.. fiI T "" C"J /C nl"" Gi\'l' u lha l di ~ lri"llt i on tlu...iI...1i. fo r Ibe li ~~\ll'.

3 L. hilt it does not take in to al'('1Jtlnt I!'! that pl.d er th an ap p rtl'illlatt'ly 70 . for alhumiu. 2. For sUl'h dm~.of d ist rihuti on varies IM 'tW('t'll tilt" t·..5 + ~) Iv 25 wllt'rt'/lI is till' fmd ion llnlM lIllld."wnls making: allYconclusion alM lhe a llIt ctual volume into wluch tlt(· drug dist ributes. extrue -llular SI). extra\w.\l"{·11 billl lill ~ to 0 p l'l-sllla protein ami billdin~ to otln-r constituents. rh-s that p< l-SS Jth that t1i strihlllt· in total lMMly wah-r are caffctm. is p erhap s a 1M-Iter est imate o f tht· nununum value for Fi~. 1T if tilt' mac romoh-c ular drug hin ds to l·m lllt ht· l i al linin ~s wit hin tilt' vascular syste lll. o ne rauuot l'tJlld ntle \l Jla lll "i~ lolls ly thai tilt' drug distrihllft's ou!y into that \UIU11It'.t.5 I. Fur d m~s I)f h i~' l molecnlur wl'i~h t (g:n '.2 [ Jk~: 14 1/70 k~) volumes of t1islrihlltioll.l-slIla p n m-ins distnbun.'s To appr('dall' tilt' n·lat iollsh ip in EII_ 22-24.relationship t'xpn 'sS{'t1iu Ell. From this relat ionship it is wen that tilt" uppan-nt volume (If distri but ion Increase when s l u is in('n'aM't1 am i t1 t'(·n·..lilt! utI1t'r silt's is V :o 7. SMALL VOLUME OF DISTRIBUTION Mod.lT!'nt \u lulIit' cannot 1M all e ' quilibrmru value . or tota l hot ly water (.). such t1 m~s . 11lis nr-ed is pa r1it'II"r1y Wt'at for dm~ that hind to a ph sma p rtl!t'in and that have smal l (less than 0. co rresponds to tilt' valut· o f a physiolo¢ l' spal't·.IIlS of . Iht' dis· · ltl)·. Bimling: of t1 n1g:s in hot l.l('t·!Iular 1I11itk Exampl{'s of dm h 'S ohol . lx-cause plasma p roteins {'(Illil. p lasma and tissues complicates the situation and often p n."n plasma and ot her extracellular fluids..1 exp lains why... ill tissues . \ ' ran-lv corresponds to a n 'al volume. \ 1uch o f tilt' d m~ in lilt' I)fMly is t11t' 1i IM lIIlld II) tilt" phl-~ll\a pm lt'ill and lilly dlang:t· in biuding: or in the distrihutioll of til(' prolein ("an substa ntially inllm·lIl't.. . cous hh-r the data for p ropranolol show n in TIlt' linear n-lat kmship b e-tween \' and jil 1I0t only Indicates thai "nt/jilT is ('flllsiant.l-sm<l and tissue binding:. A IlI(Mll'I is th erefore Il{'('tlt'tl 1 d istin g:u idl. TIlt' .:\. alltl jil tl is the apll.1.. \ '11 is tilt' illlllt'OU \Ull1llll' of Ihe illtnK't'lIular fluids into S whidl d m~ distrihutes (tolal a\'ailahll' \XJItIIlll" "" 27 L ). illM lllt 7. Ho weve r. Fur d m j.LS slltl\\1I for alhumin in Tah lt· 10-. I('(' ( IS I. 2.l1lt' appan' nl V llllllt' of plasma n p rotein s.and alc frt't·ly t hml l~h nn-mbnuu-s. Th is last situation is expected for smullmok-cular \\'t'ig:ht d m g:s tlml .~IlN' o f p].L \\1Ienjilr is lncn-ased..1 is con ceptually useful. dt's a m('.5 + (7. 1){'t'. Tlu.. For a d m~ IM uIlld tu alhlllllill. appart'nt and n-al. .. thi s apl)."i.of dlst rlbut rou. III(" volume o f diatrihunon t1W Il It'nd s to apprtlxilllalt· that of plasma .).) :lllt l tilt' lotill l)fltl)' water (42 1.\l.APTf ~ 10 .. hilt also that d ilTert'n('('s in hin d ing o f pr opranolol in plasma acco un t for most of ti lt' variation oh""'I"\'('t1 in us volunu.ITt'nl fmd ie)ll unl)fllllld in Ill{' intr'K'I·II 11tlr fluids. i rtm' of this lIleMIt>l is that il p ro\. till' volunu.).. h{'<.CH."{·n \ ' and hi Tl(l i n ~ to alhurn in . aiMlul 3 L in an adult.uor plasma. snd l as plasma volume (3 L).000 WllIoll' ). An ('X {'('pHu n is when d m g: is n-stncted to plasrua: the \""IUllIt'S of distrthutiou.( 16 I.(s rhat an-b ound in m-ither tlssiu.'ular distribution is wry slnw tn nonexistent . Even if \ .ITt· hi~hly b ound to plasma prot ein s hut not hOlllld in the tiSS Il{ ·S. th(' app m'l:imat{· rt'latiousllip !wt'. .12 1.F. uretlu-u tilt' same. A ll excepnou ca n occ..: I. ll1odt'l lo dt'serihe sud l d istri huti nn is dt'rin 'tl trihuliollllf ulllMllIlll1d m g: \\i lhi n illt' IM in :\ pl'M 'mli>. ihrate slowly IwtWt·1. d{'IM'fl( li ll ~ on lilt' d{1-:n't· In which the d m~ g:ains acces s to 11ll' iut r. IM sma ll molec.th rtlllg:holli extracellular fluids.l ran ·lllilur fluid vnlunu .1 T Ilt' m(M exprt'sst'tl hy Eel. I( ).

· '''.:(' .' ~WII ill Tah1(· 10.oc.u ll". ant ibiutil'S ill Ihat Ihl)s(' 1"l'ph a. I .IN an ' . h lJ\\ '( '\"!'r.. ami fll for a sem-s of ce-phulo s porius. II C.. liuM'.. \' ::: \ '" + " n t.·fl. I.... \ '11 _ Z7 L ".lil.2 -. II ':'."id."r 1 " >I (E' I' 2.. 5 \j II "" () (Dr..-. \ '/t - O ".150 CHAPTH 10 Ihl" dislrihution of hul l.g... .g und 10 w h id .2L/k. "'IMI I I .·lh.'' .. . 1 I>:> I).. mu st parti ally e-nt er 1't' II ~ or III' INJU nd til S!.ltl.la.75 Fraction Unbound 1.. N II... fn"" .. Err 1.· f..'".11· ..lilult ' · r. • . ur 11 It·]I". '· ".I" IM 1>i".. T his dq )('mlt·lIl't· lI1 i~ht 11ll\"t IIl-' ·lI l·xplaillt'tl hy tilt' ~(' I J(' ral l11 ()( lt-l. d ho\\'t'\ " 111( ' o!Jst'T\'('(! H I l lin it' in n-rcept w ht'Il}it appmadll's lJ.lo" n ......t1" :\ ' h' i il·Lor.I.l lIM".ri.l~lI1a pr otein 10 wllkh i t hil\(k Bl'p rt·· S('1l1a!iv(' d".. ree.. Drw•• W .. ..·rn· t ·.1 \\11 nllll ld ~ l il'~ in 111l' distnbunon o f tilt" plasm a protein . " ""i.0I1 .... n N' " 1'1.:.. " r 1'' ''1<1'' "f"'" l .. 111 volulIles of d i<.I... ... ..l rthuli" " "r a .n Didolenoc Dobutom". \ 1..~ 6 ... (f"" .1Il1nng tlw (.. 10-9.mll. 1.'..l..e Ibvprolen K elOproien Nopro.lIuniloOl P'peo'ac. " " I....Ld..bprolen f u.1 IM ""..".~ )." ·pl. d .:\..-_..... . :) . T1lt' d ist:rt'P'Ull'y hdwt'('n tln..n o. "r ' '(1.ulOll.n P"o~icem Flu.. To Illust rate tln.{j Il~ .... :\ ..." .~ide Prccerecd $cllcyl><..1I .i t I.". 0..l ril m tiuli It·ss th..... ·plmlospn rim ...2 JA:... 10-9. . acid SvKiloO_ezole Chlo<OIhiozide CMorpn.g(n.... !IN' 1 1 " 0. · . .. ... .>Io.. 1 .I' tI..~].. n." ·f'>I". u f:3 I.Xlm' Oe CloM)llc acid C1OJ<ocill.• . \1I " "M""r . 10-'....lI. a vahn.. Tilt.."'.." I.r"t:~ll ill. pt·t. Fr.3 rr..ui · .1 oI .i"..g: 10 pla...II1. 1 rit... imlnut e that till' t1m j..·u. t:. . u•. • 4 •' " -v .. T ilt" pmpl)S('(I IllIII)I.. 4 _ u·r.lf.uw...·..I...25 0..ulilit}"llf tln.""' 'I 11 9 B 7 " .d tI. 111t' volumes of distrih llliOll (If tilt' 1't'p hal(l~ rN l rillS al h i ~I l( ' r fmd icllIs 1I111111ll1ld . r".it-ia... )lJlI' 1'\ lmv...u.' " r 1 '\1 fil (••• J Ii<.lo~pori llS Illat ure t i ~b l ly IlIlIlllti han ' distnbunon dm ral1l' ristil'S ill 1'\I1II1I10n with alhunun.'1 "... O.~rt'ah ' r than 'lIIaly.N·.' "'~~ • . ." " U Nllu 1'1 h"OIl . It ..r II h..1"'tn."t1I>iI..1 1 n. " i 1".<erl OKyphenbutozOlle Pheny!bvto..i ..1 2 o +--~-~_~_~ o 0.... 11.. '11/.... lll'('n noticcdln-n-. ... -f ulfilr.·..U. IN "'. .5.1MlAAl'sls that ulluuniu is till' major hilldi ll ~ pron-iu for tht.1.. 227_2.J. "r 11.Ii<.".I" . hi" b . l'f..·" .·. .''''' '''. . .. n • " 1".·. 1Il 1l ~1 hI' n 'I'ltiH'ly smal l ill Iha t hy t' xtm po latio u tn I II = 1...) 'il. A major pmhlt'lII \\1l1l1 haq . ('(l llsillt' f ti ll" tlal" ill Fi.".. p" >I. rm <t\ ('fit!.clox. .l' I'ular st n u'S tun-s .r l l N' IIi>" .. l l IAgl.\llIa albumin.....1. cL. "'..I I. . .1.. II" Ii "....19. DI.. as sllllli ng filt · ( dill'S lint var)... extent uf Ihis dis trihunon outside tilt' extracellular fluids. ''''T''.I' M ..29 I A:~ (21l l lill k ~ ) .i1...oI i1.·.J.il~' "r "-pl.... Ii. oS .·ll•..( lrrt'SI )( J lII li n~ III a t"l'phalm ))()rill wn h no hindi n.. V.''IM'''. s ho\\ll is a lillt'ar n -lation ship hdwl't'1\ \ .I..zone T olbrtJmide Totmeltn volproc cod W e.S!.. 1i. the mlu lIlt' is U. \ '". T Ilt"u!Jst'fYaliollSart ' much hdtt'l' ('xplail\('(1 b~' tilt' p m poS('(1 1I11111d .I.· •.·\ ill...1"..•. 1 1..50 0. 0.i f" r dnll:' 1 t. a \~III1t· 111111"11 larger th an thl" ptl\lIIa volume. this mudt'l is S fil-ally applk'ahlt· an. 2 . io •• / . PI' ."·Ii.." 7 . t.. ' ''.1i..ulil ..·r_ ~ i ". t.1..tl . . ~s \\.0 . III ."..·rn is "j 1170 k.I.tn i'I ~· I" dinil<ll .(lN :\ iltlrti"li:aJ.pmpo S('t! mudd .' "r \! . C II ... d m~ and tilt' pl....r.trlltutl. ( ..". !j ..• Calotet:Jn CeIIlio_one CelUf llime O [).It lpl. ·..1..· "''''1''""."" W...._ ."'.... I..

II:n·.. n .~ 'h· fi. " •• ple.uw ·r amount of tim)!: mllsl ht...2 ......lintJh· "ith.-6.Jo"I" 'ri '" "il ll 1 ·...5 1}70 k~)....CHAPTER 10 lSI the.lltle 10. II <~ .I'M.n~· .j.."IM.. _1St f'1( 10.. ..5) e2 :5 c 'C -a ..I!l <l or t1mlll~l lOlit extracellular fluids ( ' 1.1..e\tr.. o( 11 11. lllllMMltKI '~~ ll ll"" nll Kt . ' for'lll fur a (h" 11 ."."I'''"''' "'M . 11 It' (111l'it'tlnelll't· o ( plasma pmlt'in hi lldin~ lu-n. C "0 ~ E ~ "0 0.la' iI KTl·..tim l 1I1111l 1U II(! is illl'n·'l'>('t i..... n 'f'l.u natie.chOn Dec-sese Decrease Decrease Increase Increase l-c-ecse Increase Increase ~~d'soose Trauma Rf>eumalC:lld o.u f dtst ributfun. '(Tl' • dram.( 1 M n.M411 HepohC cirrhosis Burns NephrOlIC syndrome Decrease Decrease Erd-sIoge rercl drsecse P'egr'Mlr'lCy Nlyoco..l l .25 Fraction Unbound r. t1 r.(J T ilt' 11ll1 1l1 111ld \UIUlIll'S o f distribution within the series of cephalosporins ri ~.0 => C 0 0 0..f ti M ao:1n..· i" f" nrlo4li<M \. PI_•• e.11 II(' 1I'\('flll pit'l't's of information . In..o.Ii<Ml . am i ho uutl i ll pl... TIM' ""IMMI1M .1M"''' in Fij{.10..'\1ra(~. 'NIIld.r 'p.Ii"" .. • in 11K' fr. pilrtielllarly with IhoS(' conditions.9 fflr i<1.:!2 IAli:l "I' II....aut imicrohial t·fTt'l1 for IIIO'it· dm ~s with tilt' sanlt' minimum inhibitory IInlMJ1l1ld concentration. himhll ( I n r t u ma I.....5 1(5. ill or outside t"d ral'd lular lIuitls..o<~' ( \'f. IC IO ill }. tilt' billtli n~ pmh'in t'ITt'l'Ii\('ly tit .. I IM 'lk. hilt (:ullsil!('mhly I(·~.I' 1.' us the (ral . WIIlell D-....5 e3 n~.M " r.fh"l. Fur 1 M · ('(...lII\· dcen-..hi~hly l~lIIlld (low jid ..Ih tri ...I" r lha ll 11M' 1.s . 1. ef c.'i...cellflwtl_ ef the Twe Meier PI•••• PTe..i j .t... 1. k~ ) .0 D ..... . .lI llL." ~.""'I.I..dtOl info. exa mples H sted in Tah l(' 10.J.75 0. in e. than total htlll~' water (-12 Ij'.ll't..1I1 1Iar \-(IIIl IIl(' ( 1.is tilat a 1I11lcil I... in lilt' 1Illlly In ¢ \'(' lilt' sanu.) 4 e e6 > c 0 D _5 _ 7 ~ ~ e8 e9 I\q 1. 10.. allMll Are AJt.1M' " ..s lip tilt' dnl~. Fo r t1IUS(' ('t'phalosporins thai an.IHIltI_. mlt'in _ (.-1i<M' '11l1"MIlM!.. conr rust ((I tilt' tot al volunu.~ water (ti n I A Ii:I.I" " M" of . location in Body TIlt' fral-lions of dnl~ in the IMllly that an' in plasma (1lllu ml andunbound ).· t"t .6.. ...50 0.rill ' .... I Ii.

"O k~ (tI.con. ·s to 26 whkh is \irt ually tilt' ~1I 1\t' a. Eq . in hntly 1 n 'sitlt's tIll tilt' pl. and thu s no adj llstuwTlt in Itllid inv. rlu-n. App__ I.4ftI_.UI!?:t· \\.OOSTRI8lJTlQN cI-tAJ'1( R IO wh id. 2."10 10-7. Tlu. .hlp..e..l the-rapeutic n -sptm. p lltatin ·ly hy rapidly <I tlt'sirt'll unbound concem r atlon. h("" ' ''·N . Ht·lat i uJl sh i p~ to t'akulatt' these Iractton s an ' Kin'JI ill T ahlt' 10--. 2.. 1t4II DI..lrt·nt volume u f dis tributlon of 11 ( I m ~ i.... t10 st' is needed. . V 27 111is t'tlua titlll indica tes tl litt CII is indt'I)('ntlt' nl of plusma h indinv.It lll(li n ~ dost' 1It . iv:no rill/ot till' first twr terms in Ell.. .. i. h owt·n·r. · Ell' 2·1.I. Iatlon. fl('('t'ssitutiuV. Tl n-ir dt'rivatiuns an . In e~"ocellulo.. so would lilt' initial '~I I II t'( s ) flf c" (and G). C = Cu.lsma p rotetnTl e-refore. tissue "ind i u ~ ifll ft ) Wt'T(' to d l. \ \ 11('11 rlu.'han.L "ma p r o teins. l 11t' tota l plasma t'ollt"t'nlratitlll do es.app. is for dm~s wi th small \ Ullllllt'S of dis tribution ..i IJ'.lIlV.. If..·" an' /oth" 11 10 rapidly uchir-ve . SIlt' " )(· hilltlinv.F.lIl~l'S in tht' di stribution o f p l..r Analysln. Auid~ 42 . Cv . it follows that p rtJdlld ll~ Amoun t In body .e . ..Kin' n in Appt'lld ix I. . largt· ( ~n'al er than 50 to !lX) L ). Drv.. fu V V Au. 2.. of course.ds 7S11+fu1 V V-75t1+1ut V 3/1 . ls tn 1 adjusted .. l. \\i th \~a lues «pproachi ll~ 7. 15 ..t::t· t l.• much greater than tilt' " ppart'nt \Ulunlt' o f tilt' him linv: p rot ein .M V Bound 10 e~"ocellulo.t-'. AI.inv: that o nly a small fr.~ ... . pl'olEtins 75(1 V lui V V-35·fu-75 . . Iht· ttut's tio ll ari ses wln-tln-r o r not thr. ' AJtered B inding and loading Dose IA llUliJl/ot do.an ' d l . \ \'ith variations in both p lll-'ima anti ti. 11Mrt altHls .o f tiistrihutiull ts h rn-ater than 50 1..th uln-n-d p h \ ma hinding. h ut th is is o f no tlu-rapeutn..tal ... impl..hout T. Throu.ter 3/V V-3 V Unbound on body wale. DlatrU. a tlt'li sillll tn c...-." tlmt p n -dten -d h. Fur llla llYd m v:s voluun. ."t lllt'lIl't· with res pect 10 It l.. .trlbut.·h.n edrocellukl. I I I Jl~ ) fur a tlm ~ hound to albumin.l<!i n~ tlO\(' n 'tl uin'lIlt'Jlls.'i. c. .1l io n o f druV.'> appm xilll<llt·ly rt"tlll(. lu Unbound . that [u .t· lt llltli n ~ I!tlS« ' ..ody W...major p rat:tk al app lil'iltioll of Etl..5uud rt"aliziJlV..

O O 1.phslll.l!it' III's serum alhumtn. frdl1ion unbound.. .· tll-h loIKI \'llui libri uJII distribution rutin.'n ·a!ioll. -to T Ilt' lo la l (ll'ft ) andunbound (righl) coucenr ruuons of D m g A folllJ\\ing si ll ~l l' is . doses ure SIlIl\\11 in tilt-' Fi ~ . c. and jlt·rtusion -ml t· ami pl'nm'ahili ty-mtt' limltations in dm ~ disrribntion .. h.5n O-m g dnse) fmm tiSSllt' hinding sill'S only. whkh sigll ifil'O m tly (two-fold l'han~t' ) d isplat"..t 2. lissl1{.:-llub r fluids 3.') l"tllls islt' nt \\i l h thi s ob". l ilt' pmlt·in 10 whidl the dmJ.CHAPTf R 10 1S3 STUD Y PROBLEM S lAnswers 10 Study Problems ore in Appendi.'('nl agl' of dnl~ ill l ilt" hody that is: I.. plasma cone-entratton is 0 . O a. TIll' volume of dis tribut ion of qutuacrtne. TI lt' plasma concen tration when I ~ of d m ~ is in til(" !Kllly would therefore he = = IIlWL. . IIi gh ly hound 10 plasma p r oteins. b. In l ilt' p n '".: hind s. TI lt' pe n.. Il1 ~ d ust·) whe n the jl.1Iltid palt-'l1ul rn 's l)(lIldillg concent rations of tilt" d m g whe n a dnuuistcrt-d: a.o f distribution .svnd ronu-). oulsidl' Ilu. Sketc h on each of tilt" sa me fiW IRT'S th e ... a dnl~ IKllIllI1 to albu m in in plasma. 3 6 Hours 9 12 h. 111t t1m~ is: · a. :'\01 bo und I" plasma proteins . Ind ie .. wh en the 1 l. ni lldi n ~ In other constituents in th e IxKly is unafIt'l·!t·d . Hound 10 1. in extn«.'m "l' of D n l ~ B.llular fluids. is reduced [mm ·12 til 2 1 WL ( (. 111l' Iracuon unb ound in plasma LS o. AI a SUhSl'"(IIII'llt tiun.( 1 I M M ).1 l.0 15 mgl L is c. 2.·n ·t'll to Ill' s L. amount of tlnlg in tilt' IKKly when IIII' 1Il~ . TIlt' \"UlllllW nf t1ist rilllltioll of a t1 m g {molecular \\'('ig hl = 3S 1 Wmold ill a '. 3. . IKlllm l outside extnll'.ns . is about -to. T ilt. 10-1 1 and 10-1 2.()lIlj)(llit'nts outside plasma and is h igh ly ho u nd 10 pron-ius ill plaxma.llit'nl dt."" DOlI!: A (.J( 1 1. 't.'O -kK suhjt'("\ is " !l.lt e which IlIIt' (or mo re) (If th e follo\\i n ~ stat ements is (an.!ops nephrotic. Dt'fi nt' rlu.h'nns a pp an'n l vnlunn. ~.

kR. 6...'i . ~e&lcllla lt· tlK' tilllt' n '(luin-c1 fur tilt" aIlK MUl t.ma i..' fnllcMill1l: . IU-9 i!lmt r...'.5 ~. in .tri buhnn rdtio for a dru g h..-tw"..in i .'t"n l~' t1m lll~lloul total hnd. ~ a !tOIUli and an appropriate infll.. lIlt' infnnll<lliull pnl'\itl...· h~u l'lt lpllialitlll'ii.·i~hl h. (. ih \1I 1U1Ilt. .fllr a dn..'IlIS \\it h l ilt" Ill-phmlil. 5' .. ·!t'nllirlt" if di~nl..1I1lhUlllld dnl~ di. II KJrt · or Ie.2 : 4 .tl i u li is kt-pl constant wit h hill!" t l ~' J:i\...'t. ~nlll p" a\l' r'(~I "( 1 7U k~.. \llIdil"(1 tilt· phannac:ukblt'li<:s (If warfarin ill I I ll<di.u1inn "f dm~ is unbound in Ihl..I' II nllllmls (n" pmh 'illuria.. ~ n tllla n il cliffe'n 'nn'S in w. .. man lind i. in . 10.. DiWlndn !I.. Talii.'t\101''''"11 li\l"T "lid pla.. D i ~(l\ i n h'l' a \Ullllllt" (If d i.. us.-linll = 10.hl.J. CH .1 di. n til(' rnu ~1I1f" wert.. in (".... t.. For t1.i'i pA.rn·· "pollllillj.I 7n-k~ slIhj.:.·m . .l ril ml io ll whe'lI l ilt' art e-rial h lood ("o nl"t' lIl r . U "...l('dllllar tllliel.inu)..tatenwnts.K:II o f tilt" tiSMIC Ih h-t110 n-at:h 5(Yl o f ti ll' equilihruun vahn. l'ltltl. lIf" n u u ('n 'ati nim' .111 p 'rfusin n OS r. than d i¢tudn? g . i n~ h.th'" tI.. se rum (·n·u linint.am'\'all"f . (..."(1 ill proble-m 7.¢wn.t1 t'·lilllilt.\!t'lIsin·l..12:." 1"'9' -" I(tdoey~ I 4 '0 4 3 15 12 0. ..tri butes ... must tlistribUlt· primarily illtn hi~bJy I)(·rfu. " lliIt fr.('T. in th.. )"( . i .l\lIla.. ..illJ. lrihulin n of ahout 5S0 1.i\'l'n tluu tl u."O-k~ 1Il<U1 i\ 2f)(I I.. U. TIle' t"lu ilihrillllJ tli.l. tlwn..b. Rank til(' t illl'~ and tI..1 <llltl Is 23 % 1 h"und ill pl.110M' .~ \\. .0 n~a lls . ( .l' a \'01111111" uf t1istril mlillll of $ "1 I.l.Y6 : 2U JI \ 11.~ tilt' ill(n nlldtion i n Tahle l()...'" in!t· n.111111lt" of " tlistrih utio ll in it '. water. Brit·lly l'tJIIlIllt"1I1 011 1I't' \'cl1idit)' of eech (If I"..·llliLir flui d s? .. fun. . difft'rt'IK't~ in wa rfarin kindil. d.. it.\~ mlnllllC' lt Ltil)' uri nal)' jlnJl ein e1..· "" UL') ~ 32 ~ ~ I ) \'I'n.\ elm!: t1ul rceches dtstnbunon equthbnum within 30 min. in it man wt·iw.I1'T E ~ 10 o nc.IIt-s. u f tlistrihlltitm IIIl1st be at least 75 1.. 3 6 Hours 9 12 o 3 6 Hours 9 12 .l\m" . 97 % huu nd in p l...0 08 0 0 24 .I 70 -kj..-d . .hou nd in int r. .. 50.

..... 11 C kl tlc Pw..· 1HI1enJ.. M ..1080 .llf-lifl' data 1101 Ilt'l'Jl ¢ \" U.CHAPTH 10 ISS .7 020 :!" 0.. r~ <.. C iwll a fml1ion unbo und of O... After 0-1 Q 4 :!:.~ Hin t: den -n utm... 2..I VILI CI!VI-IlI '. . o f ..trfa rill h .. 11 Neph c A.of di sal trilmlioll if fi' is inl·rt'a. .. 1.till' \111111' of filft ill tilt' contr o ~n m p.G 137 058 18 125 ~~rJ""'""-' :!: :!: :!: • 66 0 26 11 65 '.v ue calculated in "a.... .same ill tilt' Iwph m tic patient s.""""-.. \\'.l~ a sma ll vnlnnu.07 36 :!: 14 se1um elbum.Ief W rI.I.p . . AM e-.j . could )'011 ha\'t· predict ed till' o!)S('I'\ 't'l l sho rtl' I ' lli ll~ o f till' vulur.... and a. h.. N NoPwcl 1$18-80.e _. I t u I tilt" h. ..o f di st rib ution.. l c.I..pi lt it'II IS? 111is condmon usually S Il~t'St s induelinn of 1lll'l aho lislIl... ..n Igill 43 • 5 ~MO ~.nmp ... .......~SIIllW it is tln..lln3 ill tile control J!.Itt 10-9.~. / (hI) I• •.. es ti mate th e n J ul' expec t e-d in l ilt' llt'p h rulil' ~rn J1lp .. ~ a....~ 'll to tlu..... PIMI c.. "" ...". . """'"""=. 'f. ."'9la<"'"' a..ill till' Ilt'pl ln llit.. .P. Cak'ulatt' l he expected vnluun .

c·. Dereemre the biliaryclearance 01 c drugfrom il$ b. I] It · IIll·l lul(l.. ill IIII' lm-ath. Colculate the exnocnoe rene ocross on eliminating organ given blood clearance and blood flow in rholOfgon . an. delefmine if c drug is predom'nonrly recbsorbed from Of secreted into the 'enol tvbJle. Lh-n- ih p lr~ . unOOund clearance. iul()t:k Il W. Ir elimiu••tiunof t1n lC:' fflllll t In.l1lillt: h t:iwlI. r-wn-tion 11t't" UI' pn ·du1l1iuilull. biliary clec-crce. Descnbe where 'iltratiOn.trI{'t· . hepatic clearance. " HoI I~ile ceceods upon clearance and volume of di~'ribulion " Tlli' ('hill'k r i' tUII('t'n ll~1 \\. I ' Ml l l i l~ 'i l l ~ t "l.' \1I". k id rlt .1Mlli 'lIl i' t l n. an. I " r-wn-tion .d'.1IIt! II wl ahul i'''I ."ia 1111" kidll l'~ ' . ELIMINATION Elilllillalioll t l('('lIr. lmwr-v e-r. 10 . I l.t1 n't:' an.lll'tju r Illt. \ 11"1. Descnbe the role thor biliary secrenon con ploy in drug dispc»'hon . drllt:' an' "\(Td . Anliclpale rhose drugs for which a change in e. allt l -.n ' lali\ t ·l~ ".min the nephron 8 Sene the ovefoge value 01 glomerular filtration rote. Fur lrImt d ru g.15 bepotc eorocrco rene 01 the appropriate infotmolion 10esnece this vclce.llli' lII f.pre-o-uu-c l. li lt' l't lllt'ppi o f d c·ar. SO" . and -ecbsopeco 01 drugs occur w.~l d<l li lt" luh-.. secerce..1MM I~ . ".. I).. 3 Ascerto. . 7. Explain the ~totemen t ..le-to-piosmo cceceoeonce ren and the o bile flow.· Otlll'N. 6.Eli MI NAT IO N OBJECTIVIS The leader will be able to : I .~ " bul 11. . c. Ht i ("ll la r l~ m lalil.laun·.n Irom the volve of it$ e:d rocliOfl rene wnerhefme clearance 01 a drug by on agon is perfusion me-lunued Of is dependent on ilS binding to plasma proleins 4 Cakulalethe IT"IO)(imum 04'01 bioavailobili tyof a d.1 dru~. III ( :l lap. :1.ug given either ..rhef unne pH Of uline flow may alter The volve cJ the.ndl 'd ft 'W ." . 11.. blood clearance.. Q Given renol clearanceand binding dolo. Snun. Define the loIlo-Nil'l9 USii'l9 boIh 'NOfd~ond eqcctcos: clearance. S.·ara lu 't· wr-n... and renal clearance 2. . renol clearance 1I ~toin the relahve cantribJlian cJ the renal and exeoreocl roces to toIel elimination from !heir -especnve clearance yol~ 12.f.lilllilliltioll pnl('t" 'l " allli p ilr1it'lIbrly wil l.." 1i'" il lilh"tl alluml ' ·l1tirl'l~ IIlldMII\:p d b~ II .

.>:yglvlelhimide ~ Hydfo><yglule!tl'mide glUCVfQllide P.. ho weve-r ..o· chemical alteration.CHAP !H 11 157 TIll' II1mt l1I1lIIllH lI m utt'S o f dnl ~ rm-tabohsm an' oxida tion. hl(l(l(l. ohg>".lCl .tinl.'UIIII)('ttng l)ll t hwa~ .Y. Phase I reactions. .. ~ I d ahol i les lIlay Ilndt'rgo furt lll'r lIwtaholislll. oxidation . may b g e .. tI1the fo rmation of small \"(·sid t·s ('allt'1l mic n A'lI JtIU'.\ illlultallt'1l11sly undergoes IUt'taholislll 1'... n-ductiuu. <>o ~ 1~1. of IIwtabulislll an ' d .. the e-ndoplasmic reticulum is disrupted " . 111t' fmd inll goi ng 10 each IlIl'1aholitl" dept-'mls 011 tlu..N ' a (~:Il(" rd"y..is an' ofh-n follo\\"''1I I'.n 'q llt"l. therefore.rdath"l' r ates of eac h of till' pamllt'! pathways . the lin 'r is the major and sometimes (lilly.tS I'h .. ~ro. Several of rlntrunsfo rmatlons oc x-ur ill the endoplasmio re-ticulum of tilt' lin 'r and o f certain other tissues . d . sk n.ations s II reactions.ed".~ .mode leI .f"11 ill one Of mo re other ttssucs . P. ~it~l)'t.. Fo r example.*""". _f'IOOOOb:>I. adiollS IK'l'U f in seri es O f an' s aid to II(' .ilsl mi ntt'slinal wall. ~ Jok.of drug metabolism. 1111:'S(' re-{'()nj ll~illion . n-duction ami hydml~'!ii s are {. Be causethey ofh-n (K'l1 If first..s if!t'1II'. ami F.rq '" ~ ".tssif!('11 RS mlcrosomal a nd noumicmsomal. . such itS 1 tile kithwp . IHI ICi 101 11 0 G1vlelh.o' a co njuRation reaction.. lIletabolizing l'IIZPJ){'S o f til(' r-ndoplasunc n-tn-nlum an' l'llllt'1l mk n A 'lI)JJ1f1l l'fI Z!lll U'S. I I-I Illusrrau-s 1 l1llh' m s of hiot mllsfon natioll (nwtabolislll) of representative drugs.()lnmonly referred to a.l<a<>" tOI. hytlmlysis.C ~ _ odo:cted ~ '" c""" _. ami Frequently... sin. For th is n-ason."l'mll."".d "'1lO'''<loug . a drug .t\.. Occasiouatly.0' s('I. allli hydml~. oxidati nu... ami t' lIIjuF...t'ri ll is such all example. 1 d m ~ is l'xtf'lIsiw ly IIlt'laholi7.. Tht' l )llt hwa~ . Dr u metabolism.."' .ne 1 01 "Clm>.ed"'i5Olone ~ 11 ' IHI Svccirtylcholir'le -----------1.~ Svccir¥monochoI..fHl~.. IUII/-..~.. reduction. i "' Tahlt. 011 h CllJl( ~t-ni zi n ~ t1wst' tissue-s...iSOtle ---------.

. is thl' concentranon in tilt' n ·tunl inJt H ' IIHUS hlood. wtwn' t'st'1IIX'S pOlSt tht. run." Ibat is.Rate of pre WJntotion lin 2 IU ) T he t'\tm l1inll ndio lit's !)(* t\\'t"('n 7. Organ of IIiooIoatIoo Ht"<..of prescntanen of a drug to an u'l'. thi s assumpt ion is n 'a.. ~It't a"ol i h' Kinet ics .. 10. It is also tln.com pound l' adnnntsn-red.<l.lImll . d m ~ in the el imill1ltinJtul)!.(J!lt'('ntrdtiun ill blood t'nte rillJttill' urterial sitlt" C. oftl'n !loth .'I. plasma p mtt 'ill hi lll l i ll ~.g 10 tht' l'1I1.all is llSSUIllt-'t1to have n'ad lt'll distribution t>(!uilibriulll. t1mJt is t:'Ii minalt.lf1UIlt'tt'f. Billt nUl sf u n u <lti oli pm\.. partil'llarl~' in er prt"(!itiinJt and ill l'\1tluatinJ.It:. ss Clearance may II{' \iew("t! in another way."S and tll(.ifi(:ity.1) .( the elTt't.'XtmrliOl' mt/II.U1l'C:' across all e1iminatiuJt0'l'.' r ate at whic h d nl ~ lea\"('s Oil tilt' venous side is Q ' C \. pbcauons. tln.ltiull IIIt '(.III' d mg: alit! its 111l'laIMllitd sl an' active. dt'S a t..'1t11 F rom C hap. tilt' \"ariolls way~ of \it"\\inK IUllSS hal. 111 pbarmacoktncucs o f ati in' metabohn-s.'* in OS ' s tilt' hody.1h i t)'. Q.C~ If tlu.)11]("5 h i ~h n-spousibk. tilt. which an' a monJt til(' most hi ~ltly perfused and ht.m (If elmunanou is the product of hlto. 1ll1.. 11 1e <. ('f1Z)lllt' . 3 that clearance is dt·filll'll ll~ till' p rupo rtiollality Iactor rl'lat ill ~ ran.of tl nl~ extraction is related to tilt' rate at whidl it is p n-seun-d to tilt:' o rga n.t·d in whit:h l ilt' ad minislt·rt "'t ) d ml{ is n ·ally a n inil(:tiv(' pmd m~. 111 l1 J!l!i. ' livt-r. is then-fore of tla-rape nnc concern. :2 1.)1IU'S . 11ll" d uration am i inte-nsity of till' n* spOIIM \"al')' "ith till" tune. thus. 11l(' d ilT t. for the kidllt:..<.so le n-ason for auv tlilTt'n'lIl"l' bt.body. loss of t1 m ~ ac r o an 0'l'all of clumnancu. TIlt' r an.Q{C.'rt'llet' 1)(. namely fmm lilt. Q ' C A .. or M ·f('tUI)· acu vtty 0 11 till' d iminution of a d m Jt.m..fur tilt" o:dtLltiull ami f('(lm1iuli of d nl ~s ht'lon.tw("('u tilt:' artt'rial and ' ·t'lIllIIS l'()lJl'l.II· anism. 111is lat ter physi(Jl~e approa ch has a num b of atl\'alltll~t'S .of d m~ extract ion (t'liminalion) hy thr.l n·!alin ·ly dt1!:n >t· of structural Spt'<.t'lI I lt"rt" ' superfamily of cyt ochrome P4..'nnlllct' Il ll~ tilt' ~f( 'a tt's l putt 'lltial for d ink-a l al).. whid l is 11 I11H' r1t-t l inlo a plrarlI\al'lJlo~kall)' aliin' spt·dt·5. For all but tI~t' earlit'st monu -nts.. SilllilOlfly.)ud u/t acttw compounds.." . a cl m~ is ofh-n a ~oud suhslmft · for mn. whe n ' C \ . Role of extraction .of dnlg elinrination to tilt' pl.l~1lJa (d m gl conceutratfonThat is.t·m .courses uf tlWM suhsla ll<.ran.. E.o f t'limination "" C/• .('l:IIIt'Ilt'l'S or dnJ~ llwtaho lislll an ' man ifold. 11-1 summarizes "<. :'I:U lllt'W IlS (" 11111(111'5 an' nuw rt"t-'('!-rni:t.' s a n' (' m ph'L~i7. cI."lso.'n tmt iu IlS is e1i minat iun. TIlt' l'Iiminat iun pnJl. Q ' C. hody of Illld l·simhlt· fort'i~1l 11l1lll'MlUIltls ali(I d m~s.! How..III. Tilt' tsozymcs of this family displaY.0l)!. C.iun. FiJt.'tluilihratinJt orgam ill tln.lblt. us well as tllllt of t jn. a IIst'ful P. Au. wtwn' dnlK .('ll ZY'Ilt' hili nol a nother (M'l' also Chap. is tlt'rin'll: f Role of extraction . . it also p m vtdes <I I1l I ' IIllS of p n ll.lSI CHAPTER II 111t' majo r (' 111.'( ) III I1U lI\ plltllways uf hiotm nsformat ion and the kiuencs of uu-ta b ohtes are pn-senn-d in C hap. ) . (J~an . til(' l.m. and l. I II this scheme."(-hanis m for ridd iu!!: tilt.· most mpid ly 1.twt"('11 tl l('S(' rates is tilt:' r an.1II0!\t IIst'ful pamllll'tt-r for ti lt' evaluation of un t'!imin.50 CONCEPT OF ClEARANCE of till' t'()II("l'P!S in plm nna('(J~illetit"S.i s o f dlallJtt'S in blood How.

' '' M 1 . dn ' 1'll1o\\in!! impurtaul rt·lalioll... ~ "n.t m hl'KKl l1nw is II / min.c) • ~ R of Leaving ate r"h..l lItl\\'..lti" apprnadlt's 1..I .a] Ill' IIr dt'a r.f" .' " . 3 in l hb instance. .1 ul It<.1' of ' <1 · ' • ~ E Extraction Ratio 3.w1 i7....'1t"'I.~· .I p<l 'S(" th rnu ~h tl u.1 10"". I.lIlu ' (CIl<tp..( )lIIi ll~ ..n~...I r...Imll:in 1" n.S Illwmi n.n' "f ..CHAPIn 11 ElVV\NATI()N "..... 11M I Il ' i Rate 01Ent ry Rate 01Extraction 2.It. an' . Furthermore. 1111'1l bll KKI dt'ar....... in .. blutKI is l' ffl'(..'di. Clearance .' ..'Io·n·d frulll tiM' fu)MLouM..(' a pp rnad't'S a maxunuru.. CI'I.1f to l K' n-uum-d pt'r unit tune.Io~ loIo litK in E'I" I II.inll: I.. 2.I ""'1 ''t1....I('n "".l1I(. lr.M · I of .hip is IIhlai lll'(l: Blood clearance CL b o flow f Blood b troctia n ratio 4 TI Mt i"" hlolKI d l'..u ""'1 for 11K . ¢ ..illl't. ~ ' '"'w1U:inl1l . n.. Exot1l1inaliull of Ell' .• . lo'r I.. organ hltKH...". h.• ' 1.s and of). tlu-n Ihl' mit' nf elimination is n . 3. O n slIh".. -I.'· IH.. ·i!l: I I -I ..extraction ! r. ~ ( JoE Clearance ... ill(. u"'y 1M (~" . Ih.' . all o f). :31.tall is n.5 IJ rnin tunes I lllWI....o .. lnll1 l~' a" .n .101''nnitm'l1 11K' (""'1.' rt'~al't lt'(l it-'" till' \'Ulllnl(' of blulKI Froin wIJil'h all tilt' d m~ wOllld a ppt'.tio.. n~ ( n ll . Mass Balance Normalized to Rate of Entry o-tc. For t'xa mplt-. Mass Balance Normalized to Entering Concentration ... .t. "..'."'11.II I .. tilt' ('tJ!ll't'lltmtio ll in hlood is llU"il"'Uf('(1.1UMI('t'p!'''( II I. or II. ' .. ll M . 1M' "' . t"1'I1·".. if tilt' artl'rial ('t)Il('('lllnll ioll is I mWJ...J".. shows Ih"t if rln.tiw ly f('IIl(J\I'(1t'"d l minute as hIIKH. allYvailit' ..J. Fur 1 Mass Balance ~ .· Iilllinaliul': "'1t"" tlIK . 111t'1l all d m~ ill 0..1..· '~lllIM .. nn e o htain s.lnllo: n. 1fill" frum it> r"I... 11M . (·Io'ar"'K't' .. II . lilt' \ ..11.•t"h' ''OIkl. " IIK'.·nll)' ro " i<Io.lit tltill!! Ell :2 into E'I :1.II.. If tilt' n Ih ' of dmg t'xtral1iolJ is n-lan-d to tilt' ill(·tllllill ~ concentratiun ill blood. bloot! d t'a nu Il't'." f ..... .. nIIKK d l'a riUlt't' (·<tllllot 1)(.IlK ' M .'lr 1im' r.' lh '/lllitillll . II. if tilt' t'\lmdiun ratio (If a drug .5 L nf lh t..lriUI('(' IIHI.

rt·Slk"'l.tirnah' ('\ I mdinll rano. 11l1:'u till:' h ltnd ck-arance \11Iul:' IIIl1st II(' 11\( ._\\1M'n h... I. it follows tlrat : Plasma clearance Blood clearance Blood concentrotion (C....IroUJn'." .~ •• 1 1\(1aholic ck~d.ttiu n in bInIIll. dc'ar..f}l" lilt" d t·drdIK'l. .l lllt"tC Ihat dm-ctly n ."l.· I.'l'i. 11l1ls. if em. F l. tilt" .)" dl:·fillitio ll. t o...' tlt'. a mi e xcn-non (i llio hilt ' ) IItW"S 1"""lf in tI.' r tlra n l.l'it"t:1 011 IIW. ('. a rt' ("tilial to lilt' ralt' of l:'lilllillalion.. t1S in~ pla.d t'a rdlK't' IlUIllt"lll-iatu n ' fUf a spt ·d fit· Ilm~ . II ))' C'\11lII'""\(.'. Il t 'l l. alw1l)' hl:' flut .1\l· r.wllt'tllt'f d ('a nm t't' n a-asureIIIt'lIh an' l).I-ftt-pl. om. wlu-n a dt...<trdllt't· value i. ". ht' IIt"!O(.)' UlIt' 0TRall at ltL .IR.. seve-ral l1UIllllt' n b an' ill nnk-r. ('\h'ns.1Ihdll hk lllli d l'.\"(' r. How all n~all d c·an."lJlll't·" tra lio ll rollio. (I I' pullllo na r)" clearance-. it matte rs htt h.. wllt'll dnJ~ is n~trit..ma Of in blood.. "u1tJJt"ic Of n:cn101"J wl lt'u d t'StTih iul!: clearance I. dm ~ t·lilllilla fl.... POlr..m 1..-s. I". 11\(..·ar-uK't· o f .. Description of Oearonc.: " in the..'. pnw · :t"Sst"S ~(' nt'rd ll)' occur in tilt. h . n "Spt"l'· tin.ttio mhill is tlt'ri \t .. tilt' nahan.tun tlWf.u lllpliun. 1..I). 1IIldl'rl)in~ tla. d"a"'' I""'- P10sma Versus Bktod OtarOlK1 FUf IIl.ma concentration nu-ar.ma is Iht· common sitt· of lIwa. i. n Ut o fll-n ' drop-.. Process.r pnx'l"S..·ndi\ 1-(:.. 111t'n ..lsllla ..."". ami h llIlJtIt. l't ' nl ml ioll ill p l'l""''' tn 1II1t. 111t' n ·l.1to p la..t. is a t"l1ll'it'fjllt'IK't" of th t' dmlLatioll. to lit· "pl"l. theln d t'a r.1It "t. tlt')(:ri ht'(l by lilt" dirrt 'n'lll 'l' IX~l'('1I ' n -nal r-wretiou . lism ..n 'alt.t"t:1u n III(' ll l1llt·lItr.!>llt's til t'stilllalt' t'\Iml1inll ratio.'l.lism in 1!K·lin ·f.. I" .-rit alll i of tht. pla..l\l.of ti lt' (·Iimi llitli n ll pnll. for ('ump ll'. .~ Il min (Tahll' 10.lIdill ~ tn h lllllli t't'll.tIIt. n -nal ('«ni 0I)' pla. dl: 'amlln ' is llIun' fn'fllwlIl l)" n 'port...lItall)' dl 'h' nllilli ll~ tilt' hl'Il". a('('IJIlI' pH.. ··d t'a r.. 11M'W' fu n '.1. I ~ · flln · ('t)n si{ I( 'ri n~ dt'anUll' -'(If {I n l ~ I."...1 alltl J. .u n-na -nts .UI I w Jt ~· Ilil1ah-s th at till:' dt'ar.rthc·nJM ·.. rt"Spt"l1i\1' 0TRans .'t' (~ III hI.' "al llt...("!>.m tk". J.\l'.10 11 dm!/: ('t ill · . ll1i.u.t. hill(lin~ o f dnl ~ 10 IIlJt" ph"lIlit pmtt'ill.tiollt.· ti lt' li\"t'f ami kKlnt. tn d .· ewn-uon of ' e. a. t..I~(· ur~a ll hloud flOWl.... a ll nllt Ih al i.. llc.... n-nal dt'<lra nn..til' lIll:ialll. 'f • Ell ' .u K..l\llIa p m h-ins p n lllu('t'S a mlio 1 l:'Ss t1. mud l Jl. '.1 I.tl ('x(n 'l in n dlltl hl:"P'.J Plasma coocen ITotion fC) 5 11 lc' (lI l1('I'lIt m tio n mt iu is a fum1inll o f tilt' IWlllatot. 1I1t".. 1 tn l:·.1 0 11 dm~ in pla. by Organ.~ n -na! and ('\tr.. d m !.uI<. lI owt.. Of Sitt 01 Meosuremel' ( :It'ar. d imi ll.0 " it " :1 IO WN lim it o f ( l -hl:' rnalnl'rit ). lut'I"lw.... 11lII"l...kitllll'p would lit." . tilt' prtllllll1S of tilt' f('!ipt'l1in' dl:·ar.. l"lUi\"l:'rsin n i.a IK.'eall \(' tilt...· o f if. n ph."lJlllpolll'nh...mil lro -r.ul\(' It i. Additivity of OeorOIKI 111t' all aturn~' nf till:' IU"'I .'t.IOIft'S to 0 TR:m h!untl flu\\" anti (' \ l nK1itm mho (st.:or ('~l'WIOf)o' d t·arllJ)c.IIt.lItl't' \ 1J m ' lJ...ul<'('. III p rdl1in ·.Ull'1' of a dn l~ I.llt. tilt' te rm I" II-"'Ul is tln 'l ~""l:1. tlt' pl'nds u n tlK' n ' f" n' II("I:' Buid . an" 1. fil· o~all s ... till:' rotlin IJldy ht.' llal (:!t'ar.!t. · lJolh n 'n. L to l"OI1 \1:"rt t hi. thi.. St nm~ hill(l in~ tn p l..Tiht'tl h. S inl'1'."S Ut'Ctlr in ti M kidnt"\'S... till' ". Thi. llk clearance..u re nx-ut .md e-limiua hou hy all otlje..fl.. lal-oul i.11ms. TIll:' l:'\(l-ptiull i. It can a!!I() hI. ('Alllsidc'r..0 ...' Spl"'l.160 CHAPIH 11 kitlllt')"!' .11 .ho nld .. l· . tilt' blt:llJl:J uf (I nJ~ mav at.tnllat"lJkinl'lk s.u nit! then 1M Il«'flitliC mt'fahnlic plasma clearanc Similarly'.1in-ly..:...J clearance.. In atklitioll.l'i.tSlIrt'lIIt'lIls in h lntlll a nd pl. li\l 'r .I) ...~ .1n) ••p p lk<ttium ill plt .1 in App.'t' an d {"lJlll't' IItralioll It'n ns.mn.cnbed in terms of the d i llli llatill~ o~an .

lun gs lx-Fonn·adling till' sill' of 1l\1"lO.tlld in part to tilt' total cardiac output p'L o.')0 and 300 lU I/mill.-. TIlt'S(. ami Enzyme Activity T ill' fol1 U\\in ~ priuciples.l1ll"l's of dmgs by the. for which vuhws an ' 10.(lIlS('q lle lltly lias lx-en Ihe most t h Oroll ~hJy studie-d. plal"l' in lIlany 0 'l!:. Dill' exceptiou to lilt" addithit)' of d eard ll{1:' is pUlmOllil!)' clearance.('. TIlt' lise of thi s concent ration to ( H. Indeed.:. with ot her o~ans of r-lunnuuion . ant! !tt'p'lti{' 111l'Ialxllj(' dl'ar.sing thron gll tjn. " ('{'all"!' of lilt' atltlithi t)' o f d earalll... Hepat ic blood clearance '" 0H Hepatic ' E H Hepatic extraction ratio blood Row 8 II N ( ' VII is tilt' sum nf hepatic portal and h('Il<ltk arterial blond fl ows . tration (hlood nr plasma ]. Fo r ('. IIII' rl'IIlIJ\'. whidl for hot h orga ns is tilt" same (C ).== + c C 7 R enal Hepatic clearance . 1of As \\i th orln-r o r~<ln_s of elilliinatioll. Protein Binding.. r ather than in parallel. tln.IIlS .clearance + clearance Thus.Un'I!Wnt. tilt' n 'lath":' contnbuuon of an~' o~an to drug cluninunon is readily m l{'ulah'll.ltio m hips. l k-patt c ck-arauce Includes bili<l!)' eX tOI)' clearance. til(-' lungs. . if thl' pulmowl!)· extructi ou mtio is h i ~h . tlu.u n .Fract ion of drug exert-ted unchanged (t!esig. s sotiah-t1 with that pro{"l'ss: Rate 01 elimination Role of renal excretion Rare of hepatic metabol ism C T01 01 =. Cll'ar.her-r am i till' kid lll")'S an' now cx armned. n' spt'{1iwly.('. This is din. ploLSIlI<l protein hilltlill~."l.ill part to til(' blulxl sllpply to tin' IUIIg.and extruetion ratio to llltemtinm ill j'lI'rfllsioll. is jus t renal clearance d i\idt'(l hy total clearance.nah-t1.. SI.1 dm~ by till' lin'r lIlay Ill' nlllsidt. usually h lolXI in a peripheral vein.1a1 auatonuc <t!ul physiolo¢ c fea tun-s that req nin. Th ai is./i'.. lclllat('d in tlw usualmanner lIlay ("'l:'11 ('xl1't'{1 l ca rdiac output.t\ tlH'{l is that It'a\i tl ~.'1' Chap..I takt. Illakill~ interpretation problematic. cleurancc vahlt's {'. HEPATIC ClIARANC! Althou gh dm~ lIwtal M llism ( H 1l .mh' of n-mcval a. appl y in ~('I1 · r-ml to all 0T"WIIlS of elimination . a\"t' m~1' Perfusion. 3 ). total ch-arance is the Slllll of tilt' clearance s hy each of tilt" diminating organs.Ill-lI lah' d l'alallt1 · is in("l)llsish'llt wit h its ddinition {see E'I ' 3 ). rat her than ('ntl'rillg.so<-iall-t l "'ilia ('m. rt'l ati n~ ehall~('s in clearance. principles aIT'exemplified here with ln-patic cxtrac- non.''l1. TIlt' ccucentranou m('.l1ll. Each o~all has SIIl"l. via n-nal cxcreuon .CHAPTER 11 16 1 Rate of Rare of Rare of elimination = reno! excretion + nepatic metaboli sm 6 Di\itlillg.'(. whlcl r is subSt'(!tll'n tly d isl'rt' l'''\SI.' ur.of the liver's abil ity to d iminat(' a dnl~ is hepatic d earunce-.its st'pa mte consideration . dnJ~ coucen.. till' lin 'r fn '(lllt"utly II<L\ tilt' ~n'all-sl mdalMllil' (~olll<l{'i ty and {. 11 1 (' most di n -ct <pmntitat in' Ill('a. or lnhen-ut elimination charact eri stics.Impl('. gin 'S tilt" clearance a. "l'i n~ tilt' frd{1inn of total elimination that 1M.rt'{l [mm 1ll<L\ S ha lam'(' n '!.s Ix-iug in series.-II p mc't:'ss hy the illl"llll1ing.

u l .'......2). II.I II .. d \\11('11 the t'x1md ioll rat in of It d m R is low.. hluod dC'afiUl l'l' o a ppn).. II ""l ot.-it. 1i.l(:t.. hut llil' ext raction ratio is virtual! v unaffected .lnll: It...o f elimination.....!t.." I.. 11'~"i< " ."...o ·n tI · ... hy defin ition.. fl. ~1 ill lUI i. d' · I.·..lic"..icM' ."t.ll·h.l tn Ill<ul .... hll )..." il. i. In h~ ••1110 .. ..'ntil'.. ill tI. ' ..• ('Io. " l ot. it i.. 1\..· I... IU II..i'''· I... " " \\. a mi lit. n .-in. 1.~' Jr.. Ii"".2.lit. dllier SS metabolized by a ll ('1l Z)1 11t' or transported into the hill'.III .1 " ·Lar... lI '1"'ti<.'S in blo od How pmd lll't· co rn-spondtug d lanp. WiT hin tI. ( :m" I....O..." .. i. <li n"" pn.1 rn .· <·Io.... 0 .ilalit.. (1"""'.d n.r. Ii <In. tilt' drug must haw !lild suflicit' nl tune whilc' in the her-r to partilioll out o f tilt" blood {'(·II.\\'.. in ti lt· on-mil S lClIlt" (Fi ~..p n ll'( ' Sst' S dr-pict ed in Fi ~.: ... " ·lI<lt·" ... III cont rast. ill mh" o f (.'... ·r 1.t1m lln a 11).. ."m ) mu st ht..• a.~ ....). I..d..S. 1I" lil'yri ll" d. (1 m ). J.jcon ut" a.. At I. pal' ..al "illl lilt' artertalconc-ntranou.1'. l it~ .l. R a.. "'.G.... "·rf"...I. a Unbound b Bound ~ ..t·<. t. elimi natio n o f a t1nl~ \\i t" a Inw ('. 11-3. ~· "r . lrt i.Ik-.. ... .I. inlo hi!.. 11.. j.":... "lr..ll i<-' h lo ud flow.lSlIlil pmll'i n.lh · fmmillt' pl..... !liL I hm ll ~ l til(' h l'Il. M.~. i. '11/:..A.. "'h· li".hh·Io..-rfu I .t>. ...... ~ kJWay.: C ln "bh "') l"'I I".. or b eth.'." i'l< litld d lro mit · pI.=. rOn llahon .t. J.t~· "r II.r...:.t.1/: 11M.... II..·· p"'I<ot)'''. Dn 'l: ill hIo••1 i.pI.. C TI. hilt· ur il l• •UI>jt. 1 .'.·. ')' . \ 1...1.or.!t . C.o. "1 1 1" Tt·lic'n 10.'l6."..."I..""-"oId".o~. o· ' ' lU..d i". (p" .· 1. h it'" II" "''' ... 'I ) Hepatocyte Bile 15 '2 Lidocaine Colloidal C hromic Phosphate ~ ~ 10 §....t 1I"·r. " ft" d n j~. 1'1I'. lInl" "n"I . l"" u. Therefore.. shos vu in Fi ~.. lIIay afTt·c:1 tht' ahility of th t· dnl ~ fmm blood .) . I I~· :1."... Ii""....ltt"· lilllitt'll l>l llllt'w !ll'n' t"IS(. fnr· m. dim illa tio ll ts rate-limited by pe-rfusion and 110t by the spl't"tl o f any of tln...IIl....d i" h u.limillatioll nil:... ·. C h:mg:.·.L. Illl' \'('1I0US d m K comvntra nou is \i rt llall~' id. 11.." M .'<!ml1ioll ra tjo (ilppn). 8 i" p' ...2 hver In ext ract ' ' ' ' 'OON CHAPTU 11 P.J...· ""1""'1'''"" "...'i. 11-2. .• 1. U nder t his co nd itio n .<~a".oi.11....: :\ Illil~ri' ..ltic meuibnnu-s..2.1" <". <!i!Tu. Ii.· rfu.n '" hi¢ r fl.. 11.lUKl' in lilt' dnlKcoucentratton \\ithill tltt' u!"K" II.itl "I't. wlu-u ti lt" Iwpal k c·. I"M <I) Illld to pLa '' ''' I' " ot. (1"" tI ) o:r In ''''''TJ. 11> ' 511'l~')!)'j. i ll l'!l'. r. 1117':'. • • Antipyrine 10 Hepatic PerfusateFlow (mLJmin) 20 ..... .l fi.·...·"1".l litltr....t.1 II.r • or..should produce 110 d l..... li(...·r..... U fI.1....-li d Q Blood (1" t"l lnlo II.. IOala "1..lralll. CI. .&l.. 11.l" lTll'.m.. tmetjnn ratio app ruad ll's \ 1...r h. · . ..-anu ..... .t n.r.... iII.>..n 1 110..l....-. r.II" Iur11. r..·1O nlln ll../1' d1l't 'mk 1'1 "1'". ~ ~oi< W d ln ""it· pIM ""W'. I! uwt"vt' r.. " .·. ). ' and nih.j..0r~cg -=== Drug Unbound ~ Metabolite Drug .· ""-1.n " " SJ'. ' W .."". "..1 f10..llitot " . "I I....· r..i"l/. n wid..~ ...... -li r. or 1o~ l ll ·...n . "f til'llit' I."" I. I .~' fn 'IIl " I rf".1itM r. .. l t" d .0.i. . I...... Ih.... ..1c1n lj{i..ion. " .. 111 a. u c • 1 u e 5 0 0 --. ' 8f-to. •. I..a.. AI.·s it s madmum value..· pnll'l'SSt's. dla ll~l'S in hloo. di sso d ..i ll~ . \kEl".." 11).· r.1. j .

\ Role 01 elimination - CLu Clearance bcsed on unbound concentration Cu Unbound concentration. and h i ~h (!-:n 'a!t' r Iha n n. Haft' of t'li lllilla!ioll de-pends Oil tot al concentratiuu in hloud .. 1 Bl'p n 'S('ntatiw d nl ~s and 1I1daholih' s \\i lh low (It'SS thun 0. Examples . clearance tlt'llI'ml s Oil plasma prote-in hilltlill.o'r~ ~O" i " No<':llpl'J!.l. O~.11 1 1111' limp iii t1 m g ('tllll't'lllmtioll .'(-u m lill!-:Iy."'ll(1' of hmTlt'tJstatie cont r olmec hanisms and a IlI'rfllsion .ctI_ epre _ 0-.nM proteins.!o<orl<> """'*' Cefa1:oI. lilt" li\"t'r is d t"llrly (~Ipahlt' of fl'lIlminl: .".n. _1 b:tr..!.1'l C.i: hl't.lIIgt'S auvwav... For a d nt~ with a lugh t'xlm<1ioll rat io..7 ).Ilt'itllt'r t'xtmli:ioll ratio nor dt'a nUil't' is man-ria llv afT in 'h i ll~l i ll g.ts of hij.l!ie ext raction 't'll ratio vu ru-s illH'rM" ly \\i lh hlood UIl\\' wlu-n l'!('a nlll{'(' is constant.2.fjnilioll in dl'ar .lNATlON 163 or hy d(. Fur a d mg \\i th a low extracti on r atio.2.(1 )l\(laril~' p roduce such an ('fT('(i:. ~o" 'od''>e """"'" Llmi. t111'n gs ' art' ph~-si llll ~~k lIlt.roe Amol<iciMin Am. :\ wenl of cautiou is T1t't'tlt'tl hen '.proI\o>cOCll'l Cvrenove Cephak:>tr.mn.3 10 0 .. . From Ell_S.t to blood cells ami 10 ph..lillli h'tl supply u f cofactors such as O\ "J. hm\'t'w r.in Tel!ocyd.1 ioll ratios in tilt' llvcr an ' lislt'tl in T nbk. • ...It•• 11.t ' in binding aids in n 'll1o\ing a dmg..ne . ) Bindi ng WUhin Olond .t 111I' liver is almos t Idr-ntfca l to that ill the ein1 11ating p la..(l-WTEP 1 1 ELlfI.. :\hh()u ~" mass-bala nce pnlldplt's sta tt' Ihat d l.3 ).od ne C~"<! N!~. The 1I1llll.'1'.... llluti ill 111I' ctrculatillg plasma.\I.JI tilt' tlntg Pfl-st'IlIt'l1to it ill spite of hilltlillj.7 ) ('\lnu. Ct' rtainly.. 9 T.('.lIIl. Then the mit' o f d rug t'li minatioll ill tht' !iw'r is tlin'l1ly n-lated to tilt' concentra tion of dmg 1l 1l1II. Cu . .11. ...'. T hen-Ion.' .(. 111t' S(' expect attons 1"1' ~an li ll~ jll'r fusioll for d nl j. .U1~t'S in blood lIuw an ' !lut expect ed to alft'r lilt' l'!('amn('(' o f dr u of low extraction rat io.t'lI or sulfate.th ami low ext raction ra tios lift' iIIustmtt'tl ill F i~. 11 """.K' n JOiS tht' [ivr-r is small. FUI'~de Genlomi(.. Hepetlc M .JIIlHi coucent rution ill plasma Il'a\ill j.m ' thl ' pn '.. hut ill this <'a..anisllls thai llIay St.all"l' only unlllJIIlld d mg 1'II ' I ]('t ralt'~ membranes and is available fo r elimination and · "1' 111. it is cSM'lltia lly all n-mocr-d t"l1('t! hv d l. it is M tha t th(' he ll. a dt'l·nw. illtt'nllt'tlhlt(· (0 .

.-'1..p''' I-..... : 11 " 1' . ..1 1"1"'11(' ... it h il. ( ..· 1..o. ill .. · ..cl.. ir.... d. ...1 ""...I 1 ·"~1l1in (.. In .I wrth pn'f'O""'&<l1 (0) '"' .." .11. .• 111:1 2..11.it ·I" nilo.. fll' .. _ ." ..J ... ". . .'c. tht' (·\tr ...Ii""' .""...m in."~".~ .ul" f. Ii"J: ~'I<""1... TIll ' ~ 1... " .. I I :tz\--W .. S lllir.II 1 Wil~im.I"' J: fur 1. (T f 1......II........... tiM' IIII...rfu\l:"(1 rat lin'r... " ..In..... 10. .{Tn 1... .·IlWII..~.:I't1.t' IW!'J...'h" llltnidr... . 1_1i" " r..Il ic { :k-arann '.1ioll 1I111)( IU lld .' al"" 'IK'l..... \A IIl"itlt' r fin! lolhul.1i1l1( ... II 1 .. .. 1Q7 Di.."......u" t..·. .oant. fi: ~.1/.... it. .J nI It.. ' '' 'lId.n .... IIi -...J .1 " nlu"od.· dr.u..li'lt..h' ''.. R....i ". ~' .\ od \ 1".H.t. 1.. '"'''' It . 11..r 1 1 fnn.. U C:..I in tht' isolalt'tl..lo1t~ 1 .'i 1IIll :llallJ.:· "ho w .J"... t1. '\01:) d Ol'S h(' I)... if/II \'aril"S l:\\ufll ili .I .. d ." . preparat jou .'iioll can be Ilt"kl (·(In..I... " . prrxein hilJ(lin~ can l)t° n'adi~' alIN\'(II".rf"... As l "· pt 'til"ll.·: U..r:-. m ... In .'§!J1l-......'''''''' ..."'·p""n" .'.. .-In..ll1I<'" ""lu". P""'"I"...... inl rin in II.. • 4ot. !\1I1l11.\CI" In frood ' "f (Ino~ un l " .I 1 ...11~· p mportimliJ to Ill.. ... tI.<I .l!} with dl. ...lr... ...u" ... .11.w. '~"" .. 1 fn .lt.1""'". .rt.l....t'limillOlholl n·laliw· In till" plasma ("1I11('t' nlmfillll... p.{1". ( : ft. .0 11-4 .lll.1I:n... M : I. I\t>r.t...c ..n.. W.......&.. ..'"' " 11"'"..-s. Il..........1..' .i... ..(.· " nhn' n"" · "f t...I....1ill .mllK'" '\ 1Iri('0........... llt·rf" ..0 Propranolol Diazepam ~ o Phenytoin is 0.md I" fr. "I · l r...~. a d nl~ o f kM' ( '\tr M1ioll ( "\ 1.' 64 Cl-W'Tt R 11 E\lm· .. n· d Tt '0.. -t......... ....... Chi'llt.an~n~ liM' (ull('1'n l ml ic lIl uf tl tt· hil KLn ~ pml t"in... l"·rf".h'"i'llll i h. ..."I hi""I .I..ll1...... .w_ J" '" lU I .. Itt ..."" "".ItI..>I"..... ' fr..'ll..b llt. Hepatic: cleara nce - CLu fu Frodioo in plasma unbound Clearance bc sed on unbouod concentrotion 10 For ('\ampl.1 tl.. iKtl..t.n ...{ I" . ..liun.M1.••.... ·ar. n J : \ twn.. uf.\ ..-ar..........I.. II....5 J Tolbutamide o o 0.11 ...'" tJ. J.."l!.1 in Fi ~.... 1>I "'''~1' ''" .I.' ..J ...· ..ntI...: 1·.n .. "'tl.....(Tin.'11 ill tIlt..'''''1.r1M.is di rt't.. I 'M _ TolI......... I......t... pan'ut lll.tt1'I("'od h... r.' .5 Fraction Unbound 1......lin" .. 11......<'i" ".. 11-1 oh l ailH. S.cl•... .. and pt·rfU ..0 )...lralll.1. 8 io 'ph.M'uu.t in tlu' p "1>."..1 . 1".tanl .' loi.1\ "j >1 ...... "1 ...." ..p. linl!. 11....... u .lit' points liMIt. '21~ · 1 -li".... . C.f "".M1i... in f 1" .1.·'1....lH...in . 1 n""I" k .. ..... ... 1 "1""1...{ l>ilo1t inlrin. nioJ." ~h..c .. " I ". ... ...11<'" r"'i" i.f llt-patic' ...... Pn'l . • ."'tn. a tint( "j 11.. L.'!> I pn..t.· dl.l('I ' ~ ' lif~... r ..1_1..ll1M"'I'lIIM I'I'" '1".....nlJitk '.II ...1 ""I~' ....lti l' p la\IIl<l de.. 1' ''''r tl. I" I.· .K1icm mHo (ClIKI d.. • •In'll: . I'"".... .-hod. n ·I.. iIIu"'rah' ..n ..5 .I1..l!.".• It 1i""I.... Ell r... ~...II-!\I"'.' o r hillllill ~ ifll .-n"...ir. "I l>l... prrf" .. . p ropo rtiona. .. "'·n..Inc .: !'n"r in 1.U1~I"S in till' fr.l Ii.. nu..ll K"t") o f tolhutami(k..·.."" · aI. (I ) "'" ' .1'. " . oL.. Ii .. .' · "'11." Ih."U1~ <: ..il "1 1~· ..n . pt .... M .: ... .h'"' I.ill~ till' rail' IIf Ilt' p"ll k.\--1.'>Y.t< >&::!'·• .·. t·.11_".·I " lo.lI" i....M ... noll .. . \\1..."OUIIII d l'arAIK"I' n.· SU... "lt ll....ly ' n" '" 'I''' '' In d". 11-.1 B... 19'i3. " ".Inolo: I."'..tin ".."'.'. I"' ." tI...

. tlu. 1 Th is is shO\\1\ in the' lo\nor part o f Fi ~ . till' at1l1l inistn ltioll o f dmgs s lll)\\.' isolated.Il11't' is tl·fim'tl iLS thl" r.l'xtmdinn m tio is high.1h i t)' cralI St' hu ll' o r no d lan~l' in d t'anUlt'('.'1ISst'tl 'l~..S an ' con rmlk-d. . S ote Ihat the hiJ. iu tilt" rt1-. UIIlIt>r IIll'M' mort" n-stncn-d n mditions.CHAPIH 11 ElM NATI()N '65 TIll' llhsl"".t~·" :\ ~ stalt'(l ahow·. K C m + " II ill whtch 1\.l' jl.s ic princ iples of l'lI7. ~l m t of our p n-wllt knowlt"llgt' of t'nZ)111e kiuetics is dl'r1\'f t l Imm studies in d tm in whklt ' lIhs tr. 1·1IZ\11U'..app roaches tilt' m lut· of \'m . litt!l' wi th a lllotlt' mh ' (: ha n~{' in E n7.. C ll·. in till' rt'¢OIl wllt' rt· tln..s ma llit' l'tJllt'C '111ratilnI. 111l' extraction r atln (am i d ea nlllt.' to thl' unhound pla. dl<\1l ~l'S I". till' ~lidlat'l i s· ~ l enlen constant ... typic. a \<lluI' "flt'lI {'alll't i the i' ltri ll.1 of ~ 1it'hat·l i s ·M {' n h· 1l kint'ties if tIlt' all" p mad l toward till' maximum rate.. is ('IN fusioll mtt' ·!illlitt>tl.u..1I'tI 'lIl}w:J. Howev er. d ('.0) 10 one d ose 10 zcm m M' 0 11 d ( "'n'. :'\ot t"in F I I that a value o f ell t"fPI<U .lhilil)' j'l <"iU I.11111' d O 10 I. / KIII .. clea rance is din-ctly pmlxlrtionaI to fit. 11 -. An ('stimah ' of tilt' t rue Alii n -qnin-s nn-asun-meut of tilt" 11II11e 1llnd dmg roncentruuon al tilt" lI11'tahnli 7jn ~ t'IlZ)'IHI' silt'.' \\i tll thost.U and 0. rate an d couce ntranon lOU)' in direct p m portion . 1fll'st d l'anllll't" is tile' mtio \ '".n ly. for diuZl·jla lll." 111:)111(' kim-tics tlu.th at is one-half tht' maximum .is Sl ' nUll'h Iwpatot. a t1m'(·fold d mllgl' in [u wnuld lit· l.\("( h.1 i\i ty is th t.ll1hi ly. At till' otlll'r r-xtn-nu-.1)' of dl'fininv. Kin's a ra te. III practice .ha. C orn-lanou uf Sill'l l StutHI·.rt l\{'ll'ss. 11111s. 't"lnpt 't lto 11( liln ti~\' d mnges ill d t'ar.11/ is a constant.d pt·u tk' l' ltIl't"Jltrat ioll s is di ffit·ull. lim iting slt' p.·u liea lly..i p l("S ju st dise.. this is a l'lIIH'nit'nt . ctly proportional to .. n~ satumhlt· IIlt'tal M Jlislll at t1lt·. Vm ' Cu Role of melobo ll$m . ~ I I M I. TI ll' ' '31ut' may hc' so h i ~!I ( tiM! l'l illlinat iotl ill !'it. alld (1lfat1n r lUII('(·utmtiol\.'.)lll<' kinetics have applt('ation in phan llill"kinl't it" .' n ·. Will'lI (' hall~t·d hy induction or inhil utinn hy anot her d m v.. the run. tln-n d t'anllln' is 1 and dire 0. .y.fold ehangt'.IIM Am .L'it'S at t1 nl ~ l1l11t'C' utmtiollS app madli ll~ alld l'Xl.si ' "u1abo{ic c/t·arml( "f". Lal"kinRthis cap.n ht· t1illkult to n 'Ill' ·IllIIt·r .ill ll lll i nllti n~. 't!.o n when. 22 Oil Dose.fl' to K". \ 'm.). Tk.." :uu l T imt· Dt·llt·mlM eTldes .U (ill till' absence of bimling.. 11--5. 'I ~ I. tlul't" " lan t. if t'nZ)l n(" . s 1111" llppl 'r l'III"\'(' ill Fig.. Vm Km + Cu 12 Its " 1 m' dt't... d m~ lIlt'ta lMllhm is lLsstllllt't l uo t 10 slluw satu mhilit\' . l1 ln lllgllC lHt tIlt' w st of tilt' IM lk t' Xl't"pt C llltp. ·Uub r :ll. The hl'h adur tlisplay('(I.. till" unbound ph~ ll1a (111l('C 'lItratintl is t'III\'l'ntiollally UM AI unbound plasma t't)fl('('nt mt ioll s well lx-low Am . a 2(). Almos t all tilt' d m ~ is l·stm<.' of metabolism II)-' a ¢n'lI t'UZ)'IllI' b oth ill d tm am i ill I'lw..extract ion mtio is low (I1}\\'fi..1/1 .m llli' u f \ '1Il is d in'(·tly p rupu rtillllal to ti ll' total concentr ation o f en zyme..f lll'pOItk 1. nlh·.. Sinl'(' IlnlxJIlml I\'{' lIlt'taIM d t'a r..·) [r o a \ .frt "" 1. pllltt'i n hilld ill ~ ca n limit extraction if hintlill~ is high l' llImgh. pl: rfnrllll'ti in ri w has 11e't'1l diffil111t .llt· of 1Il1'talMllism rdati\l. tllis snnatton is lJolip hysiol~e ill th ai tilt' fraction unbound is vilrit'(l llt·tWt't·1l I .( 't'tlin ~ till' " lhlt" of 1\..05 .g.. Nn~ till' fnl(1ioll unbound. In 1. ~l allY fa(1n rs an:' in\'ukt'tl i ll !:i n ) that cauuot IIC. e.(· wht'lI . then..Iimillation !JOIw"IIe"('1I dl.msitlNt'tl pa rt it111 arly b~l' for a drug bound to album in. C onversely. follnws th t' rela tion ship. till' l'~I It '(-'ft't l n-lanous hip b etween d l'anlll('c am i/ II holds.~-Il1t' .. lTll.thi ty th at Illocll'st d m ll ~l's ill tMs a<. TIll' ~ell('r.. an ti Km is an inverse fUlld ion of the affin ity IM 'tWt'l' n dmg and 1'1lZ)1I1<'.(~<l Il Sl' o f tltt' l'Cllllp l('xities inin-dll l't't!. At {'(ltll'C'ntmtiolls . :\ Ml"IIl~)ry' Aid . whic-h apply to mmt d nJ~s use-d tht'mp.lnul ('(' \<t rit..'> is d laml'kristi<. S I·\l.\IU an ..lu-n cleunmce i~ Ix' rfus illll rwe-huun-d.ltinns with di :v.I!t·.ll p r1n<.

lIli.'llr"'''''· (1• •Uu".)'1111" silt·..·1IZ)" act ivity .</f .ol k mo1 i~m r..· K".U"'"1ll i.u ..· " ·JoIlie" "I. '01(" hepatic extract ion ratio.. Vm!K m m.'('ll·..uK't· i ' tlllt··luI ( tI.·lis· M. Irollk . C/.ul('(· that n-lates rute of metabolism to unboun d concentration ut the ('111.~.' Km Unbound Plasma Drug Concentration ..'n I".I. \ '''1. \ h :h. MI fill \\'.~..• clo·ar.h ) . Cu .. .wlInl a Ul<W mlllll · tIlt.rtit's at tilt' limit s.. · 1 l\l1l ill("ft..... will.t"I.dirn.nt 13 when.11"11: (''' ll. p la.. at ·Md .. The art' ''fl' '''litl'n fur II.· (uK't'nlr tiu ll " I ".(' OIll' is part it'u larly attractive b ecause it m il « 'atl ily II(' t holl~h it lila)' 110111(' qua ntitat ive...II-5.nt fUb ' Cl.. n . .'1..i(-h instant aneous andcompb-n. n . Om... t1l('S(' pn ncipk-s. .1 to SIl Ill Ill'U 17.1 "u)l/d .. tl. i.tntrtnslc d ear.pla' m..fi'/t ' C/ " ".Q'I is ti lt' Ilt'patie hll.. :4I.a..1 allli ti lt' ('. is mu ch ~n·ith· r tha n Qu..'t'n . 'ul r.\ ('1...""h·!l "'in<"fi<. is tln.. illltifi l/t is the.. til(' model allo w s QH • Q H -+ /vb . Cl..'66 CHAPT I I H Vm Rate of H epatic Metabolism ..1 drrccnou o f t:ha ll~(" TII(' well-stirredmodel states th ai 11.1 . j n('T1~ <iIlt: . Thus.! " :d" J1ic d .Iml: n >lK troltio.· rAil ' i. a1.orfUSiHII..I" ....hid. 1I1(> ' the 1t. tl. II. < ~h. \\l.. .xp('(1('1. Incn-ased.... IV" \01... Vm R = ate 2 Vm-Cu Km.liu ll i.j~ "" .... Even to p n '1.lid: th uS(' siluations ill whlch eitl l('r clearance or t·xtr...ll!.fml'lio ll unbound in hlood.he· 1lwa.. _ Hepatic Unbound Unbound Vm Metabolic Clearance Clearance = Km + Cu Km Un bound Plasma Drug Concentration p.n i ll lllm i... ." . wln-u 1':" app rnadws 1... CI' b... W"I.~ then 14 TIlt'S(" 1\\11 equations haw tilt' desln-d p m pt. in wl.. . TIlt' UIl " mo..of IIIt'M llllMlds..I» fall.~lIl a p rotein h ill(lilJ~.. >... . tho rah' tlf m.l(1iOIl ratio is " fft"{1('1..!n' aln-n-d..-s (" 'I' 1o:r." IQII' i.i...x i n~ occurs withi n lilt' li\'t 'r. ami ..0 (tilt' pe-rfusjon mh··li mitt'(l l"omlitil)n )...t.. .

!>n"...pU'lx)s("S.blood-to-plasma concen tration ratjo (e ... and the hlood clearance (C U (C1 C )] Is I. the two terms are t'(luis-alt'nt. iLS whole hlt ~~1 t1t'liw'~ d nl~ 10 Ihe llvcr. wlu.fe )C I . AllY dm~ \\i I1l a hl~h ht"lliltic t"Xtr.h Ihe liver ' ia tilt" po rtal "plt'm.I.. 2 l i m in.lr. l1lt"fr. The fr..1.56 for a hepatic blood f1nw of 1.he patocellular activity (jnlrinsil· dt'arallw ) varK'(l t'vt'nly from 0 ... the maximum oral bioa\<lilahilil)· is ". Af1.S IJ mill.t ) is 0 .3 . A1JS(lr ption.1 "l f ll ~1 d l". QII ha\"(' an mte mn-diate extraction r atio. 011 this value fnr an ' oml dosa gt' forlllulation .l1lt'1l slIhsl ilnt ioll of Illt'se vulues inlo E'I . Di \itlin~ h~· hepanc hlood 10 ohlai n tilt" Ilt'(l'llk extraction ratio.. C I .ll1('l. 16 which..h great er ' than jill> • Cl~"" . .Hepatic extraction e cnc 15 Hepatic edmt1 ion rallo run lx' (.a1 circulation. ACe :: 3. Suppo se. v" ItIl'S l~otwt" 11 11. 13).CX)()-fold mn~t' ..5 mg-min/ l.'is ' t's:tmdinll ('ml hI' prt'(!idt'(! using: lilt" u:ell. (." a ndjil hen ' art' lJOI I'xlx't1{'(1 to illllllt'!lt".K1ioll m ho depends 011 all three factors . For tlitlal1ic. when EJI is small.. C1.n-as clearance tlt'lx' nds un ly OTljill.). i. 11la t is... For iIIl1slmtin' Pll'lX>St°S. an explunation for why Ihe e xtract ion ratios of must drugs appt'ltr ttl I ~' eulu-r [I'W (E" < 0.. OW'f a IO. 14 inl o tht' fl·lalioIlShip"'lI = I .:2..3. QII 10 2. 9. .f.' upproacln-s Q" (Eq. Bt'in g p hpiol'l¢lwdlly dt'h'nnim. 111('fl" may lit.( h lotlll 1I0w ...e..• that tln. m lingly.IQI/ a nd fill.tlma !I'(1if tlu· lu·'lillil. 13 and 14 are applied .I C) = 1.lUt" in lilt' narrow r.104. 1111 amount of phunueceuncalmanipulation cau Imp ro\1. lu-n.'5 lzuun. ."1... F".e-...2) hilS a Inw oral hi t ). or protein bintling: on nrs l·pa.1'.t{1iolll'l{'rt. a m i 1 1 hy d ilT t. and l'!t'ar. . and tln. am i tha i none is bound in plasma Ifut. a t1 m~ ~'''-' n orally mu st ! liI.] is 0...1II~" of OA3 .J olTt'r. 13 ..01 10 100 U m in allloll~ a Illfl{e ~mp of ccm pounds.approxinuue hy jill.I ..is of dlall~ n).. intrinsic dt'aran l'i..Q..v.3 alld 0 .lllf'l' (fl· .rt'II("-'. is 0.Eqs.6 [J min. th t. in th i" example.) clos e (seX) III~ ) of a d m g: C lIlIlulatin ' 1lI1101ln! excreted unchanged (.. is till" IIppt'r Iimil of tilt' oml hitlilvailahlli !y...l(1ion mtio (s("e Tabl e 11.llrs when till' blood -to -plasm a concentration ratiu is mudl grt'all'f than I. tilt' 1lt'(l'ltiCblfll)(! clearance [( I .O).3 ) or hi~h (E I/ > 0 . lT t"(. Qu mu st I ~' muc.l\'. hll\\"( s "\'Cf.. Stril1 ly.K1ioll ('s('wdpi ll~ ehuunation b~' tlu.. It may I ~· calculated from tht.(bllllxl) clearance and Iwpatie blood 1I0w an' known o r can bt' approdmated. Cl~. d n. ll1a.i(' h itKl\<lilahility..stirretl m()(If'1 hy sll hstit ll ti n~ Elf . Cl~.SSll lllt'(l to occur onlv in the livef. Ell' Shl(" Maximum Olol bioo voilobility . iL~ tlt"Sl-'rihed In Chap./1 and Elf much. Ihe Iracti on uubouud ill Eqs. (('11. and CI.4. l. . IlI'patk extraction mho. Equalion I. 14 shows tha t only those drugs wtt h an lutrt uslc ch-ar... ' 111t. A major d iS(·n o 'lillll·" IX"(. Conversely.1\\.tt-d lIndliUl~('(1 / (AI'''. e .CHAPT 11 ER ElMNATI()N .3 L'min. l1lt' d t'a mlll'l' ( D f)S{"IA VC) is then 1. Changes in To n 'ill: h lilt' ~I'li(' r. Extrarenal t'!imi nation Is il. ) is 0 .fer to Ihat ill blolMl nnt pt l.hwr.\ S thmllF.m"ldt'f tilt' folltl\\i ll ~ dat a ohtaillt'(l afu-r an tutraveuous (i.CI. m: !. here and t hmll~"o llt n-maimh-r of tilt' lXIl)k .' Otlll' f fal10rs Ihat limit dmg: n 'ac hillg: till' portal \l'i n and so fu rtlw r tlt'l'fl'll.Iml 14 should n.g.u lahi lit~."J! a n.'Spt't1i\l'ly: lilt' \<llm' oftlw l'xlr.) "" 15:2 m~. :-':uw E" a nd CI.

111lx-conu-a high extraction r. 1· 1l. . IIII' <Inl~ mu st Ill' at1 i\"l'! sC'<. h iliary dear.\i n~ a\ till' extraction is so sma that t'n' !)1 h i ll~ presented ~t'ts P.111 Ill' t'xpn'sSl't1 hy hili. 11I appm..l\('S h io. 111t' principh-s lu-re n-fi-r to tlu ' n ']atin ' ft 'll dell(:ic's ti M! 1II11(It'si dla"~t"S in tln-S(' Iacto rs an' likd y to produc e. ~(· I l(' r.ly 0 . Q. the bilt·..t1 i ./ (jiII. 111 ('Il Z)lnalic al'l i\ity: pt:rfmiu ll alltl prote-in hi1ltlill ~ help 10 1Il0. . Dm ~ lIIily alstl llt· 1l1 ilIM e-d ill tilt' [iver.l\ma.'f'('t!lf) · y s . 1'" . En 'lllllally. o r fu"..ldl IOIXI.l\('S hiu.\( ill t'il llt'r ('1I0·tllOlIi<: activi ty or ' in f ill.lIll1' is lim itt't l by . ' CT is nmdl ~rt'illt' r than QII' so thOlt E" approaclu-s l .t"(l lh<lt tln." . t. . thai is..' dmg lhn lllgh til(' onsm.'nt mlion mt in (.!!)' dl'amm.1'11 n-absor b cd."" . Elf.an t'n tl'mlwpatk l·yd l' ... 111l' bilia!) ' Inlll slXIt1 of dnJ~s. Biliary buelion and Enltrohepalk <yding Small lllul('<. bilia!)' d t'ar. l'it lll'r (lirt"('lly or ill(lil'("( ly '..tilahility is low am i d(.l ·r.. t (I f fu j. n-gaf'(l in~ th t· (. .!)· e!(·ara lll.pt' lId('nl on all IIm't' factors. i ll~ 1!It' r. I u . !Juwl.. wlwrt'. ' 'l Any dnt~ in hilt· Ilot reabsorbed.'rt'. Inll('t'tl.:1a nu-tabolue-. Ilt'pa li{' (It·rfu sioll . ltecull fnnn C hap . illh ihih't l. Consider ll Ill'X till' t" nd ilioll in whil'lIjill.ph~lIla l"tJlK...l\ i ll~ Iht.~h Il1 1mn id.til also Ill' .ltioll ill 0 th(' hilt' 1"tIIl. hio.l'tl hy rt'~ardillg perfuslon and protein himlill~ to he ill t"I llllpt"tit io l\ \\. lI1. when.l\. A Inw ex traction rat io e-st d mg ('".lTlltt· St:'<.L. i ty n'moves tl m~ fmm till' l)I'rfu si n~ hlood. Bil(· is not a pmd lll'l of filtmti oll. CT. for a dnl~ with a n m(1·IlIr..~.. Dnl~ in bilt' i-nte-rs the int estine afh 'r sl o m~t' in tilt' ~all blatld(· r . to a ~1 1I(1 lR lI1idc· .1lar .suali7.t·r l'all he al'iJit. EI>'v\INAT'ON C HAPTEi 11 17 II shou ld Ill' re-e-mphasi. an' Il<l'it'll Oil mod aln-rutions.. e.111(1 " it" d langt"S ill QII' CI.. WIWrt'.1. nIt· p ll of bilc' ll\"l. S Conside r first tile case uf a dm~ wnh an Elf near . (Concentration in bile) (CancenlJotion in plasma) c 18 Hile flow is a rt'lllli\"e ly sh ·. 172 ) ill tilat it Illay 11l·(' llIlpt ·til i\"('I~. is iucn-awd or if QII b dt"(....' This is nul S U T'p ri. In lilt' ill!t'stirw umay bc' l't Jli.II'(l to .. ami otllt'r stlluh·s.ul(.pn-dictmn ln-n-.w m.5 to OB mlJmill. \"ailahi lity hy int'f'('.U\~". II.'I).l t'1IZ)l llt' . ). which i' 11. 11-6.l tiu t1m~ if el...lTIt1' .:l·s ill CI. 2 tlMI l'll!t'I'tlIIt'Pillil' l.l"t'(! "'/1 hy 1I slIffide lllly l a~l' factor (F ig. hilt mtlU'r of St·c:rt·tioll o f Ili!1' at'i(l.\\-. tllal is.{· it !"u'k to till' d nJ~.Iim inaliu ll.. 111l' d Tt'l1 011 first-pass extrac t ion c.·I'll.. or fill. is similar 10 lu. tilt' bili.'rt·h't l into Ihe inlt'stim'.~urt· ll i ~h bilhl!)' dl'amll l1'..t\"ai labil ity b~' dl'(: rt'. A f(.' f{'. Q" Illudl ~rt'Olh' r than fill.. 11It'n ·fon ' .In til(' gt'Ill'ml circulation. F ir. maktng drug avuilabh. wln-n.·m~l·s alltltll 7. I I. !Iowt·wr.•.. The dlk ic'lll) ' of hili"r)" excre-tion ('.(Jlll in~ total (u lIl't' lilmtiou ) dl'<... lim e t1m ~ spt'm ls ill Ihl' lin 'T'. An inert-a.·ti. (whid l nuses lilt' unbound couceut ration fo r a ~'l'll i lll. f'('ab\unll'tltn comph-n.u. ist'sl' rl'l t'l l frrnn till' IMMly via tilt' fl't.Ult'('s u fSoo m l /min or hi~t.'ll:'t('t1.Ul ht. ' Cl' i'''' 1111'1l 1'"" is indl 'pl'mll'lll of l'l liIlI ~t'S ill Q" .-s.t..n. The ~1 1I('lI n llli de is 111t'1I sl'<.t'!illlillalion Ot't·UI'S.t1 1 or It'Ss th an th at ill p l.1ly <lilt! im lin"('lly 1 11rt1ll~1l a nn-taholite is rep resented sdlt'lI1<l!imlly in Fi~. C L .n' i ~h t d m~s art' fuu lld in hill'.1i\"(' Sl'Cretioll in tilt· kidllt")"S (p .n.-di llJ' is <l (111llIXl!I( 1I1 of d istribuliull lint (.th · o f eliminanou for a Wn 'll mit ' of pn-seutauon a In lilt' live r.t().a lions t~.lilt' tl.l' pmh'in dml-:s !c'nd to Ill' excluded..ty . Biliary clearance (Bile Rowl . Thus.4 . for l:h a llJ. of (1)\1N'.l\t till' llct-r . Illa~' haw a rt·lali\"('ly h i ~h hiliar)"d(·ar.JJ..ham{1l' ri\ lil'S nf a dnt~ m '(. is small. An illt'n'. .l\t' t'1\0'llWS of till' n -skh-nt 1I0ra lII<ly lIyd m l)'l. A t1ml-: that ('Oll('t'ntra h's in tilt' hil(·."" In thi s case.u. E nlemhepatie t)di n~ of dmp dirt'<.l\(' ill blood fluw inn l'.

... Bile @-----@ Elim ination of Drug and Metabolite Intestine .... lll.. a and. J!.. SI'l-'(JIJ(I.. .>rl. I to 2 m llmin 1' Portal Vei n . .l· lim e course of a dmg ill the bod)' (C hap .of urinary excretion is dt rectly proportion al to the plasma dmg couceutralion . Liver Flit.. it IllIISt he polar....l ."..'n inlr-<ti.t to .. Factors th at inllueuce ren al clearance include plasma dmg concentration ( SI..apparent P 0 «JII S as well as lipophilic nature of hilt· cannaliculae..(' and T inu.r i'll·."(' C hap. d istal tubule...Iil('. and have 1Il01 111ar wl'ights t'x("('('{ling 300 WIlIO](' . RENAL ClIARANCI \ \1 11'T1 tilt' ran.11.Dependencies )... . nnd un-lon br-d compounds.·"1 u { . 111l' ~loll1e m l m receives hlood 6rst and filters abo ut 120 m L of plasm a water each mtnute. n·.. 1b ·I..1~ ' tlm"..&lk l. 111l' latt e r two requirements may 1)(' <I ( 'o ll!O(·f lll(·!lt"(' o f tln. " 1..-.l"'-p. Thi s constancy forms th e b.>rilfod (".. 1.. II-i).nl. How {"( d thes e Factors illllut'I1 ' n -nal clearance is explaine by the 'U1atomy am i pll)'Si(}I~· o f th e kidnevs. u has lltKIc·rxun.'OIt{"(1: i ll~ tubule ..01. <"0 " . .!tf.ri). "....P<L\ SI... Both nonpolar um] small mok-cuh-s mOl)' lit' reabsorbed.T1inlt (. @ . b ses. a mt1a1". onl)... II ~. .~1(J llIt'ml us.llIl" uronidl' conjngutes of dnl~s an. 111 filtran .. . W'crf'I".·n· trrut"'P"lk t)t1inK in It.. \\ "h<-n a (In'l( Ill) j.•dOOR I "'. Basic l 'OIllPOlll'lII S a rt" tlu. ioni/"('lI..b ("' irKI.*. @I ..I..\.. t"( 111t')' are ofh 'n I li~h l)' dt'art'li into bill'.h_lril"'lk"" SimiLr.PTH 11 ELMINATlON '69 Int'l:hanisms t'~i st for ad ds..m · inl...-n1. 111t'S(' arguments do not aid ill prl'llil1in"..\t of the water is reabsorbed. but till')' do aid in pn. last. . . .1 in hilo. aI"". 1In h iI.. uri ne fl ow. (". am i urine I' ll . ...... II. tilt' nature and spl'dfid t)' o f the St-'{'r(·tmy mechanism s. 1>0<..>Iii.. ami (.po tu.1".. ' t1il1inR tilt' likdihood of a h i~ll biliary clearance . .J (".Inl .o rf..l~i s 19 for th e use o f urine data to determine tl. ~ I o.) UlKk·f'Io:'''. tn drul( in tho. h lp of Henle..c t-t..1 (da.." ... its molecular wt' i~h t must exceed 250 W innie..n. p roximal tubule . m"'... plasma protein binding. The Nephron: Anatomy and fundion 1111' basic ana to mic un it of n-eal funct ion is tilt' nephron (Fig.1 " ·..li....'. 22. Rote 01 excretion • Cl II • C n-nal clearance is constant. 3 ). .. For example. Iuterp n -tation o f uri ne Lllt<l with respect to plasma concentrauou is clearly complicated for drugs whose ren al clearuuce varies . t n a droR is mnwrt..' S down th e rubuh-. I'M about 3..h. ( M) thai I...1 lUTl l. 1 dn' l: i...

(' firs t h m p n )(. 11.uKI Fun..1ing d l. llfi.. .1 L or h lucxl P" minute ~cx's to till' kidneys. ng lilt' glomerulu s.... illld n-absorptton..w.. n . Rote 01 _ I _ F [ R 01 ote Excretion I RI Role of Filtration + Secretion I 20 when.... insulin unr] my{)~lolm lin .s t1m m~h tln. "it) · p ..· KM " StT1K1un· ' It.. ~lo lllt' n1 l ns.110 CHAol'lU 11 1 ('01\\-' tIll' kidneys as urtuc... or 1.... ..SOIllU' 111000:1 p t · rfU stOS both p mxinml and d istal po rt ions o f tilt' tubule lh n mgh a w rit'S of inh'rt''Onm'<.. mcent r auou is doS(' 10 Ihat in Glomerulus Proximal Tubule Venous Return . y"rk ( ~ftJnl Unn. ..: n . II . lumen luck into tlu..· fund"' . ..ss Involves till' movement of d m g (mill th. l oop 01 »> Henle 11_1. . rlu.fr action reabsorb fm m the 11I1IIl'1I..·1 us loo k li t eac h p n ll't'Ss in 11In! .(' Sst-'S add d m g to tht· p roximal part o f 11ll' IUIllt' 1I of tl l(' I\eph n m. " -\ . \M....\\"... N in 1I...U1I1C 'k Aplll-'ar.11)..u.... tIll' ' last pro(.sk'\"t· with ease..bloodstn-am .· . 1..J fmm Smith. 11 .• Ill'! n-sult of filtrattou.FA is tlu. A schematic n-p resentatiou uf Iht'S(' ed pn M :'t'SS(:'s andtheir approximate lo cation in till' ne phron art' gi\"t'll in Fig.~ <... Glomerular Filtrcrtion App mximately 20 to 25% o r ca rdiac outp ut..! . or this volume.... · ... and ('\ "(' U for smal l p mlt'ins SIl('il a..'. Small molecules (moh-oular w eigbt les s than 21)()O Wlllole) pa-. • 111t' exen-tkiu mil' is.Jth 11I.l!mni<:>o! .nlt rafiltrate (....Ul<" · of dmg in tilt" urine is th...'Jl:... about 10% is filtered at tilt.. S . O il ]ea\."'". Iif. t1wrt'(on-'.... 11l'> 1 ) M' . S(-'o:: rt' IiUII ..'.·.. tln.

.).ht of tilt" protemexceeds 211. Si lll"t" n-ual d .fu' G FR ' C ole If a t l m~ ts only filtl'R'l1 aml all filten-d tlmg is e X ll"'{ l Into 1111' urine.... -1-.rano of lilt' unbound to total plasma drug ronceutration: therefore.." .... Only \\'11t'1I tilt" molecular \\l"1)?.. 120 m lJmin in a in-kg 20->l'lu -oltlmitn . '.I..tUbU le .i i "~.-1). It fnllnws tha t Role of filtralion . R<-. 10..-brn rT1"'lC..al t"I.. ...dl~· ' Il'n..~ I... unly unl xmnd d m g in pl...10...d'.ting .IMk) " WIIlO is 1I0nnally fOlllK I ill till' nltn lfiltnlh'."{)n lillgly... as tlu.. hy de finition is 22 til(' rollI' o f CL _ R pto~ Role of excretion concenlJolion 23 it follows Ihit! for snd l it tlmg its n-ual ek-arance (hy flI tr.-pi.l... II--'l . c t./{.Io.. I(Ic. s1rit.. G f H.l~lI\a water (coneent rutkm e ll ) is filten-d (Sl"(' Tabk.II . .. Tt"li.".i"w1IUh.. TIl l' l'xtr. n ul' I" 1I.GFR ' Cu 21 Ht'l..i...".. This follows b cause e FI g ..I . 11111111> no al bumin [molecular \\"{"i ~lIt 69.... i...t.. TIlt' ran.u. .('11 if th e d rug is tOlally unbound in blood ( e ll = C. hnk-ed.. us it ge..-MiIllU'. ".ldion ratio of such a d m ~ is IO'\\'.. is t"{)nH' ntilillally calk-d thl' ~lo lIll' OI la r filtration rat e.. tln-n I're exen-rion is tilt' rail ' (If Iiltratiou. \..!..Filtration Proximal tubule noophlUfl ~' filt.f 11M 0 1' ' pri m.i . 1111hal jil is tlu.'It tl.j -Active reabsorption Loop of Henle Passive reabsorption Distal tubule Co\\ec. t'\.. .C HAPlH 11 ElMINATlON 171 plasma ( st"(.tm(>(illll ratio is still only U.10.....nlpt ic •.....' "~ lo II. Talllt' 11--6).Secretion .. 1 1 1 M h""....".....it.11 ..aI""'l'tit'" 'I('"'" .J. . For example.lkk) tint's filtmt iun £111 ofT sharply.ttioll) is [u ' G f R. l ". Glome rulus ..at whid l ph~lIlit wa ter is filtered..wntl mk-..n in tl pr'lO. Ae(. . A. pnw m..binding: o f mllst drugs in !P) plasma is to ulluuuiu or otln-r protcms of similar or lJiglll' r mok-cnlar W{'i~tlt . . IIII' l°:l. 1 R of fi llJolion .." .. fo"iltl>ll itMI ' 1('- n..

db t. exc ellent sub stra tes for tllt' S('('n' tol) ' sptt'm that tlwy an ' \it1ually completely removed from blood \\itllin th e tilllt' th ey art' in luntad \\ith tl\(' ilt1i\'(· tr.1J at:tin>.1aily if d n 'g: is highly ho und within blood. Al'('()rdill~ly .of hltrat ton n (/u .located p rcdcmtnantly in tltl' proximal tubule . -ith pt·rfusioll is t'~)( '(1('t1 under tltt·S(· circumstances .trt-c of spt'(ifidt)'. am i inscnsitlvc 10 cI lall ~l's in """ 11<11 hluotl H ow.h substance is exen-ted into the u n lit'.i th t'adl otlw r. and all the filteredload of ( ' ll(.s are sud . Reabsorptioll Heah St.. n · C ) t'XI'('l.(·ft·IOl)' pnx'('ss. t. hut as shown ab ove. As expect ed.·t·u w!lt'n tltt'}' an' hound to plll~ma p m teins o r l(x" '(l in h l(KKI l1·lIs. however. it follows that c1t'a rdlll'(od ill' tu sec rencu. Ht·ahSt.S Iln. T he !i('(rd Ol pmt'('sse s ' ) an. Under normal conditions.'. or C. tllis con tact time is Insuffich-nt to transport much d m g iuto the IIlIlWIl..i deutly disSlxiation of tllt· d m ~-p rolt-i ll (1)ll1p lt·X aml mH\l' lI1t'llt of d m~ out of til(' hl(KXI <.(· h\' filtmtio n .·S . Flgun.. Furtln-rtuore. suhs taul.. va rit·t)' of sullsliUlI. p Blo(xi r(·sidt·s at till' proximal Sf'('rt·t0l) ' sues for app mximatt' ly 30 $1'(' . must also he di rt'(11~' propo rtional to / II . these tra nspo rt sys tems appt'ar to lack a hi ~h dt.(!s tilt' r an.influt'lll'(Oof protein bindi ng O il secret ion d epends O il tIl(' ('ffid t'Ill')' of tilt' secretion pnx"C-'Ss ami on the contact tune at tlll' S( '('n·tHI)· sites .. Al'(:(J n l in~l y. til(' t'xtfllt1ion mtio o f PAil is cit)$(' to 1.0..1 s lIow . Silll't' tilt' rate o f se-cret ion depends on the unbound d m~ cnucentratiou . Obviously.~ is suffid t·ntly mp id so a. III sudl ( ·il<. G). as t!t'Uloust ratt'tll ... Pam-alllinoltipp nril' add (PA H ) is handl ed in th is lTIiUHlef and is not rPabS(Ir!)(>(1. . St'l'rt't io n r... is nett hcr hound to plasm a p r oteins no r secreted.IIlSport sitl-·. Jrl.('s tran sp orted hy tilt' sann.. 0\\. Adive Seallion Filt r ation alwavs occurs.. Stated differently.. TIIl'S<-' conclu sions are sim ilar to tlUlS(. GFR. SOli\(' d m j!..' of GFR. C f R .'('II. lh(· renal clearance is a II W a. extraction of a tl nJ~ Iw this un-chamsm alolle is 1 lospt'<. T!tt·ll.)'lltioll is th e thiftl fa<-1o r <-1)n t ftJll i ll~ tilt' rt'n al handling of d m~s . ammonium compounds ..(' is perfusion mtt·· lim ih'll. Examplt's of d m gs . O h\iously..mllll. tilt' su m of dt·ilr.. secrenou is ilppan 'nt wheu CI. AIt1ulIIj!. St'('rPtio ll is inft'T 'tl wllt'll ra n. tilt' dro in d m g roncent rutiou across the n 'wo ll is sma ll.172 EUMINATI()N CHAPTEl! 11 Extroction rene - Rote 01extraction R of pre s.lIlI'('S il-s_~()l'i alt't l wi th filtration (/11 • G FR) and seen-tiou. Furosemide is !t('Cn 'h'( l and is boum] to albumin. 0 11 1100 ml/min .1n~t· ..d litah 's extraction. obnum-d hy d i\id in~ rate of secretion by C. 120 ml/min . CII.f.9 supp orts till'S(' pn-dicnons fo r fum st' m idt· in an isolah 't! nat kidm')' pn-parution .11.' dra..y the \~idt.. plasm a info tilt· tuhnlar lumen.. c Protein Binding and Perfusktn Tl u.Ul('(· is a lIWil n n ' of n 'n al hl(KJl. Imm tilt. C Fn is rdilt i\"t·I~· .. the unp b ound concentration at tilt' sec retion silt' is alm ost ideutical to tlu.('S transported by tlWIII. Inulin .o f excretion (CI. In thi s p repa ration till' fract ion unbound could be varied o\'er a w-ide r..entotion ote = GF Cu R· Renal blood flow · Cb . Some rcabsorpt ion may still o vu r.n > Jrl . a n l'xogt' 1l0 1lS polys acc haride. no (:han/o!:t· ill n-nul d t·ar.unbound concentranon in p lasma ..lrpti oll mus t OI'(1lf if tilt' n 'n al d('amfl('(' is I('ss than tilt' l'iI!t. aml lw ul"C-' its ft'n al bl(Kxl d t·ar. \ \ 1lt'1l a d m g is S('Cr('h'(L hut poorly. ind mling: (I"a t(·mar~.tilhlt.~ to not limit th t' Sf. hut it m ust Ill· lt·ss th an secretion.llll'(· .2. is d ift'l1ly p ro portional to As va riat io n in renal blo od A t1IX' S uot l'iIlN ' im)' cha n/o!:t· ow in the plasma drug concentratlou. Jrl .. and al'('onlillgly. 'u for 11t' 'ltic eliminat io n..syste lll 1'UlIlpt't t· . tilt' extraction ratio o f such a t1 m ~ is J(""" .. ulI(lt'r tht'S(' drcm m ta JlI'('s.lalt'tl d t.i tlt a \"arit'I)' o f n 'n al extral'tion mlios an ' Iish>(1 in Tah lt' 11. Mt"Chanisms exis t for secn-ttng acids (all ium ) and bases (cations]. dea m l1l.

ly n-absorbed.. o 0.. iel ..2 0.. If 110 water is n-absorlx-d ill tilt' distal tubule. lipophilic 1Il0!('{11It·s It'nd to lx' t'xh'll sin.am ] (u U('(:ting ed tubules..... a. Ill iclt. ( A. drugs cou ceutrate in tlJ(' filtrate.(' if a drug is 1lI0s( I~' n 'ahsorll('(l. \\.lar . .6 ... fillt'n '(l water is n-absorlx-d ill till' p n l..' now and urine pll .U1t'S from bt'in ~ almost ahsent to ht'in~ virtu ally complete.st's across tlllJlllar un-ruhrunes. e Heebscrpuon " . 11-9.1ion " nhou nd.g.... 1. Con l ri h"hco" of ~". SO to 90 %.a] . it folluws that 5 C E u c :::J 4 E ~ • 3 FiX. ' enllSt'ljllf'ntly. Th us..'t is most dramanc wln-n n 'allScI'lllioll appmadws equilibrium. SOIll!' v-cretiou may still O 1Ir. " 1 .·"... th water reabso rption. are equal.--. Xormullv.'{'Uf'i for IImll)"t·ndogt·n ous compounds.1.(ISt'.'rt ainly.flow is I 10 2 ml Jmin or lower.. Urine flow can o nly han ' a sub stantial t. till" Iipoid ill mvmbrum-s of tilt' cells that fonn the Illhul(· ad as a bnrm-r to wOlll·r-soluhl(· ami ionized suhstances...IT''l.sscx..'(' ss.) : 0.rcabscrpuon o f water r filn-n-d at till' glollll' m ius. . polar molt'{11ll's dn not .. for th l' \11. hUI il 1I111s1 b less than reabsorption. Consequently. Till' Illajo ri~'. t:<.l\sin ' pn )(.. urine nllw b about 15 to 211mlJmill. n-ebsorption occu rs h)" a j)...: Dod oral diue rtalion..8 .1 "r . Al1:i\"(' n'al ~ so rption t)(. ind udin g vt ta nuus. its polari ty.III diff. UnMmty or Manchl:'<t.. C.' " E 0 ~ ~ ~ " ~ 0 . wtth approximatt'ly9H% water reab sorption.'s thr ough membranes. ell...fRl.lar Iih r.......-_. \ \ "dI N is n 'ahsnrll('(l to tilt· extent that urim .uKI lul". e. . Uri nt' F low lIml Prolein Bindin K. Thus .. equtltbnum is n '"dwtl whr-n the couceut ratiou in urint' and that unbound in p lasma..\t majority of t'llt~t'1I 01lS compounds . Heabso ptiou occurs all along till' nephron.l ic. In fa(1:... As wnh mall)' mem branes thnmghout the hod y. the (. Ih .... TIlt' dl~rt'{' of rcabsorpticu depends on til(' properti es o f lilt' d m g... (Hall. the concent ration ill the urine would be about 100 times as great as that unboun d in p lasm a.4 Fraction Unbound _ --_ 0. gIUl. G 2 ~ " ~ ~ {-It'.\ imal tu bult" ~t ost of rlu........· variabh-s such as urilit. and amino acids.nuK'" (al or run.remainder is n-absorb ill the distal tubuh. s i ll(~: Urine flow • Urine coocenlfation P1o.nt'itl lt'r rt'ah so rll('(l (gl'm' rally po lar) nor seen-ted. however. of tilt.'i~l l t .CHAPTE R 11 <C/ '/f < fil . ('.-e-n'h"" 1 10 II.. state of ionization.11 n'n.r.'n.ah'd with tlu. rea bsorp tion of wate r Ievors the reabsorption of a d rug that diITu.0 frar. and molecular wt. wlll'rt' urnn-How is con trolled . t'll'{1:ml)'tl~ .mo co ocenlfolion 24 ilIl d shu v e u = [u .."ly unbound dmg dilT u\t. if a tim!!: we-rt. S.ITt'{1 0 11 n-nal dt'<lfitlll. Reahsorptiou ulso dcp-uds O il ph)"siolo¢ <. 1. 1I0wl''I"('r.

it l! the nam ". Ac14l•••41 W_ COX. hy calculanou. C..11('11 u n lit" lIow is constan t..t' n inh ibitor. \\1Wll metab es olic addusis is of n-uu l ()ri~ n .. approaclu-s n-ual blood Row.1 W_.<t lllt ' as thai in 11K' plasma n.1 1I'S. p Ka less than 6.r. ill Table 11 --3 is l>iL'it't. C. Un ue pH is ahr-rcd hy diet. Equilibriu m (. b ecause uri ne p i I is never much h i ~l lI"r than plas ma p ll . It appe"l'S thaf rlurenal d ear. !JtlW("\"{'r.1ly p n llxlrt iuu. ~"-" _1 CI •• (_L / •••• " hlecte41 N_. tln-rcfo n -.. For weak adds and weak luea -s. thai equtllbrtum is "dlit"\'t't.\t low uri ne pll . Respirato!)' and nu-tabollc acklosls p r oduce s add ifi<.(lllt-'(1i ll~ tuhult" . rt'spt.5 thut n -uul ck-anmce of ak u hol is app mximatdy t'tlual to millt' /Iuw a nd..."4 Renol clea rance " CHlV' E1! 11 l' fu · Urine flow 2S Thls last f"(·latinmllip is it simple test of how du. if dr u g is highly bound to plasma p roteins. n'lla l dt'ar..I_.mt'(· \~tl ll(' can 1)(' o!ltniut'(l bY !>iL ssi\"(' lIIS...lk·u!atiolJ o f n 'na! d t·anml. "'" '" 01 02 10 1.4 24 64 10 4 . .LS the l'Olrho lli<' an h~l. whereas Ihat of all>' base cannot.llt'r l' till' lIlajo r d l a ll ~t ' ill p I! ( )( 't.ltliellt lIla~' exist betwee u ptLsma amI u rine.. n -uul ll d (' am IK" ..ing.plasma ronceutranon ratlo was calculated using ti n' Henderson-H asselbalch cquatlou (Chap. St. extrem e s of Urilll' p H art.rt••• V.also that n-ual ck-araucce w is tlin'<.41. CO IIM'<jl lt'lI l ly . It is unlikely... 0 0001 0 1 10 10 QO . D m~s s\l(:h ..) unde-r foro-d "t:id ifkalio n and · ' \ alkahntzat lou.5. aeetnzolamide.~ .. o f u comp oundthat is 1101 siW lifk-anlly bound to plasma pmh-ius a ud is n . til(' fr. urine p I! is all add itional factor a ITt'(.n i ll tt' rt"Sti ll~ ull'it'rvutio ll may 1)(' nmdl' " IJl U w('ak b..3 tu 7.lIl~t· (If plasma p ll . can 1)1' mu('h It-' s than llrill(' lIow ( I III Ij miu]. :"on. 2-4 ami 2.m('('ntm tion Il'a. a larw · p H gr..IIl<" · of SO liit' acids . .~. listl't l in T ahle 11. and thai ti lt' i0l1 i 1~ 't 1 fon n is not tlifT lIsih ll'. A B C "'" ""' 2 6' 10..l b etween nu -tomzed (I m~ in urine and plasma. the l-. gin'n that tILl'S(' compounds do not hind 10 plas ma proteins. d n 'w>.for thn'(' n 'aM till' d istal tuhu ll' and l.."t"n' calculuted usmg E(I' 24 . A dmg muyhave a re nal d t ' a nllll 't ' hduw this \ 1UlIt ' if iI is . urine is alkahnc...'l. First. .0 2 10 10 . urt_ pH U."ltinl\.1 iw ly n -absorbed.s and bases. ..u\('(' (ami extracnou mlio ) would l)t· exIrt'IIJt'ly small sinc II rine Ho is nor mally only I to 2 III IJ min. und n -spitu tory an ti metabolic alkalosis produc alkalilli7"ltio ll. which usually su ~('sh "ti in' sa-en non.~lIIltr1u. .. S). Rt'llal clearances o f s('\"('ml wt'ak add. ~ l un"( J\ t·r.h so rh('(!lo the extent thai its coucentruttou in uri ne is vi rt uallv till ' s. TIllis.\<. that such a hi ~h d f'll.r .1w n "- . tilt' kid lll')"S.. fo r example.. O n till' avr-rage.. ".'on"id~ral jml1l.t' mHo n f Urillt' l'lII<. ami till' d ink-Oil state of a patu-nt.i('!ioll of l'('nal l)lood flow that n '. urine p ll is d oS(' to fi3.. T ilt. p n khll't' a .' r. ..uka lilll' urin e.'t'ntmtiOlI to plasma t. The urine-to.' n-ahsorptiou is 10 equilihnum.. E G 1000 12 4 1000 3 10 10 09 03 03 " 3 . T he se extreuws contrast .0.lht.5 allli 7 . uri neflO lr dt'!'lt·lldt·nl .1c.'ti ll~ rea b sorption. 11-3."t:ti\"l'!y. It aiM) vuri es t1 u ri n ~ the day.1 011 Il. renal tu bular addos is.ld 1("s tilt' t' ml of d ifTusion. mtllt"r th an (' lI te ri n~. is SllliJ I. lm...1. it folluws From E' ls.'>C..'OIIt I..It... Urine pH . . Ethyl alcohol is an (·xalllpit.t! to fil.IrtIlt'Ss of uri ne How.L'it.41It1 .r V. 7.·1.

't1 ill Iht• IlIlII u..4 ... O n alkali lli 7j n~ tilt' u rine..·) In " U.it-\\. 2. TI l(' primary eonsldemtiou i~ hnw rap idly e-quilihrunn is appmadll'tl.t'tl lllt'th t' ("(' umplie-tamine (11M Ill ) that i.0 1 00001 " o. V...tt'tinll Iln-iolli:t . l\ 111 ral(' at which n -ahso rp lio ll occurs dep(·m ls 0 11 tln... the high \'llhw s of cak-ula n -d dc'amlln ' ap ply 10 Ih( ~· ha... III «'ality ..d m J!.I'Sl i n~ sodium h k~. 1.: ViiOWl)' ("U"trh<"..... ZtM'i :I2fit lo-.'s .ahility o f tilt" uu-touta . 15 C " E 0 ~ 2 -c 0 0 4 No pH Control lkallne Urine 'l! 7 608 2~ 8 12 16 Hours . f( ln ~oi ll V: d iS{ ssio ll W. n-abso rp uon shllu ld he C'l ms i dl..~J 2::.I_"" hlecte4 W_k AcleI_ ••11 W_1r: . "~Ii<:h dep"'lIlls Oil the coucentranou of un-lonbad drug. . as "'. hut Il<L ssin ' n -ahsorption ilia)' not app rual'11 t'tluililui um. :\ simila r af)..1. .I. .\!:· al non nal u nne I'll pmhahly SlIMt'Sb alii\'{' ~'(._ _ . 0 .ocos 3 W 7 10 0 .1 frn. n ° ak Ha llt' ll .(·ulll lllati \"(· amount of IIl1l'hallJ!.t~ 1 wln-n tilt' urine p ll is 1101 co nt rolled . thus the rail' of IIll J\ "t'II1 l'1I 1 th".lt'i(~1 U II t jn .l-\ St'l1 lald l ('t!llaliclIl (C hap... tl.'" conceutrut to n hen.lJ. I It.. (Ao Lopt. Thon lll lu1. uri.l' ll riRl" J_"rr h"" "r w ~ c 6 4 ~ ~ O i! E EE Acidic Urine (pH 4. Tln nl .1"1'''' (11 mil ur.' r('li ll" ..1<' I'll .<1".. UrI_ pM- ceo A ~ B "'~ .4 64 10 4 24 10 4 12 4 6. Tilt' ('fT " t o f u rine p I! 011 tln.. At" rtlin v.dd mg In (' di fT \(' ac ro ss memb ranes.L IliL primaril)" 011 ('(Iuilib'll S 'it"t! rium concepts.')'. \1 .. I I -t O.a"' p.. 11-4• .i rhn llatl' .otr. T he 3 calcnlanou i.11" 1' "1. its pnJ. Til t..lI ~h rlu.JI1('mhr-..\I. a n-nal dt'i mlllel ' n thll" j:!. A Ra' r P NJ('('1I11 ill Rl!ality. A t-lI.. ..\11 .. ( 111)."i ll"· in frulIl .." truefor ab sorpuon of d rug s [rrnn tln....s listt~ 1 in T allll' 11.0 100 97 0.Il t'u dl'N lIl-II .. I to 2'1 o f lilt' doSt:· is in ..t'l1 for tjn.Ill.-.0001 10 . 11.01 W C E F 100 W 0 Bo~ 50 100 100 50 0 .9-5. particularly wh e n the ex tr action rat io o f till' dmg is hi~h -a I'w rfllsiull rdte· limilt"tl u llld ilion .• by illV..n~ 1 From 11 khw tk rather than From all t'llu ili!Jrilllll plliut n f ..sauu. alld Ihl' fr. I I .lrit)'.3 0 .'i t'xl· rt 'h~l ill tlll' urine .\Crt"l("(l lI lId mll J!.' 11 ill T able 11--1. ... Aft('r 161m. 9 ).003 G ~ ~ u x t"l1l.is SIIO" l l iu Fig. aho lll 16% o f tilt' tloS(· is t-.' an' ~ \l.0 . The pt' r('('lIla!{t's IIIl·ioui1.U .3) ""1. thr-n...n.I_ _ . whit-II al hl ul K! Jill v alues n-nd tn Iw almost co mpletely iOll i7A:"(1. l."". 12fi 1..n ". 1'1 ).is I. G FH for ('itlw ( 0 11 ad d IIr a (:n 1I0 11S ha." I\<'(·krt l ..rt'alt' r tha n jr. 1 \lfi.ttl.'ll lllt"1l1 appli~ to \\"('ak ad&•.riM 1 " .U1c..1 ".-L. (-.i'M·lic:" flf nIt1 h~i.'i l ). 1'..rI__ V. . is n -due -d.~ . U• •I.F:< lm inlt-sti llal tract (C hap. ·ss thau Ihal ('ll h'rill ~ tilt' kitlllt·ys. .

At 11ll' ol l.\t In". both {'Ill ilihrilllll .. for th is . IIlt'lhilllllJ!lt'la m irlt') 'Olrit'!l ma rl.tn ' pnl\idt 't l l~' Solli(.Ki d .lm p lt·. (lJl till' l'xll'1I1 IIf n· alN:'rpt iu lI.... t'!'lll. II n nt · p l l varies t1lrnll~t.'\ fnlluw.L ~illa a I)M vahn..• su mmanzcd . ils n"1<1 d t'ar1 am.'tl...·lIm·utl ..u f n-al.5 i. a H' f)' wl'ak ad d \\ilh a I... ami 1.· l'(llIl rihlltin~ of 1111 ' WII"I " Hilt' In tot al t'liminafju!I.. (·'I)('(1I.. roltt' . ill !!t·lll'roll.1 i ' I · ~· Iroln'\purtl't l... and tl l(' auIIK·llllinlit' ..Iar IIOIlIM ..p i I 1 1t '(~..\ (' ilIJi.O.!y iOlli.p ll Furthe-rmore. Ic '(n·a..'(·r.I.'j( tl} is t·\ (n-It.lautiai d. all ill('n 'aw ill I' ll ('.\....:1al m' atl llrim ' p l l . at.i d wll"\t' fl 1Vl lk.'] ti m! fu r ..aliull in lilt' urtm-. \I ll'll a' pll t·II)11Iill..·a r'III('t· is ~"'I U' m lly I... (1\\' 3.ll.. t'l illilih rill lll fa\'(n~ n'.....11 or Ill·lIM'. ad lL an ' .. nit. !!u .. ~i l " '1 p Ka IIt·t\\.'t· is im k·· IIt'nd.' t.nent of (I nl~ in tI......orpt iu n.g..lIl('t· t·xl)('(1I.. lIIllol II(' iIKT(·a.Ka Ullm· IN·flu ·. wh il..ll..lI IIII' dnl~ n-skk-s ill Ih(' nephron.io ni7'(.". .llinll II\' i ll:l:l'Sti ll~ anunoniu m (·hln rid. ..!!li¢ hlt· 10 allllmi ('t)lIIpll'f!' <t" l' lililmlliu lI) ~il " dl.lInil~~'{.111...tU . n-u dl'"rdI K'I ' of . l'u fTirit'nt 10 han' no Iimitin!! 1 A ·1T1'(1 11I1 its ran.... atu] tI. i.:1 I h n JU ~IIolll till' ra ll!!I' of 110 m ' pi I.· u f nonpol... n1!an ll. -' Fllr .rptioll tlM-an l ' l·n t.Ip ply til wt 'ak ad d. 1I11\ '..· tll").1" . n '!lI)('(1in .."t nf urtue p ll 01 11(1 gt·ll('r... !lJ('n·a'\{.f nn pi I contr ol.1 il' pu!' lr ill ih III1-iu lli7A't1 fonn jl' nol n -ah.L ly. A('('t)nlill~Y.appRiadlillK 12 ur Kn· ah· r. I. l lIill li lt' lillK' Ih..(.m" I"\ in I1OIK ' pll .0 ". . 111....K1nr uf 2.~" uf urim. I..176 OW'TE f 11 1111" un ne.. n 'a lN:.rim ' p ll . ..lIK·dlilliIW.Ka \'a hll' ahll\'(' N. li(· add . n 'nal d l·.lh~ lrption . n pnlk '!'l' of Its .r t' \ t n 'III('.u f Il"alxorpt iu n .uMfioll fur t1w<. !!I·lll·rolll.. t h a Wt·"h·r pt'n't'lIt uf tln l!! un iu ni:fA't1 ill tilt' tubule..It")!:n.st·mili\1· n 'al N:)l'plillu ... .'tIR· 11-1 2 'IN' ..u rll('tl lt·s" and I. .l'l lly \\i th UOIlt· p ll . t·'pl.1 ha. Tl w n ·n.... whn~.:!.!. can II.ithil)· ill n 'ual dt·amlln. 3 .ang('!' ill renal dt'<lrdIX't" an ' sald In ht· p ll ..• litt l.U tl lt'. i.'(·n ·II'(1 U n '.•1I.llN:lrlM'(1 011 Illl(llMlurilK' tlo\\'...0 aw l • . t'111'II'\iH'I)' n ·a1N:ln lt-d al al l va hn -s of uri ne.\k· nonpolar dnl~.. III.11t· p H ~. !Jutl . midn i.'Uy if 11.-aric·s fmlll IIt. .l. I I-II ).• '\ul)l.. 111 1\ ' p ll . h<t. i tll a \111 o f 2..(' oh'ot'r... ' h alwa) 'S 1 alld ill ·II.dfl't1 Clf Unlit' p l l111I IIIl' n 'ah"iflrptioll ufh.(1..L'\ic lInl ~.. I...aH·lalw ·r n 'lIal dl ·ar.t t't"t All ad d \..'ry ' in till' urim...ln ).JM 3 ( FiJ:.rp tiu n i.141 12. fo r adds. hul n 'lIal d ('ar. ~·Il la . . I II pi.· of iun i:f.' addifil'. 6.·\ 'I·r.· n -sults in 70 10 Mt% rt"'l t". \\'I·aL.. tL <llId lJa 1" .Clt·arly. its n -nal (·k·a r. .2 and 11-3.ut k ul ar ..'t·1I 3 and 7.1IIt! killd iC' ('tlllsidt ' m !in lls (anl T hi ~t. Fu r a ..:1 and ..im pl...UII.KIt.\ p m ' Ill)\:)l)" t·lll'.: . 1>. ' i()lI i7~ltil)lI .t'Ct ( 'O I K 't"ll t r d l ioli in n -n. 'nit' n 'lIa l d ('a m ll('t' of slId l a d nl~ (to.. . \II ("l)lI1 p lt·tt .. · II .UI\I'" Ulli n. IMM' IInw . Al h i¢1 1II. til(" p...·.~K· d m~ of al 11M Ill . ·.I. h 1111 11)' lIu-in ni:f. ('tluilihriulII am i ra te ('Umillt'rdtiom (a'l lr n -a bsorpeion. 11111 . .0 IIr II·ss... .· I'M b an MUlti 6 .. ewn-non o f md halll phdamilH. 2....ulI l lilt' .ili'o'· tl) p lL Dill)' for a lIullpul<lr a(....t. ) 1II'l:fillt'. unue pit is importan t ill dl·lt·n ll in i ll lo: th..1 1111. \' Tlu.l' 12 .·al. h .~ ..uK't" (.Im~. ('... \II .. ·n. I)nl~ tl ldl . tlifTu'\ih l. Inm!! b.' ·111 III1.h'nsiH· Ihat it lilllil'\ tilt' ran.ly.1(.lr wt'a k add.L \\i tl l a 11M 1 1l '1~ 1 't ' f1 6 :tlld .. ..urh.. UriUI ' pll .(~ <ll lli!!lll' r .l lIrim · fl.l lly hi ~lt . A!!aill. \I.uK't" is ilHk·pt·nd(·nl n f Unll(' p l f... IlM 10 (T<thl(· 11-51.. T Il(' p rind pll's d(·\l'!op('(1 for w('a l. tl\l' t·lT uf I'M on n ·ah.~ IJf1 u '('j".. A \t'ry Wt·OIl1)· IJa..la supportin!! till' t·'I)(.:1in!! T abl.•.I II)· IIlIm ' Ihall a f.d d t'.. Noh ' in 'Llh l.. ti lt' t'lh'lIf of n ·ah.11k'" n'llal dt·amlt('t· is d lall!!t'tI IJ)' unlit· fI( I\\' (It' )('m l. nlll l.• ull-jo lli:f 't1 form i.. dmll lll ~lyd(' add .1 an d 11..:1('(lurill(· p ll !o(·II......• drug i...L\I·s <I1"CI . '\11t·1I .k lIollpoLlr tlnl!! "..J. h i ~hl)' bound tn pla"lIla pRll t·ins .......r. Unde-r ('o m litium (.'\it· (ImJt th. ./'A . If 5l )ll of Ihat 6Ih·n. such a....:lth m llgho1l1 til(' mll~I ' (If unlit' p H hl":'allliC' ionizanou i."\ \ (lc'pl'm lt'lIn " A!o!:..mIlK't' of l'1l(:h a dnl~ lIlay vary with UO nt· pH hut its ' 1dm ' il' Illw..II ...."-"'· to ...11 .a lll' ·s that it i. n 'II01I d('arollK. lin 1". Cu ll." IK't· tilt" llu -inn il.-aliolls is coutaim-d ill Tabk-s 11.\ h. . The ..rp tillli ..lil·t1I k'..· n r 110 n·aIKl.·II'\ilhl·. ('l illilihrilllll fa\1I1"'\ n·"hso IVtio ll.at tl lt'n" is li"w opportu llity fo r n 'a"~1I1lt illll " ..1I0t n ·ah "C lrll(·t!: ils rl' lIal d ..... r(·'lh ..i ~" alltl iU\I'm i!in ' In I' ll. Fij..:1 to hi ' p l l \t 'IIl'iti\l·.. \ n 'f'" k .·.· lIu(1 \1d l l "!lo '1('t'l JR li ll ~I)·.lII(..5 :IlId nonpolar ~..·s 11.lIIvt io n is '\1":'11 hy iu"pl.." is ~ l small tt.

1 1 .) '-' c '" .c. uri".... ~l . . ".... Ttlt·r.. ..'-'.1..2. (.. io..'J 7:21.t:o ""' "I\i><a'pMoI"...lio. . "' ~ ~ - 4 • • •• • • •• • 0 • • • 0 4 8 12 Uri ne F (mUminl low 16 .. .M· 6.~ 1.5 .WoI'lATI()N 171 250 • 200 • I 1. lUtt.. (1t<"lr""l ' r. " i tl. <in-k-s l. h "........ Ch.rIHI.. Tt. ..· I'll " I.Il.· Iw'.. 198 1 12 ~ ..... Sh.tm . ..l'n ·u. 1946."rt. 11_12..S (A...'04 t:~p. of ..11 . II I..·•... _I a.".'......I B ri~. 7..·k..ttt..... 1 Smitl.. 1. a.G. Uri.._IN• ."".ll'p lie" hlln in 1 104rhitllllll.tI tl.ltI.diull (hi.2 c 0 ~ Q.G. Ih""t albiitlil..1 rl· . I. ..1 • •• o 5.. R. ~""" 86 38 0 10 t"".LtI'h'< fn.. Lant...I (~"" ...l.. . "ill.'). "..... . pH· Not coonolled r-6 3f Ac. 1007.. : ~1 . Urill<' iteM' in I'WlI.. L ' intOil.1... S... > 7...... " 'ill.lI . ..! .:!.. <rod Woifd... Sta ll . unb...../ w1ie::o-lk: • d i' llTU .tI.5 • 6 6... tlr (.1 dn-lt.1 d ".5 Urine pH 8 8. . 2:37i ~WI. . -lott"S J 11""0 ".CHAPTH II El. •d .0 f" "d ielf' uf Uril1l' lIl t " . h (l ." ""." i1..1. . I'. <55 Alkolme.. .lty" DI. .5 """'''' .oli.... oJ.. G h i A '" ~ v ~ ~" Onnt.. . .. It. .ninll:.. • • / Iw.K..lk.noou '" cloo. M l E . S A I!o...." lIIbli lli.·•• w>art 'ilal . poi.5 '.1r""'"t k .I..If"'ll" . ...' .c ~ 8 • 15 g ~ ~::> E E t·I!t. ". 1l 1I * IIl.I it. I I _ II .() .I . .oi'o...IIl.t.5 •• • 7.'1.~I... .u1l. .J Clol FlvI'"<>Cd I] 1101--8 12 ... e.... It i. .....

1I I1i{L~ and .-)tusis and uu-tabohzcd then. tilt' kid ney is a. I II(: r( '. of tln. Gt'lJ' ' emily.. yet !itt lt.renal clearance of plll' lloharhilal (" Kit • .b}'lyso wmal t' IlI. of till'S(' an' Ilsllall~' found in urine. C hap. Ht'lml excretion under condmons o f (nn:'t'(1 <Iinn'sis mu st 1)( '("1111 1(" tilt' majo r route of dmg eluntuanou. 111 converse app lies In tln. As SIl()\\11 in Tahlt.lumen. Fo~"(1 Diuresis a nd Urine pH ('. 11-6. The amino ad ds an ' then (. if 1I0t tke. Ill(' ewn-tiou r an.' for tilt' P U '1)(IM' of dd(}xif~i ll g a pal ient who is overdosed. Ill. m il Incn-aw the excretion of some dru gs. l!l'lTI~'."( 'ular \\'('ighl. Several criteria must ' ''-' TIle! for fOR.000 OOOl e .}1111'S 1 .'simhl. o n alkalini7j llg tilt.cases. SUPIX)S(' thut. b oth fom-d diu n-sts and p ll control ilia)' he of vulue. 23 ).can unlv lit. " Renal HandGng af Pratein Dng.L~"( 1 u rim."I CHAPTEI1 11 shows how tln.ITt' n-latr-d to am i dt'llt'ml.".' I!lO!l.('ll dum-sis \\ill he of lild .L~ well as urine H ow-rate <1('1)('11<1. I lwn'ao.anul('t' normally is on l~' 1% of fotal g dl' anUI (.m hormone 0. it aplx'ars that for sonu.QOO 0 8Q 0 75 0 72 Superox~ di~lJlo~ 20.dand seen-ted. Pt'n mps the most Iuudann-ntal dt1lt'lIdt'lIl')' ill cltnk-al lATWUVn CON:::f Nl V TJ:)N fVo9M.2 ) va ru-s wit h u rim.culatun-.000 0 33b 008 Beocepo" A1bvmin eo. TIlt' last point b ears further discussion.'111. tilt' re nal clearance of this d m~ is p l l M'lIsit in ' . CONC INTUT lQN InloUlin Myoglobuln i Grov.tlow by fnrt"l:'tl intal .f of Illal Iilte-n. fllf ('xamplt'.Si"A of alhum in an ' transporte-d tnt o tilt' s ' pmximal tubular ed ls I ~' t' lIdo.proteins. DEPENDENCE DF ElIMINATlDN KINETICS DN ClEARANCE AHD DISTRIBUTlDN 111(' physiol~' o f tilt' Ixltly d il'lal('s Illat several plmrma<.(' .."\' lIlol. uri ne.\IS( ' u f p I! ('(JIIlml wlu-n fUR't'11 e diun-sls almost l'tllllplt'h. More rapid cltnunanou is.'n l Oil 0111' another. d. p rott'ills an ' subslantially filtered in the gim llt·m llls.000 32.1('(1.}'llll'S. does htth: 10 hasten d r u e1imhmlion [rom 111l' hod)' if renal e1t'...' addi tional \"01111I' .(11Iur wt'ight prctetus an ' Il1t·laholiJ'.'t't1 d iur esis to b of value: e 1. 111is applies if forced dilln'sis or pl t control alonl' o nly pa rtia lly pn-wnts n-ahsorplion ..000 16. i n ~ lhe renal dt'amll( t' of a d m~ Ill-fold.'lIkilld it: panllnd t'rs .l'11 by t'1I1. of ( llll N'.' Disease. 111l' lltklilioll of fon . 11lis low ren al c k-ara uce o f proteins ari ses Irorn t heir metabolism in rln.111'1) ill tht' lmrsh b rder (If tln. C hap. I" . 0(' o WIll'n'ILS high mol ecular weight pm lein. Althou gt.coad m lntstrutiouof mannitol or another diuretic. 111t' compound must normally bt· t·xknsin ·ly n-ubsorlx-d ill till' n-nal tulurk-.Ilow . ly PTt \'t-'1I1s n-ubsorption. As ex{X't. ('alaho lism of p mlt-ills continues until tilt' const uueut am ino ad d s are formed. T urnover COIl("('pts.. If till' n 'ahso rpt ioll ts p I! sl' nsili\"t'. ljllaTllilati\'1' ~ data art' spa rst'. till' n-absorpuou (If II weak add is decn-ased from un to )( )<. espt"(-jall~' l c .· of . rln.'!. majo r O~lI ll of elmunanou ( St.. in sorm .u llin)!.. 2. .proxuual tubule. and prtlhah l~' also p rotein dmj.ooo 44 . tucre ascd by a furthe r 10%. 3.'t I!lS( ' T\1'1 1 h)' rea bso rp tion into till' \ 1L.

Vu · Cu ~ ()tt .. On th e othe r hand ..J11\Ul1l1IS a. by tldi uil ioll.. HaN-life In Blood and Plasma Wert" 111(' interrelationship s t'\ p Tt's 'it'i1in Eqs. hy dt 'i 'n 'll-sillg d l'amnt't ' \\i lhoutltlTt'di ng distributio n. an' just llS n 'ad ily deriv from d t'a mll("(' ed t't s('i1 O il meusun-uu-uts of dOl~ ill h llll.t{ II.llIi. Cl b • Cb .' thll ll~hl of . or til \ ' and el.\ily dusi n ~ .tIIst' clearance is Iht' volunu.~ complete t'nlt 'mllt'patk t~l.Tlu-n..s a n-sult of slllw intest inal reubsorptjou.u .' It dt "l.'n 'lL S('(1 voluun.u IIU' ehmination mit' constant (i.tional rate of drug (·Iimina tion ). Rale of elimination Cl Amount in body .is a paudty o f dOl ~ c-conples \\ilh these characte-ristics .Jn. 3 th. 111is Haff-lift in pJasmo Hecall from Ch ap . Rore of eliminction . \ \ 'ln-n d l'am llt'(' is 1 ami \"(111I1I1t' o f d ist nbunon is Iltr'J.of distrtlurtio n.e.11 in plasma. 0 11 (t nta]) d t'amll(. Furtln-nno n -.CHAPTn I I E1r. \\1I 111t1 the n cause the half-life 10 iIWTeaS('. BiliitTy nhslOlt1ioll .d t'!)('ndt'Ilt'(.ult't' and \' IIII IIl(' of distrthution. ami vulunu.. Furthermore.1J. CL 27 Tn appreciate tlu.of dis tribution.te-rm can 1M n-lated to tilt' othe r using: the dehni tinllS ' . k . and therefore a sho rter lndf -bfc..llpy at a t'tlllt't·nlralioll ("{pia l to Ih. t't lllsid('r a dmlot thai u lJ(le r'J. Cl ' C .'t' and vnlu lilt' flf d ist ribution .693 V -..L · slIlil ck-un-d of dm~ pt'r unit n f lilllt' ami \' is tluvnl u uu. \ '. s d('P"'Ill]('IK'Y is d('ri n"tl . it is ap pare nt g Fnun El l. V " C .. 11 lis is not s ll rpri s i n ~. Clu · Cu 28 am i Amount in body . n-cnll that lIalf-lift·.H.) oT in p laxma and " . Vb " Cb .MI (Cl . t"lJlist'flllt'lIt"l' (If hililU) ohst m t1iol\ wn ultl Ill. water (CI.. 29 th at each dl'ar. if there is no t'll!t'ro llt'p:t1ic (} \'Iinlot. " .. 26 and 2.. V 26 Bt'(.· t·xh'1\sh'(.13 illu strates hal f-Ii\" (If dOl~s wi th cu rious ('(l1nhi na tions o f d t'ar.lion of t' tilt' volume of d islrihillilln From whit'h d n l~ is T lIlll\"t"t1 pl 'T unil tiuu -. fr.. tilt' hil(' am i tilt' intl'slim's an' not P:lrt of the \'o tUIIU' of di stri h U!ioll. Thu s....L~ fo llows .t{" tlu. Cl.lu fTlt' par.LS tilt' fm(. hy the exp res ston k .!lalf1Iw life can Ill.' 11. is n-lated 10 tc .1II1 t'TS II<L ". is n-lnn-d to total ch-arauce.' wee-ks o r montha. as d nL~ acc umnlut ion wnukl Ill.·l i Tl~ ~l' l di strilllllt'S to hil t' and subsefllWlllly to tilt' intes tines in s i ~1\ illt"llll t . "rd .MlNATION "9 phamlat'tlkillt'li<: is that of half-lift. t"s Fil-. of half-lift' on d t'ar.mt't ' o r volunu.of pl.. 26 thai fmt1icmul mit' o f t1m~ r-lnninunou can Ill. Ihmtl ~h th t' ( 'X pl"\'Ssio lls - 0. hul no t:h all ~t' in lotal elea raru-e. t l !\!.that dru apP"'ars to {1("i. 111t. rk-toxifi canon o f a patient who exlublts toxidty while nil such a t101 ~ wu nlt! Ill' slow without intervention.693 0. and occu r s1nwly 0 1\ t1.'t' ami '1111l 1l1t' n f dlstnbunon .

.. .oI." .· " 1 r r"'1i<-..1 Ie"". . \ 1' l . II 1 " :lll 1>o..u"ol...' ....un_ ni. "" [u .}1Ii 'w If> .Inll(1I"'r"l':" (A...rp"''''al ln':). I~ I U.."...1.. l'r" I'. T :'\ .. n " ' '1.....t r. ~ "I<" 110.o'HI \~~ " nw will. n" · \b"~ " ll4r . " ' ~ ( » .. I"l nhu ticm (.. ..1 1 " " . ........-o . l) iov l ). ( ..· W" rfari ll .rtril..I..(IM n). tI.'Il~· (" n lm.lI" a I '.."'IIa1J. = e ll IC!>' For cxnmpl••.. 1 rtIl..111.... ic..1fru "...."..j>l. 1 1. I) ll:illl." 1 h~·Il"' l rnm' l"...llf...iolo ·I~·."'.'1' " tl<'l1 10"'1: fur ..' ·III."II.: I)ij...A1.. ll.u ".k ' t" 1.-rv i. (:. \1 . in I I ( :Io I" ra" 'I'I"·lIit. "'-1.. C I. ..i tl.IP" Jit.1 l"'hli..' f"II..I m~ .. T" II.. r ...1n r . ) . .." .: C'''K''l-pl...I.•...In' l:' "no . nvJol.."' l. .1 . 1' . it follows t h aI '0 • 2' 22 •• 23 20 • '9 100 • 30 • ' 000 10... .tr.lt"· '" . .'I. S" lfa"...1 0.lt I" lin...· \I I'ro ll·.. · It..".. n lt·•.d. 13. "'" d .:w li' ''· (... ( :I.. II...l..· ".lnllll " f I{r"r>l.. · 2\ .m ... :26.. r".i d.·" id ll".. 1l1!j.Iiffi<. Lt" n. dtl h .. \ ·. r: 1-1 :\ "..h.Ol' .... .. " ' 1'l" ..d 22 :'\ "rtri l~ li"..-m'l.lml«l<> I. 1.lLot.·t:fin ' term ill E..1t1rup . 1 1".·) "".l<. ~..l n<'lI<".1...10..Ull"l'" .".h "....IIIIII<· ... 17 s lllfi.I .-!tar. k _ flMNATION CHAf'TE ~ 11 I II "" Gil l e illldji'j.) n . n i \i tlill ~ each tcrru ill Eel_21'1 hy tilt' n ·sllI.lic" " o f ..tI~· ill ...".. '1"....l: tl.)'111"'" -.rt"''''''''A.·.. 2. i<... "'rI. 12... C l..li"•• .. .".-.. 1I1 v " l:l.1 III 1>O'..<'J<'O' .000 (hours) 1000 Volume of Distribution (L) '0..000 nit..1 31.-... T...l 1 1 III C)" ln idll'" 2 1 cJ .•..'''15...u ......"" 11 ' n m .".id " z '\' p lo " 25... Tun "..("" in I 1'. .....I..·.I...) t"llm. M · ..1..l. ·". p.ivt.I ". (ril:l. 27. i f .. 1 ._2H ~i\"('s CLu "" Vu 30 uud Oil s ll hs l i l ll l i ll~ Eel _30 iu tu E 'I _ 2 7..·" l..!.. Io"lf." ".. 11_ 13.· ....-tr hal f·hw~ Ito.. r.".

\\11 is bolh po lar and slowly removed fmm tilt" body. All of the d m ~ is n'nally excreted unchangcd. Its n-uulevtract ion ratki is 0. h . bill Ihl' allS plil'.\"(1diu resis is likd y 1 en ha nce signifil"llnlly Ihe el iminalion kiuencs of a tim. 3.693 V CL 0 . 4. it-h 2.5 . TI lt" majori ly o f ti m!!: t"nlt"rill!!: Ihe budy is excn-h-d ill till" urine ulldl.5 IJI I/min. FOf(.) I.t"xl'\'t"t l~ 30n m lz min . T ilt" d t"ar:\Ilt't" par". 2. 2.9. tIlill~ of ie . d . pola r. k.l~lIIa d mg conce nt ranons aft" usnally IIIl"<l IIR"tI.L 1 on 'hI" Illlho und d m ~ coucent ruti on an " part i(11larly t1!wful i n therapeutics .CHAPTER 11 ElIMINATlON 111 ' 1/2 = 0 .1 .LS follo ws : R enql Cec-cece Iml!m.O. am i hilS a \1.of d islribution. Both set s o f pa nullelt" rs an" o f \.d m /-. It is nnl bOllml to plastua pro teins .1.Tt"l t .\"S of eln-ranous in prote in btndtng. a.02 State the likd y lnvolvemcnt of filtra tion. secretion . 11 condutons that ind it'llie till" probability of rena l d t"amlll"l o f a w. 4.\Il\Sl'(llIl"Il(.. lilt' value of Ihe eliminatinll rail' constant.-ntrution ill urnu.uulxumd d n l~ that is thought 10 n-late mos t closely 10 till" t"lTrt1s of a dru g.L~ lI n" Il U" lIt in blo od. p[. For whic h mos t of Ihe filtered and S("(. 3. TIll" com. or III(" half-lift".o f s. billod n O\\' . e." let ters o f all (om.1 small voluuu. !!:n "aIN thuu 1).n) f' OCli()n Unboul\Cl Theophyll.\ 1 am i not reabsorbed.lllIl" of/ .u 3 . Fo r r-ach of till" follt MiTl~ mult iple d lOil't" qu estion s imlicate Iht.is im I11 'N.!: 0 I . wheu GFR is 120 m[) mill uud urine flow is 1. II has . 2. In pract ice. Hrid ly comment 0 11 why th e others an" nol ('\)fTI"(.50 010 0.t1l"r than 0 . \\1lidl is ne-utral . " is Sl'(. a d other physion lt~l" va n abh-s . T Ilt" n-ual d t"amu('\"of a d n l!!: is co nsta nt with lillw if I.II1lt'lpr kl'it "tl O il m eas ure-me-nt of d m g in blood is IISt"flll ill considcratious of d mg extraction ill tilt" (']illlinatill ~ nrgans. \'ol unw end clearance parameters h . It is scen-ted inlo till' lum inal content s of tilt" neph ron . \\11 is not secren-d an ti for whit-h till" rano of its unbo und n-ual clearanceto it-h ('n "alillim" cll"afimn" is l.It·1i o f the-se.l llIe ill alllidpaliu1-": and 1~'ll lIalinR lilt" phannacolduetie ami tllt"rap('ulic l. It has a pKa vahu. t lr<!' is indl"pt"ndt"nlof tilt" silt. A n -uul h lnnd d t "afiUll. li s vahn..or mo n ") of tilt" co rrect answe-rs.0 ."ald~' acid ic 1l" " t1m~ ht"ill~ S("nsilin " 10 uri ne p H art:' I.(' of 56i mUmin for oxaci llin Indicates tha t : I.a!ioll of ti ll" \ '\I h ll1 l(" and clea ruuce pa ralllt1ef"S so ohtahwd is lunited . Th e renal ck-arances and till" Iracnons unbou nd in plasma of th n-e dm~s in u 'O-kg sllhjl'(1 un." lIdl"n t of urine fI (l'\' . jc = 1. of lIl t"..693 Vu CL CLu b 31 T hus.693 Vb _ 0. STUDY PRDBlIMS (Answ ers to Study Problems a re in Appendix II. 2.<lllgt"ti. 4. an d n-aleorptton ill Ihe renu l hall(". bec ause "t'( it is Iln.ne F'henyloin 10 0 15 20 Cetoerod 0.'n "It"t1 dm~ is n-a bsorlx-d aud is ~n". 'S.

~" bullOll III F.. AIe." if tlud m~ is si~lIifit'IU I I. J..h.ne] 00"""'" ""''''''''.11 .Tttf>T1C _ ."in ~ olTer for tilt" \'l'ry dost" correlation ('tllll1:°n l m t io n? D iM.'MJII S.. in dt 'le rm iniuK if tilt' l.· of tltis d m !!: is th e most wusith"( to d l. for legal n.Ul!!:('S in urine.• Ifill.shOlt ' l i tt ll' elm'l /!. al.. Fo r 100 Ill ~ ill the.t1 iollS Oil in terpretation of blood akoholk-vels dt'rlw'(! F rom :Illal)" of uri ne..."f·•.. 4... ~ny~Q1. (Pap lt'.112 CHAPTH 11 3. the .: Ohst°r'\"...IIC..7. 3:H19. 6 .. Foro-d dam-sis is most Iikl'1y to 1 o f )(' value for this ( I m~ ill a l'L.(lIl l'l' u t ra tiulI of alt-ollol ill uri lle could he rela n-d to its blood concentration.uf thei r ph)~ i ed l pmpl·rties · and disposition characte-rist lcs in 11 'j'n-k~ limn.l pmh 'in bi ll tli ll~ silt'S.1 I 4D0-600 210 09 14 Ol d 027 350 245 006 8 <001 a.11I " t ' l\\ l '( ' 1I cono-mrattous of ail-ollol ill hlood and ill uri ue? h. 5... ''''''''''' 90 [om.tll·st d ilT usio n lunnauon in (: mss i ll~ the piacenta 10 the fet us. sunnuanzes . Polo"'Y d unionized fOfm pKa 30 (wea k codl -.II•• J2 1..· o f nafcillin will j rlCn'(IS('" d~'Cn'(I. si. Foster..\'..(1.p l.till' d m~( s ) for wlJk h ('adl of t1w follnwill!!: stil!t' lIIl'nts is pmhahly must appltcable: I .r't't! and ~ '(:n' lt '( l <i nt~ is n 'ah. 1007 ) WNl ' interested .lltywt1...1: the excretion rate of "!m hol to corn-late \\. 111 ti lt' blood alcohol } U II K Il(. . 111t' n "II. D.I.'US-\ lmelly. J. tim! ..11 d l':lrdlln. ill~ statements: I.I)(llly.G.. 'a.1 t·urdlln.oc. D..• and Wood.. or \ 11111(' (of those sho w n in italit~ ) for rlnfollo.. P.W. Thi s dm~ ha. 11lis drug hiL till' hi~ll('st n-nal d t'arallt't:' of tln.toon "". '.s til(' lo\\\'st total d(·ardlll"t·.. " ... A l'( lIIS I 11 t ll l 'a~l l l" l'I tln-ir finding . Polo. Hr.. Fract ion of fi ltt.thn-e hstcd. 11ll' n 'II..1.-cy D. Tahlr.4-16 UrI_'''ee4 Percent d ~1I()n$ \Jnne ConcenJl'ollOn Blood Concenlfohon 9 51 1 2-1 4 8 >16 4.. ~t l. T.trllMrtI_ . . 'NCI. h .L\ rna coneeutrution is hi~hesl for th is drug aftN d istrihutioll e-quilibrium is al:lliewtl.r C. D . 1d ' 2.lkollol is not bound to l'(lInpo llt'nt s in hlood. lndican.bovnd [M Holf.AU. on ccd Not 0< (] bene V oIvme 01 d.(. . t N IU . tla. S 3. T lln"t d mWi art' hsn-d ill T abtt· 11-8 t<~et her wit ll sonu.· o f dn l~ overdose. This tim" most likd y shows the " n ·. s a. C irdl' tlu.. whai esplanalillll(s ) ( '.p i !. Would you (''''1')('<..o rbt'(l.lile Ih'l Froctoon exceed unchanged llei U$lIOl ~ [mgl 250 25 0 .must appm p riillt> word.· d isplau:t1 Irom ptL~ Ill.

5 ...e um concentr ation ratio of th e d mg: is O..Ti . C.v..I conccntrutiou r. l. (. Fol1 f)\~.' . tllis dmg \\illlm\"t' tl ll> l a rgl~t ACe ..wt rhst rtbun-d t. 99. tht s d rug \~i ll Shl J\~' the grea test t!t'g rt'(· of accumulation. n "lm/ loxO'I'ti' l/I . hilil)' flf tlw dmg d mpt'ri dol From a re ctal d m g ddi\"t'f)' <1(. After all i. -I. 1-t 3. Gi\ "('n th ai thl' hIc MM.f of tOl"aillidt-' in the hody b )(J( "lIIf'C! oUh ide the plasma.' hld) alltl illlran'll(lIIsly of a HKI. 1) 10 plasma p rotems Sillt..'(· it has such a largt· apP. c.l-tn-ploLsllI.ml .t('C'(111ll 1 for the loss of billil\a illihilil)' ? " 6.i\'t'll t.llt· Lv. fol)()\\ing administration (J rall~' (t.51. 2.. tJlJ.'l n 'lll velunw o f distribution. n·il<.II(: lIla((' tht>ora l hi' lil\Olilabili ty u f the d m~.. of tilt" urine . u ministranuu.i:. Intravenous I.97.that is lIlusl st> nsitin> 10 changt'S in uri ne p i I. ~ af('jlli ll ~~..t' th e ren al ck-arauce . rannot 1)(· highly bound ifu les s limn 0. infusion of 10 m I T W' . \\'he-n Ill(' usllal dcN' is ad ministt-' rt-<I Intrawuously.n g :t l'flllsiant rate infu sion of 20 m lT.0. h .·t-'I')· S hr . In Tal lie' I I -~) en.9 '.. For tilt" d m~ with a n-nal cleanuax. . mg tkN' o f a dm ~ to a 6S-k~ sllbjt"l1. to what exte nt ('emld ht'lJi tk' Hrstd l P . Cyduspo rim' is p rilllilrily t'lilllin "h'i...' )IInt(-<1 fur wi thin th(· ( cxtmcellular flurds. .'ice \\~L~ a. fI('iflijimtim.! to finl -p'l"S h"IJillk dimiualion . Chapter 6. th at tilt-' ~}"t t> ll1ic hillil\' lila· 'i. Cydospo rillt· ran. . Tl lis t1n1 \\i ll ac hil'n' ti ll' 11J\~'{~t plasma eoncentrutton at plateeu foll' J\\i n~ a ('tlllstanl-r." l il.It•• 11-9. ' 3. By appropriate calculatlou.hstcd some p ertinent pharm acoki nenc data.l \ dim in. 1(" . remains in the I)(Kly OIl 24 lirs.v. h .1f1iJ"li.data o f problem 5. 5 .50.. TIlt' l bloo d -to-pl. this dmg is (·xpt"C·It"C1 to ac hil"'"(' W' tilt' hig:hl'St pl:lslIl<l enucent rut jon at !'l hr. Ind i('alt' 1111>d m~( s ) for whlch eac h of the folltJ\\i n~ stat ements is 1II0st applicable. ('Slima tt· 10 what extent tltl' Ilbst·"' 'e 'i.Q3 105 0" 0 22 1 22 a.'i BC "llll Imm analysis of the.ltin of thts eln lK is l. .tltiOlI . hi' lit\"ailahi lit)· 1 llli~h t 1 a!lrihu!t'i.·(·nly throughout and '1<. and Jll~Ii¢h le' unchan ged t1 m g is fou nd in urillt' follu\\i ng i. b olus dost" 30<].should dl''C.CHAPTER 11 113 2.! by ". 6 .llion . 99.

l1 n pl.l iltdi(' \liIr01l11l'1'·rs and plt~ . ' 1Ilillidill.io[... 1"1)( 't 'iall~ ( :hap' . perlu$ion. Chap..\'" "pp. lilll" . HI'fPrt 'Iwt · h frt 'II'lt'1l11~ lIh1d.~e <llld l illd ie l~ >II(~ ' ph a n. I. T ill' 11 " rall pktun." i. i' a g. adl litio lla l l'\a m pl."".lrOllllt'h' r ('. of . ·n .·. lIul oll l~ III d''''wa _l ' IIIl" n-nul 1. dJalJ~t '-wilh di"'i!"l" \\ i l l..·ar. Sim ilar III n-ual (Ii.."". hm\t·\t 'r.· (·!I.lll{IIMtb ol. i' IIn.· p ill .lIlc ~(" \ a ria h l!'. Yd . ill ll llwrs a" we·1 Fo r " "Impll·.'i\( ' Il. · ('olU ~ 'JlI ' h-ann-d 10 Ihi ' point.11 110111.d .it uat ion-.·. nl\" ' llU 'l' I ~ " clf any OI W o f Ill(' alll'r'll i'H1' l llill 1)('('lIr. Of metabolic activity on the lime course of drug in blood when !he oppl'optiore plirnary pharmocokinetlc pafOITlE!fefS ole k/'lO'Wll. ...l. ~i l' ' aria h J!' . " J1ItUlIl ila li l tlu·rapy.l11.Ul al~-/j ll !! tln-ru i..11 <lh.1 'i(' \ a riah l.. dl'aralln ' o f di go \ ill. TIlt' phar1Il'!l'tJkirll'ti" par..um 'tt-r.p.1)1'I)('lId" II(·.·.lSI ' ih 1. 'I~ 0 ph ysiol "!-. "(:rt·. bepcnc clearance. determine the changes rho! hove cccoted in the primary and seccodcrv pholtflocol"neliC poromel9l'S and list the pouible physiologiC mechanism/51 i~ 3 Predct and gfophicolfy demonwole the effecl$ of on checnco in poseo prolein Of nssoe binding.lll ~l " of ph~ "'. appmpriah' [n-n-. ~ Predid the phormocologiC ccoseqoeeces 01 each 01 the alterations 9'\'$1 in ob!ecJive 3. F rl'ljlll' lllly. tll"l d"1I 1 0ml ral " alltl n-qutn. Ill' tlu.. biocMJilability. 17 ( 1 1I h' rOIt"l i n ~ I) m ~s ) allll::!:2 (1)". .\11 .llIIill" . appm. " .I t1nl~ t-au.:I.i' 1111 '11 l!ai l lt '.h I" !. t l« ·SI · l.wit ph ysi 1..111 tilt' \anll' illdi\. \ t1nl ~ INTlRRIlAIIONSHIPS AMONG PHARMACOKINITIC PARAMITIRS AND PHYSIOLOGIC VARIABLIS .11...~ie lII' ·...r'lli lll.tllIal ".lilll 'lie ' o f a elm !! i' importalil .. ·s in tln. 16). n-n. li!ol example 01 physiologiC vc. 10 c'\ a mi ll" lilt' " \Jlt' d a lioll' for all a llt 'ratioll ill ".· or d t'arall'" of a dn ll~.llIg.m.· loll.ea l j)(). ('o lll iitinn' 1".." ...uul " \lrar"n.!lilil. \ " lII ll1la ~ 111' 1111' illlt'rn·blillmh il" .lt ltl ' ·\. 11. :\ 11 "llilil ~ 1 " "j ~1I lil.·.'\.1' am ] Tiuu.. 111 ' UI"" " !' 1l'1I1 dlaptt ·" . 2.1111 1 " \lrar"lIal dl'a ra ll( ~ " o f Ili!!'I\ill . hirulill!! . I II~' inlt·c. jol. I eh an~.I pl. a' IIII' IllI'o r('(..(i t' \aria h l. ·a. T Ill" illh'radioll of lilli llid il ll' a mi di ~o\ill h uuorln-r 1·\.1 prtltlll("t:' a d la ll~( ' ill Oil" phy. art' 1011 uuun-nnrv .'('lIr [n ·fl" I'lIl ly..cbes tho! may o!lel me p'In"lOry phormocohneHc pcrceelen: o~pnon role constonl.. and v0lume 01 disrribull()l1. '1'111' firvt . · d. IU 'illll ' r Ill' 111(''>(' ..l1Il pl..\ .' ill\'I.. ~i l ' ll.:ralioll o f physiol. . reno! clearance.IIIl' IN. \ allll' o f 1I<IIf-lif. hili 10 d"('n'..nl q.'.prr-diction of IIII' kim-tu-'~ lI l""l jl "' lll"( 'S o f <Ill "Ih'ra!ioll ill .a uis rm 10 tlU'S(' oh. ' 84 .'ie .( 1111 ''' ' \·\ \It" ·I"t i. Given pk»mo 101' bkxxll concentration verW$ lime dalo in normal and cseed sscies. \:0 allt-llIpl is madc' 10 .l-.·' li ' ''1I1' h illt lill ~ and hotl."olirU'!i.i tllal iu ll' iu \uhin!! allj)()"iblc ' d).i" rtll.( p llar Hl.tJ ("\" "rall("(' a' \\1'11 (.. '11111'. m!' o f oh' I'n 'al..pS).. Boll. .I NTEGRATIO N WI TH KIN ETICS OBIICTlVIS The leodef will be able 10: 1..whn ian' takeuin Ill is dMpll 'r ill ord" r 10 illh '~rOIh ' a lld PrOldi(~ ' IIII' pll ~ siolol!k alll i p hamla.lilu'l ie (.uulr-o-n \\. n 'II.

bonding in blood.. Ph. t'l..'rilx'tl by n· lali"t'ly Iew par. ax . binding in 1i!oSUM.1 Ic IJllmmt1en. Part k11larly useful an' till' lIll'lllory ulds of Eqs. ~nol motility [Otal) ~IC emptying.sl ril' t' lIlpl}i llg.. ~ compo6lbOn.lc Vanaill•• A~ptton fOIe con~lOflt BIocxl flow ot CJl:»otpliOn~..p ll .ote Bind'll9 ifll*xxj. Ht"t'all that ahSflllltion ca n lx.. 9'U"1C empfylng tcd}. bindlll9 III blood.IT tds. S I hrotl~h I I.' . As d is<" usS('(1 ill Chaps... Bt. De~IHI.. Increases subcutaneous and muscle blood [low.I. and eltmtuntlou can I>t.aIT N1ed. OdrYe!lllCl'etion 00'''' ~ption.. b!och'ailabiloty" enzymes in bile.CI1AP1'H 12 lNT£GAATlON WITH KNTlC5 .I.several dl'ri"t"tl values.2.ty Hepo IK ~ena l 01 oeid ifl !oIOfTIOCh ced hydro/yhc Ifllnruoc clearance. C astroinn-stinal ahso1lllion Illay lx. elimination ran.·ndt'Il< ' :il's an' summarized brit'A in y T ahle 12... (lCtivity hepoIoceIIub eec-eece Reno! blood Row.·f'S hut also Oil t' itll('r dnS( or mit' of administmtjon . " PrI.11'" pH. by blood Row at the absorption silf. Slid .. Pha. TIlt'S(' dt'I>t. inIso$hnol motill'Y He.. 1oeO"etion BI( NC X lllabil.charact erized by bioan lilahi lity am ! by an absorption rancons tant . di stribution can be characterized hy tilt' volume of divtributiou.ri ma n. II.1 Se<ondary Pharmacokinetk Parameters and Derived Values Ii alf-lifl'. 1.'(-. ami diseases and d rugs produce lllany t. cbaracte naed bj hepanc and renal clearances. namely ami 2 Tall'.s.J/w nllllcok itU1ic l Hlnl llll'lt'n. He nal excn-tion lIlay depend on secretion {active tr ansport ). . ~a. D islrihution is infillt'nt't'(! by hindin~ 10 bolh plasma proteins and ti SSIl t' {'o lllpeJlleuIS am i by IxwJ~' comp osition. wln-n ubsorption is first o rder.lIIwtt·rs are llsted in Table 12-1.ullett'r'S . JX)'fltiorung IfllO lot. thai ck-pcnd lIot (lilly nn the primary pharmlllUkillt'tic p. and unne flow.. uOf'lIIllow. gIomeruIor liltlation. TIlt' pharmacokinetics uf a d m~ tlfh'lI can Ix-' dt's<. body ~ze .lI'lulll'lt.. an d ~'ls t nlill tes li ll'll motil ity. . there an. each of these !lilr.kllMllc Pa.c..xl!ic blood Row.l1. variables tha t aIT priuuuv ph anI11Ll"()kint't it' par. TIll' equations in Tahlt' 12-2 plus a Iew previous equations p"l\idt· tilt>ha. in tllat their values depend li n those of tl\(' prim<u} pharmacoktnenc par<lTIlt'll'rs.H':C. 13 and 17 in Ch ap ..cnu staut .Ulst' of this direct relat ion ship. Eadl of these physiol~c vunables is aITt'(1t'(! hy num erous factors. futxl slows ~a... umu. Thus. "/lll n IlllOlki m.lIIlt'tt'f'S lila)' be <!in"t1Iy aITt('kd II)" ' dmnges in physiul(~ c "a riahlt. jc· n-lanou" ships for illl l'rprt'tin~ am i prt'(lic1i n~ alterations in kineti c be-havior. and fracnon exert-ted IInd mngt"t! in urine an' examples o f WCII/u/(Jry . . Primary Pereeeten and Physialogic Variables T he p rnt't'Sst'S flf ahsflrp tion am i di sposition depend Oil mml )' physioln¢c va riables. Furthermore. mhh ill.c.sl ric f" IllP!)ill ~." . I'hysioloWt. tllest:' pamlllt'tef'S an ' n-fern-d to ill thls b ook <l" l .a. 12-1.

11. ti lt' Al'e n f warfan n ltl i.. dll ri n ~ 11)(' {"(llll rn i pha.·I(~ar. n il' kim·tit. 12-1 ~ II PPUrt warfari n ha\.Aon Cleao>a a..'>(..·n ·a.1 ~ coeceeeo-oe [.. hr/L. TIlt' ("'!ootim... P!>::J.OOI I 1 J1 l rll~. . SUlIIC' d m ~~ {~"II i nduce tt..ar ac:ii\i ty (im lut'fin n allli inllihi t in n ). 1M'p'llol"l·lIl1l. til(' c. h 'nlL to hI.1 C.it. TI lt' \ 11}.. is (J. nih ("1111 · dn~inll i~ I.· di\.1i\.tillll ratin b.l."(1I11 jMrt. I. ry . p mtein h ill(liu /.'l\ a low or a h i~ 1 ('xtr-t<.Ki i\(' tubular secrvncn.·hall ~. 1lI1 illtllll"tiull UC."( mSt'lIIlt'm't"!i depend on wlwtll{'r tilt' · a ITt'tit'll tiOlV. uh la illt't l I. Vet.{'it'll (III a rtllIV:" (~ aI(·lIb tin l) IIf t"!t·ilral)c. · ah'itlrIM when ~\'t' ll orall..'t·lInlilr ('n~1llatic../IV""".tII("(' of a .-..' ind t-pt'mll'lll of (:h aJl~('S ill / 11 (Chap. 10 ).ill~ t jn. · .mntul x-n-ular a~t'll l rtfarupin.JlihC.lI' !J and n.we 12-2.:.hahl..me cJ cb-ib..2 I A ~).m it" of sYll t h t~is o f tilt' ill\11 1\('1I. n ~ .tlU) rifa mpi ll pha->(''\.tlHl ~ l J1 l rll~. lOaI biooYo.1 Inw hC 1lillil. 1 of rtfampln 0 11 warfa rin di ~trihu l ion ..('(III(·1I1 t"ulIlplt'!i an' an. utly d ifft·f(·nl. .trihu t:un . uhlaillt'll Imm CU I.". <J . Indu<tloo of Metobol.2 IJ1lrll:lt.1I11c..' ' .(·)'I·mpJil)...-."" Ii v.1 on the rout e of adminislmtiull.""""'" Ponol dooo<Ol/lT"""-" "'-Ia.. im luc.t"(1 m illJt tlWM n·laltom..1l~7.5 1II w1 ~) h. Secondo".rl . • 1 1 ~ D..· alt e r' aho m.. ' 1 ( ' l1l)ll1t-{S ) .lmn{"(· is 1I ....ips.. for d )11'0' " 1lI0) c'(111.·n·'l. v I Area unde< CuM!' [()foIl A"""oge o 6Q3 • Vo!o.1 tn Illdt of Ihl ' contro l va lue..~ .il k t'\ t r. n ·f11"{1illJ: a Iai~t.(· r d l·ar4IK't·..' hlo . reed UI'lChorIgo::! c De<. ". tlt.::' ch-ar'III{"(·.' c Pwr.. are U. h(-pati<.1('11 III 1M "'::'n~iti\l' to d lallJ. TIli'\ ul""" r"'alioll is c."ticm o f hC1latte.'"'CJCOl.lobl'trl C1eoIOflCe • t~ JnteJvoII lInMion ralel/C\eoIorc:e pla teau COIlCeI'IIIO hOtl [()foil """""'" " (II" lIlt' clf ( I i ~t ri lll l l i( m t1t'lx'll(ls nn billtlill~ to hotlJ p l'l\ lllOl pn 'h'i lJ\ und t isSllt' {''Ulls lit m 'llh . 11.. F iV..-y D..). t un l'fT(.1in n Ruti n .. n ·'IM'l1i \ dy.')00 JiIOOJ(·) dn l~ wit b OJ s mall m lu llw o f tlistrihutKJIl « 11.i iull rati o in lht' d i m i n'lt i ll ~ organ in wh ic. "(JrQ~' ~ EI..... \ . i ll intri n. For u t l m~ wi lh a large' " .· .i ~h'llt " . liUlt· h ('xc.. v.<..'c'\!r-<tl1iun rutin.1C>al ~ Dow .. calculated fnllll C (U)/I.1 dt'lUlliI ~t mh ' ~ IIII' kim·tic.datu ill Fi ~.. TIll' (L da Sll~( . \ \ 'arfarin is pn-dominuutlv me1. I m~ of It'"' 11('fl..6..K.l. ·. c..l~ l A~ tln rinv.. · IIul si.l~ E I'''''nQ!1(lI\ ' ate COf\$IOtlI Frocl>Oll e. · Iv v _ Iu. 1I J('I OlI M lli ~ 1Il of otllt' rs b" illc.'.'on.oed vetoes "'eo unde< c"".."{1 of induction of wurfann uu-tabohsrn hy tilt· .·t1 .th'tl \uIU lllt"!i of di .:("!i ill ht· jla hM..... (J.J. am i p l'l\ IIl'..') 1 IJ1lr(. alltl therapeunc c. I u tilt' p rt~'Ul"t· of rifam piu.'f \t"('i~hf « ...'"U kv: or 1...1icJII rollin is 1 ·'fIl't.tlillV: doS(' (1 ."(lIltm l . nli.U :C 113fi() m ~..'16 INT EGAATON WITH ItNETlCS r. t1 RIM'. n ll' s(' \-alllt'S an' p n . \·alllt· is ItM' compan-d 10 tbe Iu-p.. \\'arfarill i ~ ulso {"( llIlp lt'l (·ly ami mpitll.. ~o that 111(' {"(1m '· ~ IM llldi n~ " Iolltl d (·.·h .._ Pri.. Low E "'lnlc.IIM IIi"n! ill tilt' !in 'r ...dic hllM Hllw elf ."(:UI"!i .. TIIt" . 11){' h lcM ltVplimna {'UIIl"t·lIl rJ..luIII{' (> 50 1.·Il~'lllc"S .· d fc. n ul'. initially t.".'n'h 'll ill un nr. 3 w!lil. 'l1 Tln.tl(l!1()n hoJ.ll n ' 12.

.. is d i Sl'm~'( 1 in Chap. dati" alK I n f"rnpi" ...t· is i!ll'rt'a\i llg a nd conceutratlnn is falling. \ \ 'arfa rin ts lIIit rlwlt.1in Fig. a .. n . ... ra('('mate 'l' \\'('11... hIK ) . 11tJ'\"(" "('r . a n ' of ques tionable c \\i l ho ut l1Irn.Ul.!.' ntnha rh ila l .ul<Jl\.phurmaco ktnencs of alpn-nolol aflN its in travenous (i...J j. TIll" n -ason fur the app.. a dnll': "'ilh a .lrrelation b etween r"'spon~' alltl plastua warfarin concentration dn rin~ til(' first 4S h r after war[ari u uduuniv tration . Kml\\ing: Ihal this d m g is l lIw lalxlliu ... ).) .·xpt'l1 under sh ·ady-slalt· .t'....a ranl" · i .. I"~ol lUKI .. of II. killt'li<...!.. O m' Isonu-r Illay potentiate.....( H 1>11 .f·lilw vnhre of 1-1 sec. rifa".....alf·lif...... sllO\\1I in tilt' botto m ~mph of Fig. ...i"". IQ'I'''' (" 1" '11 n r- o cI. R lW}J{IIU t ' here is defined us lilt' .I.. .'a r 10 h e tncouslste-nt ....l M)...·.. Induction of metabolism of a dnt g: with a lugh Iwp. whjhmechanisms in\uln. 1 ill II... farin admini. ill l..1.. ad m in- helpful 10 d t'fill(' 'mil 20 fill:. As lo ng: as ra(1'ma h 's a n ' udmiuiste-n-d.... R A.." ri(.. . in tiM' pn..v...ill. I"·n lli.or inhihit tile kine-t ics o r d)lla mk'S of lilt' ot l.. T urnover Concepts. ..I ."" Han :'maltos a re common ly used today. I t.in . I"'ill· hh 'n .. oral dose.) "'lit I""" daily f"...: 1111.. ap!)('a rs 10 h'M · Jiu l..1 ill Fig:.• •h"rt'·"' ·11 am i d . filWt.• pn ·<. fn" l1 C t' '' I!>'.. ".1<10.. ".. (Vi rnw\lit) I.. ~l '-.1<.. thcr. 1 'l' a m('(' malt'. 12.'s... 12. coudtnous that Iltl' dosage of warfarin mu st he Increase.h.-r... ~ ....."">"f j:(f"I'I.. 11. .Ilg:l· in 111 half.17_141 1.. (I mwJ . in addit io ll 10 ti L aIXI\'t" l' ml'lltio ll('tl pro blem of rt-"laling warfari n concentration 10 rt's po nS('......g"'lJN a lly l1msis!t' 1I1\\i th ind ul1ioll o f wa rfa rin lIlt't alxllisll1 by rtfarupin. r In war· 40 30 20 14 12 2 4 Days ." 'I l..!.... app n'l1:t1ed [rom Ibe d iO'. It s euantioun-rs 1m\"(' d iO'e n' nl all tk1).. I..1 (J.. 2.is liltl(' appan'll t d l...· an' p roblems wi th resp"'l1 10 Ille Int e rpre tat io n of IheS(' da ta.Llta pnl\i d. lIi g:h Edmclio n Ra tio..-rs.. 1.l.·\·alion in pmth nJlIlh in lilllt' ahow' a h'"<.. ..' ul ralio n (C ...-) II ... UI.... •md the . I. pi'" 1... .I . Inl" OI.n Mi".lr. althou gh then.1 in the p rt"St.tral ion ...I"nolw.I~u lan t !x ll. Prt't n-a tlllt' llt with tilt' Indue r po..1 ' <in ·. is suhs lalliially r ..OW'E ~ 11 111 111l' IIlt'mp"'IIIil' l'(JIl~"( l ut'Il{'t' of induction can ht.f ". cbirahty is a major issue in therupeutics .l'II1'''''S.mpin i.'lll'''-" of rifampin to main tain the sa nlt' prothrombm lim e..-uci.1 "'i" i n .... TIll" II\l 'rall n ·spoll<.. inlo:w . Fullu\\ing oral ao.-n-nce.l' kim-t ic l111lst"(IUl'lll'('S w ry d iO' 'rt'ul {rom those of a d nt g: \\ith a low h"' pa ti(' ( ext racti on rano.l'III"\'(' aft N Ih.am i d)l l<un ic data on lilt' pun ' euanuom. app....l wi.~..v.1i..lItl"l~r....t i. . Hifa mpill is a known im llllt'r of IlI'pa lil' dOl~ metabolism. Fu rthe-rmore... Co nst"(Iu(·l1 tl)'.. ""1: .ttr.. 1117-1 ....2. instea d of a p ur.l if(·.t·Il('(· of rifarnp in. flIrt' (l>I.dla ngl' iu prorh mmhlu h llw Is a l1J1lst"fIUl'Il(.1 un. n -sp onse-t inu. I.....f a· n il . (' (' Tl u ~ ' Oh~·I"\~ll io lis ... L 't 1. J d...tti<.lw n. pri.....J.. Clearly.llin. ...) am i At 'C' an' t1 mmal it'al ly n .ut"llily puo r l1.1. IX>l:1.extracl ion ratio h. 0Ilt" wo uld . al first g: alllt'. an. hu-..\'l 'r. 12.&I.-s a nd (liO''''n' nl kim 'til' pmp.11 . tilt' pe-ak ('(}JR.. t-It... thnllnl>in l inw ( ft" IX"'''' ' a ft' Ik" l.' of d lan g: 's in l sevr-ml d o tt ing (.! 1 "'.lminblmlio n. .. !-o in 'lI by lilt' un-a muh-r 1111' respouse-tinu.I ad mini... tln."'"lw. II fl\H.. wln-u rt·SPOll<.J " hik' (. 1IInly in tilt' lin 'r a nd olll'llll11t lling: (fn ull dose and AUC follo\\inj.... th... singl. ·rti... as iIIustra tt.'slx lIld illg: da ta ff)llo\\i n~ t h..!.::S.... 'Ul. ('< .. ~ 1 :J... r-nuntjouu-r . effect on tln...

· ' h" lm -.llt'pal il' ext raction ra tio tncn-aws 10 IUJ-I ... .1s till' ha lall n t.!.' in clearance.. (' otln-r d m J.\ ll'n·" .. wnrfarin .r II.0<1 I". L ]< . is 0 . is <lIst.. ".) 'l:.N~ t'lI ~lll(' activitv.. ." 0. _~ h....r. (" d. T Il(' lack of dl.<-".. . i. all l'Xp lml a lill lJ ean 1"-· o lT('H'(1. >1 .-.t!t'm hl" l'us t o r "" Il.t dl"(·rt'ast' in alpn-nolol oral hit ).'nloharhi tal l.ltie .. a pp m \ imatdy 1.-<:.' ofte-u l'llll s.l'xtml1iulI.. lias tlll' T. · I~' 10 Ilt'pa li<.>1. 11. I~ 1.I.". " f " M l . '"l/: 0.'lws Iw pa til' blood flow ...001 (1 1tl1t/1.h.. 12-2 . ' ill tr-rnnual half-life arh'r inducttou also il\(li<'alt's that l'Il. AftN ind ul1inn . or "I· o 2 4 6 Hours 8 10 21.. E\. and IWIl(l' clearance.L (C l... or . 1.lis m ur IIlll('r t1m ~s an ' ~\ l ' n in C hill" 17..rur III(' m i\l ufl:' a pp ly il'i wel l to ('a(·11 or the Isouu-rs..ll i<' ('. I'l.. whil'h fon.<I''' 11O ''' O( . lilt' ml"l'malt' is Iha l It dtM'S nol Incur " III.. (5 "'It)..· · " wnl I'no.v.I O W TE Il 11 "-1.is u llly a s mall ill('f!'a". • 11.. o r plliln nul'IIkint'l il' i1ilT WII(...llly. i'Ioo._ "rah and III . almos t a .lr.a p . adruinistrations.. ·S 1" 'lw('('1I lilt' tsouu-rs..11'(1 A UC ilft N uml ali<I i. h. T I.22.-s t1 m~ thm ug.l'I'Mnitil' . · "t"i~r"'il ...· llppn).. " 'h ah "'l 'r II\(' ruuw of 1I '" . .lrisu ll of :\ UC . whit·1I llI." .2 I J lIliu in tllis ind i\itluitl. rlo" . ).31fi. . ""\".\tml1i ull mho ( I . ami ht:lIl"' lh t.... .!1 im llll1.ls i l\~ Ilt'pal lll'l.\ lp w llolol.<1111p ll's o f t l m ~s that inllih it tilt' 1I1t'Ial" .'.IIlY t..1 j . likt.. " .it.l·tinll rat io. .. im lll<1it'll of 111 ml'l al"Jlism o r this d m~..h . tilt' ht·ll:.~ .llit.('IIlId ll. ' " 1/. its dt·ilfann .·(..: 6.hr .. 1.IlIJ M ) ~ .t1nl~.IHl.1 'M' IF m ".. Io:iw..ml l i ll ~ til(' tsonu-rs..'! 177 h f r<ttiu IIl 11 dt·.01 li"..: O..IIl. an d nt llt' r ("I II1t!it inllS.iti.01 I".5 [ / m in .'u lil' im plil'lIlioll s wlu-n a<lmini' h'fl: '(1 llr. c. l'l. Thus. \1 IKI " '" It..(from O..'\tn K·tio n n ltiu of «lpn-nolol is h i ~h ...ld ('h'III~'·. rI.Fil l is 0 .I. is oll l~' 21)'l.·s alpn-nolol nn-taboltsm.. ..is 110 t'\id pl\('" in hu mans that pentobarbttal altl'rs IlI'pa lil' hll '0Il Ho\\" the-re.\n~..li . bill not wll('l1 ~\'t 'n intr. h . i . Eir.. G h 'l'll thai tl a . or mort· fft>( IIlt'1l1 ilclministralioll. the ...lnif(·sts itsdf 'L~..Il('patil' ext ract ion r.ions he-n.1' kinr-tic ("IJIlSI'tIIlt'IIl. whil'il i lll'rt'.twt 't'll pt 'rfllsi.. - 4 .-s 10 n . TIlt' !l" Il:.. and 1'll1)lllati l' aelhi ty..'s i1I'Ill. Tin' ar~lII llt 'll t for this eouclusion follows. A laTJ:('r urul dust'. ( .lIubr a< 1 1i\it)' fo r a d m ~ or low !I" Il. Ht'(lu(.-dU~' d t'a mnl'" h I't'rfllsioll ralt'·limih 'tl llm l lll. I n\il'u l( ~l' . Penloharh.I(...· .. ..'t1or . TI lt' t' ITI"( o r t1''('f('.~·" l r-. di d .:II . .'(1 IIlt'l illMJlislll can alSfJ I..... t'(1 ' IlI n i n~ all . '(1 mt 'tilIMI!i{· 'l<1i\ dy.(1)1.7foi to OJ).UJ('( ' IIf 1. S(' Ifi )..1 (1i\'i1y n 'sh l" s "illl lilt' t l m ~.\ '..lntl: j\ Io!lu.oil a po·ntnh.m ll:.ll'n·r. ".. 11lI!" t'(l. t1ilTt'n 'n n ' in tl ukillt'!il'" " r l hl' i"" mt'rs . e ..: wi th a h i~h hqMtie t'\ l r.it.IIll...~. tI . Bil).lt:-"(::!I n "' ~. mlminislt'fl:'(1 iLS" ml1'lIIah'..·1lt1 011 tlx. ami its o ral hioa vaila hility ( F) .lH·llllus ly.. if the ft' are \i rt u<lUy no pharmal'ol og il'.l . n~..1 "'\on""·.In l l"li n n Rlltiu.llllll" uf t1h trihllliUll of alprenolol. -alIl1's ) dt'(·rt·a-. nrul "ina' ~l ila hi l i t\' (Il'L "I'(1 on c.ld i n ~ I ) m ~s ." 0..11th t' organ. l'Io Mn .\ '.3. 111I l' r. .'\lrad iull ratiu is illll'l ra h'( l by dala ror l·h lorJ'. 1Il1" (" 010..78 .low h ioI' 'i\" llilah ilily is dIU' sol. ~1 t!.....llin o r tjn.m...(f. wh idl n..rl<.j )...!<-u la!t'(! hy ("I )Il1 IM ri ll~ tludOS -U lrrt '<... 111 lncn-aw ill 1'('lla !i(' " extructtou rat io .:.ilily ft·f11'<. is 1l("I'(II"I1 in tilt' p rt'st 'nl'" " r lilt' induce-r III Ilrl M ' lilt' sa nu .1 "' ·11 "'.· a l"l lllst't IIlt'IIl'" o r IWPilti<' d ist'. a lx-m-flt in us ing..'('no..·it ll liUlt.m:azOlII· aml l'blonlia>'.. asllll. l "t~ ..1 I..L~.u" d l' fid l' lll'il'\ . <:Ii" ...I\'ailal.... I" '1 wi"·.'('aust' then.n " r. fOIl.... Bt'<. .moce-s dm ~.I.."' ""1"'.as 110 dTI"( Oil lilt' 1 \.. Lo w E 'l. l\~'il ahili ty .." IT .

TI~at chlordtaa-pcode has a low hepatic extraction rati o (' V{' II in Ilt'althy subjt"<. Tb.. TIll' uu-au clearance..iJl ih~.1.. Gil. 53:64J.. l of C.. -allie'S ar .... ..mg dosc ) and the limited lillie of sa mpling ill tilt' llill' p rl' S l·t' of th e inhib itor preclude ht..:.'in~ highl)' queutttative.. produ ced with pN mln io n of C . Ord.li. K E.m. al.h I' . S aran.2 ~ ~ ~ ~ U 0..• 26 . Chlon.'iO.C HAPTE ~ 12 . I'Y') ...1 hr in th e p resc nt-e of disulfiram ...n ..• .·n. E.1.lOIn..ltc norm"l subjrth..-for... Pharmacul." lfinun . . c l.. . elt... u"" .fi.. Ch ll.. s §.t:\t--<l. di.-d in I""'twILI5 . ~Il"" ul ( ~ S E ~U and ilMlh-i<I. J...) if..an...In'K".in a subjl'd after a 'j!)()-lIlg oral doS(' is W I) ' diffe rent from that seen 10 h r after a single 5OO.a... p rho.1 'nvrpoom t1i' p""ilion in dnt~ltks.. ~l.. pn.1aft..r .<''<&'''''1O' n. 11<:. R. m: A d ink al p robe.n for a drug with a low t' xlnK1io li ra tio... ho" ·n. 19'.....oIl .("<1.. E u e ~ c u .! volume of distri bution (110 1 Sh(1\\ 1 1) are unaffected.l d .·n l lei.. Till' cha n~ lI~ co ncentra tion of tilt' Inlulntor (a mi its lllt'talM s follo\\i ng tht· sillglt· 500. Gro"'n M.-tllh"li..oJKl tut al d.I"" liu"'p'''idt• • halfj...0 $ • • .' ~ . ~I .n m ll . ~ :E u E ~ ~ 0 ~ 0 ~ x l>i.1 0 3 6 Hours 9 12 Normal Cirrhosis 1 ~ ~ ..1IIt. KTl".i<. ~ ~ Normal Cirrhosis 1 1.I n..... " ~ c c c 0 c u 0 U ~ 10 •• • •• inl"1'\"lU.. ll " '1' n.'3).D . ..3 mllm ilv1g ami 1.in ("!c·ar . 50 40 30 " '"se . 12-. tIt'l'n 'a".-n h o m Kharn d •..:_ 12-4.K" I.hohc adi i~· b tIto · e re. trM1i. """ "['.hlorzo lUOno·.l.l1. ''''l lu M .I"I7. n. J. ..IIi.. In('R''''''' in half·li ft' lind t1.9 T Ilt' concentration-tune p m filt' of tilt' muscle relaxant chlorzo xazom. 1 1. ( ltt-lIn "' n Irom s .m (... O J .\".\". dfin m inhihiti<lIl .· pt.. t: . ·•." 0.. .for PoISO 2F. m. IIXnl "~Ih ('t"mli..U . Nonetheless..jh· h ... the effect of t'lI ck-creased lx-patoceflular act ivity is ell'. S . Another example is that of lilt' '1II..2 hr ill the absence and 0 . i...-..." 20 0 ~ ~ " ~ ~ . Mh)n ...0. C.and half-life va llies we re 3 .-cn. 00.nl"t· · decreases and half-hfe Increases . opoxiclt.iol~til' d nl g chlc rdiazepocde ( Fi~.·nll1dinl1- 'iE 3..-xp''('If'(1 for 1I 10 ..24U-246 . n WT. sin· ~ ~m!tond dOM· I..am.'11 1Tll'1..4 0 ~ ~ ~ ~ . ) i~ dr. e li" .5 mllmilv1g and 5. Its half-lift' is increased and its ck-arauce is de reased ill pat ients w th hepa tic ci rrhosis. a se lt'{t ivt· iulnbltor of m:idali\"t' mctnbolis m. ( Rt't1ra. 11 . n 10 hr h.fi\o:-of clJlonrl1Ul""' llf.t s can Ill' dt'tllll't 'l i F rom the data in the figun' if one also knows tllat the dru is ellmlnated primarily g _ 100 tlK..'1. ~l..!ii U :E '2 0 to 0 f I .II. I 2-3. t..! I . IU><I ~I .! bioavail c i ah ilit\" ..-patil' ctr lif. n . r h.....8 0. ·d .. Th.. 12-1 ).!ii 0..I'M.500 rng ondJ~il "<I.0 0.A. .:ol .li.1 _ ..t.Ih l. ·ott.6 22 0 .mll r... 0. >!.. M o d '}".m~ oral dose (If d b ulfi ram ( F'i!-t.r.: Sin.·aroUM't· I..

~ )/(20 IIl lJm i n/\.. mill .. 12-5). '·'I)("l1.•I..l ac.li'. It slMlUld IN' I.-tee ~\ l'" in ti ll" arnck-L "ppm.' follcMillZ i. if 11M dl1:n.. MOI.1nl ullo a (Imlot of u M·lll-patic..! flow ur ..til t! I. Il.. Oltlminislr.lIlSt' IIIt· IIC't·" flf inh ibitio ll of IIM 1 'r.('"l 1ll(6f)' to all .·.m '.I" " .• uf illh ih itilill ".(· drug.i"nifi. .· •• I..!in [CI.1i\ity of lollllt' llIlo l w llt'll ~\l'n nr.1.:h t:d nlf:t ion Ratio.... wuu kl nol I". 12-. J e l"...Kl m inistr iun of dnlt'h· ' .1.1 bv d i\ idi u J: tht· i..: n .'u trdl iuli mtio i.. d l .. IIi J.. f "'~ 10"· \ 1..... 1 1.ly..of li " . This t"lilld us iu ll is l lol-" "I 011 t1w l"lJlJl'l:'p t 11 pC'rfll.\ U II ll'.1 io ll mtiu is hi ~h ...'lok.'lItl~'.Jh ' ." &e" AUC Oral I.1 .1 in tJ)(...· t'du".hilit\..It" li"lII o f a ( Im~ \\.. 1in (:t.palk' blond fill\\' and fRill..·fl''''1' ...III~I'" ill O~dll hl n ocl llnw . "'( .. u llp le'.' .. n .. 1 e Jr.('io(" (:!U'l) W " \("'11 ill ti ll ' h.tlicm n'fil"l1s IIII' minor (L..."l'n·a.IIX'li d iIK' .y h ."n'iA. It cll'C. a tllJ:t' iIK'n ' a "..h'~ ..I..\'{'mg..t\ -ait . -1"I". ih itM lII IIf IIII' 1..." 1r llF.. k' lw rfn sillll (llll . FliTt' -. .v . 11"".wl · I.·.llTt"l1 (·II·"r."'~1..j...1 wlwlI at llllill i ~h'n ....trote. 1 h « .urnild f) ' of till ' kinl·l il.lt(.fic" .. K.IQII = (0 ...1 hy a d l'C.II ~·.11.1" .' in AC C fo r lal w.Iso Ill' alt t' n oc. 1 fn llc""iul-: in l. lIcl 1I1'I M ~ lthjt "l1 10 1" II' min' fi rse-pa.· .20 ~ NS...e-n wlll'lI in ilih itilill llIl'(110. ·... 'Lo:.· ' 1·\tr.lt it.III. 1." .llwm of Li))(101ol ('.r. a m in o Tclc"l'Tt".r •. 11 M' i..d.I ·rt \ .." '.1 "" ..1 . in tilt' pn""'IK't· (If (. tilt' h luud-plaMIl. u..'5 JIl I )rn i nf1. lII " y SUIIlt' f'.v.1" ..... .ly hy h'-pati(: 1U11id • .. (n '". ( 1o:1"ot" In " tlKo (um ""ll lflc liul: ..tt:11oc. wllit·1i in h Jnl 1Il1ly llfT t"l1 lll'pat ul't ·lIubr . III subjt'C."p.· "r. I~I ' tlMI t..'(11I{1't1 [rum ils dt·.) d'''"(I'.." .. thai t' lT("l'h !.. 1I. IJl"l'auM' 11)(' ( I m~ i.. 't' In h mil till' 11l'11...... w h ill' 0 111\.(' IMl· of l'inlt'l id iIM is Iwi~h h' m..111'11 Wn ' lI intraw-uou.06 lA ir {t-sti mah .. hilI IKII ". id t'mtMllls ... '1"." .li l' lIIl'la holislll . I ('(II ~' tilt" (u..·" f> 1 .. I"'w·. . hl'patiC I.· f.u ~" ' h ilt lIo t ".tlw•. 1 I»ltJl.·.I').." .sillll ..-\CC folln".)(1 ht' IM in ck -arance.1 fitM'. 0(. di N.· 11/... 1<tJ 1I)(~1 t"xdu!oiH.L d "U l~("" in ti l(' prt"i.· i" IIII.llk blulltlllo\\' i.I ReM' t.1wlI ~\('Il intmH·IICIII. " . .. t1K· 11t1}.lhd o~ol h IIllldl ~lIlall('r than tiM oral (LN' .::I)(.\ ..l h l' JlNlll u'" liMy p nJl llll"t' lUlII\ ill..oc."lr.1 b l'i 1ll11i· v (lim' 'ill 1111' h t11... !JnWt'\l'T. 1I ..ht'lnlnl ( Fi ~. rather th an wi th ib 1I )( 1 ahohh~ ..01 -oflrr. <t"'''(I' '" .."" 01.·· " "'.~mlilltlt . w..lhc (". I. 1111· 1" t m(1 ill ll mtin ma~' .-\! "C -of" .t ranon i.1l1 KIII m iKI. This oh"" I'\'aliou i....u l'i.altt'n.K·hin~ ht...' In 1.... 1 (:\ . n it' tllt' rdj llt'utic .K1 i\i l~' primari l~ hy Ill'p.K1 iulI rdfiu is . 1Y'>4 I o . t:\iCLt.tt1i\ i ty a l1l l l" ' lll 'l:' tIlt' ('\tntttin ll mlio .lldrl>· ".l ml:ti ull r. 1.. 21) 1Il 1 /Illi l1/"~..lilllill...'C.ly .· I . " .m .....w..'n' ...'''1.. hi ~h IWp l!il· (·\tr.IK·h a'i 10 n-d uce LaI ... 1.· "'...!'\. ..K1inll ratio 41. ". \\i l l.lim ihl. 11..I"·h·.· t"l mt1«1Il ran o. T . " IJlJIII 56'1 . t . ' . 1o..' 1 1l'1l.. .I II "l l ' '''Il: '''' 'n f> I. II . ....... ('-\. ". 1..... CL F ~ .. . and IJl"l~.lllIIlt' ...I. nl i...n lt' ill nund....111 .. AItlfod Blood Flow As prt' ''''' IIIt. 11 11'" ' i. II ..ilh a h i~h lM'p ali(' 1"lrdl1wm r.1 ...--.11('11 t1' ''l·rt·...1'\' iIIl1...~.".I!tC . " "" ' ''II.ll t Jillt· ..~1iIlU mfw' "..tn..I Mool... 1 "'i''''''''. ·f". .lrdlll'('..Irt it1.. . " ""II' 80 60 g £ 8: c 40 C J c .. . ~ ) 1 i.l dm~ "..in~ nral al lmini.5...t io ll ...v..Ih( · l'1illlin. 11 11' la~t ' irK"n 'd \( ' in .ti..1I1('I:' I IIII~' when t. n it ' 1ci1lt ic {..10 .l'C. ....h(· 1·\Ir.1. 1111' lark of dMII~t' in .TI"..".1§ wnb nnnnallll'pa til' flll K1io ll ...lfw lII of .lr. ' ..\lO. (liN ' o f I...·n · ~ •. -n .. (·limill"h.11..l"". IlI' n ' ti ll' iIKTt'1II1'u t i. iIL. TI la! la b crolol is a dnJ ~ o f h i ~1 h' 1l..'90 INTEGAAlION \MlH ncs CHAl'TH 11 ahu lIl um u r I.. 1.. a ('Im "'''I" I' IK'I:' of iIK'n'...hdulul i. I ~ :Yl1-4U I.1'" lui ~ 20 pt m . hi~hly (·..1l. ·f('ll"..V.\t'C. II...(· lIw pha mM(uIt ~c 't' ....('l'l 1.10 . the-n " 'f'l't11't! In I I(' o nly li\(·r.

.'all that F · DoSt.... T his alh-rution ill tlu.IIIS(' drug ill blood n -mam s in lilt' hep atic SinUSl:litis for II sho rter !'I'ri IKI o f !inll' with all lucri-used hlood flow. Uu fo rtunah ·!y. . l'hnmieal1~· I ..lill(' dea ranl't' follo\\i1l1-: p m p r:lllolni acllllinisimi ioll is 1 1I~l'r tha n that (.. Ihl' n-sult lIIay Ix' litt le or 110 l'ha ll~l' ill .tlc• • D.l\'aiiahi lity is t'xac1ly lrIaldll'll hy thnt of d t'.llly. of glXKI ' !Ualllilath'I' infonnal ioll 10 hI' slx"t. aud tln.'ifil. · :\lIC or AV C "" F Dost'ICl.tn lial' s failun-. K lIi~h Hepau c Extral"t io n Hliti n .. with th l' n-ahzanon tha t in therapeutic Sl:.'(llIt·ntly l'xalllilll'(l aknu-...1 lIigh Il('pat k extraction r atio. T.'l.dl'~n'(' o f sh U n l i ll~ or b~V'L.. .) is indl'IM'ndl'IlI of hlolKlll uw.'l.lll~l' in lidl ll'l..HI e (last ~mph of Fig. HIlIl·le ts (('(hll't' l"lrt lial' nutplll aud ht'Il<'tk hllxxlfl nw._'cJ~.. Th m . 111 iUl'rt'a.. lI e (('. ('tll\sidl'r the.. hut Ix"t. "'1. rat io. t'(lnation.l'i a 1 lIt·!l. an ' n 'ad ily appart'nt.... "''''ON E J0E1W ~o Wl/IoCT ON lAl l() !-f'AIOC . It•• 1 2-3.CHAP ER 12 T 19 1 hl'('aml' t'n'I)' bllllxl n 's<.wi n~ (build -up of fluitl in Intestina l Spill't'S and botl.kN .lilll· is a d m~ \\i tll a hi~h hl'patic c'xtm l1inJ1 mtio am i wlu r.lfi(: t'xtra(1 inll Jrly 0. d m g II. Altllough 111(' half-lift' i.... adnuuistrut ion of a tlmg l with .ll1uln] ur Tlll'tnpm lnl pnxluc't·s II dt'('n 'll'il' in till' d t'anu lt't' of Iitloea itw.. tlc P. :'\ot so apll. am i thcrt-fon. p.U1isllls lllay alS() lx' 01'K:mtin~. suggt'sting thai Ollt' ur lllO((' (JIliN Il\t"t.. Ht'<. A dec rease in hepatic bloodHow..llil' ' hllllxl llow.. in which ca rdiac uUlp lit is dr-cn-ased.1 t'll for thl' dmngt· in !I'1l.. · l'U\. . is Iucn-ased. of Two Hypo. till' kim-tjc ('tlllSt.kl. w 11t'1i hepatic blood no.".X!)('<... 12. oc c~Iot""'I... L ) \\ ' Ill'plllil' E ~t ruct ioll Ruti o ...\'alt"tl hC "t.. iL t'XI)('<. "-.."tIIll' nl't·s o f altered blood flow art' suhSt.. in lllilt thl' rlltio o f tht'St.~ 6 77 .lmrll·lIl'tI.'l..(..VAA. its major pml)('rty is low ext ract ion in b JtIL oth o rgans.' (Img L ll.. D m g II 11l'i a higll Ill'pali< extraction rano ami is almost t'xd usi\"d y d iminalt'll hy 1 : tlll· liw r. l1 11l~l'st in:' l-. sallie t'xpos un' of 1111' dnl ~ 10 Ill'p al il' pa rt 'l 1l'h~ll llll l't'lIs .. T Ill' HIIIC1 111W tll'!w lIlls 011 wllt't1 w r or nol tilt' illc'n-a. II1I'n' is II lad ....oo OW 005 0.1 in tilt' o~all may 1101 pn l\itll' lilt. alte n'll bllK l lIow has Iittll' o r 110 ('fft'<.Ill'rl' . For (·X<tmp l('.sociated \\.lrt'lIt an ' ti ll' likd y events th at follow w 111'1l e1 m~ II is ¢\"l'1l or.. \\i tll a d l an ~l' ill h lIKKlll n.two d m gs ~\"l' n ill Tabl e 12--3. Al'('t l((l ill~ly.. s andunder a varie ty o f condmons.. Figu rt' 12-6 shows th e t' fft"t:t of a doubling of lu-patkIlllllxl llow for til(' I'Il K clean-d d rug .U1SI· tll('y an ' unconuuou. s p. ful ..... Udlll'l. pmpr. drug I ~ 1~'edUSt.tln-re is less chance of d m~ l l('ill~ e]im inah 'll... OlST ~WTON 09 7 005 • CLE"'~ . D nJ ~ 1...p'ltlt'nJ of chstnbunon o f hlood How . """ l H III().l(ill\C wheu hlcK l lIll\\' is incn-ased .f)).1 I"t1. til's). Tlus is nol 11("t. tIll' l1J1l< m 'nt a<1ministrdtiun o f t'itlll' r 'i :u P-hllx.. is 1·limina!l'(1 in IM Ill" liver ant! till' kid ll('~'S ._.si ll~ of tl\(' pa n' lld l~l nal l't'lI s may oc cur ill certai n lrepatk-d iM'a.7.ol8llIiY" "''''' '" 26 A30 . 11\(' dl.. Fo r this theo n -nca l pn -seutanon.0 3 0 05 0 05 0 06 · ~ O:b "" ..'t'lJarios th l' t'ffe"" s of dmll~l's in 1IIon' than 0111' phys i olo~ic \" ariablt' 1J1"t"t1 to lx' considered ..·m ls to po rt al hn w rtt'ns ion ami t':lJrdllt'patit' shunti n~ of p ortal blood.. 2 't' K and 3 prt "tlid 1·lllIlll t'ffn :ts ..'it"t1 thinl. and sloWt"tl dt stnbnuon to the tissues .ami n-uul fll11l'tions.l.. 111(' events folll: \\ill l-: Lv.. oru l hioll\" ailah ility is l'Ic.... h n ml-:ht ahout hy cirrhosis.h..e ( rlllxl t'\<lIn plt·s of till' kiuet tc l'tIllSl'llllI'lIl't'S o f uln-red bllxKI now an' hard to find . ~_ 'C_.'~I ' fi ll."blood . (CI. All l·xamp lt· o f a d la ll~l' in kirll'til. is ~\l'1I \\i tll lidol'aim' in Fig. ttlun till' eltmtnal inl-: ory{an may d l<U1I-:t'.w d ellr:1II1't' is (X·rfllSinll filh' limih 11.c...1 011 the pharmac o kinetics o f Ihis tlmg. 111l' IlWllmry aiels of EllS.II1St' a 1I111111x'r o f ad d itional comphcanous alwil~"S st"t'1I1 til IJI. 12. . dc·anll1c't· ami ura l bina \lli1<lhilitv an ' iJl l'n'll~"t1 simultaneous]v.I/ Fu = CI. diuuntshed lu-patk...St' in hio. an' oftl'n a.(·ur concurn-uth-. l'tJlld iticJIls such a.' "" Cl.

l . 0. TIlt" substantial renal excretion of allloxk illin explains why a rt't hl('{'tl n-nal t:lt'ar. . .. .tioo FiWIrt· l ~ s!low!' tilt" efred of i llh ih itill~ tilt' n-uu l tubular secretion of alllm. 'r lUI n...IiFT... 'nal th e exert-non rate n-lanve to Ihe plasma conceru mnon .. of holh t1nl~ is 1.'n·'l'i{· in rt"llal d earam'(' occurs bv inhihiliun or rlu.0001 0 0.001 0 0. INTEGRATION WITH I(f\/fTlCS CI-W'TE 12 i Intravenous Dose Oral Dose 0. 0 ...Ic· 12-3 fur uti pharrnamk illti il: P"'1)C'r1 it-s or th.. Ih..M1.. . :". ......·..lIIl.] (31IlJ""'ItI .m llo pla.killin by prolx-ncc id.t· in clearance.... r"IIo:.. · . Drug H ..f Il mlt I ~ .Q1 .JrI~ .v.tlill~ that p m h(·l\("C.0. it rt· lIc :f:s a dc... Not> ... "( Tlu .1 -o·.1 "" tI..'Ilt"C..l! or l.0001 0...1 Orug l 0..-s in \"....... 1 11.n. ···.1 or..J..\0. Til t' inhibition o r renal excre-tion ur this pt'llidllill by pmIN..001 0..O f". 111'1 " . li"'.... I... (--).Q1 ~ g c c 0.12-6. s.o.·1i.sked by Ihe contrtbu riou o r filtrati on at ti lt' ~lo l1l{'m l ll s . 'Jt. ....hsorphnn half·lif. (lS-1Il1U .4 hr.·id . · ..: or Inhtbttlon or this pml'('Ss is ma.!: II.'IJ('{·id he'c-'umes appare nt w!lt'll this pa th way is Isolated. TI ll' de~rt"C.....: !l c <.1 D rugl 0. is d t'ar ly 1't"CIUl'{"C1 hy pmIN.· "fT. 1l1: sill""" l.1II<...~"...1 the di stribution of amoxjcilliu..It -s.1 Oil total t'lc'a nllJt'{'... An Increased A UG of a moxicillin is o ll..1 .... 11.....h... · . . linl. hilthlJ d. .sllm prote-ins. .. 12 Drug H 0. i llt l i {'.1 0..001 ~ .> Q 6 12 18 24 0 6 12 18 24 c 2 ~ 0.I lili (· .. .00001 18 24 Hours 6 0 6 12 18 24 <In idtt'l" .{'.. o nit. .2 ~ 0. a dru~ that is virt ually ullhCll.·n.i o \ls..i d doc's d nut afft"C.lI1('(' hus such a p nlllou ll{'("C1 c'ffc't..K ... 11l{' dt"C.11>1.In~ _ Altered ActiY' ToMIar Sea.01 <: ... iUt'S fur D n .. HC dt'ar.. lf seen-non is . I .'(:rt·a<....11:."'K 1d T 1 "" Dm lt II.o.v.001 .tubular M"C: rd oT mechanism Y for umoxjci lliu.Inllo(..... T... . .l. -.pn llllJl ~lIti(ln of ehminarion Imlf-lift' is also dlle' p rilllarily lu rt"CIUl'{"C1 elearauce: Ilnvolume of dtstnbunon (CU k) is change rt'lalin' I" littl t'.... --l: ronnn. lili.. " p nlo. Ah.. I... .Q1 0.. that is... ..

.·n· .10..·Iiminah"". il"· .. in ~ a -I·min 1. lr.... al1...· l .... _ 2..nloac. i ll rll~i"ll (3 ".llio ll 1 of total n lHl~ 'n trat illlt lb ta. 1 "I.. I .· t-lt·ar.I1~ ill "..o...Ui' ''' h...lpt'"lkally important... . 1' ....uKI I" 1"'lil· " 10 1H -....· ... ·r.. 1"..'. nl(·Sl.·d bimlilll! afTt'l1:s lilt' unbound ptt-slIla com-entrut ion .~ .')l....·no.. \ \1 \(>11 aet ivities...1\ . .I"ti"" I" f".. I II. I f" Hn :5 0 11 0 C.~ to pla.nocl..· 0.. 11"' ".. U.i<"..·O'..1 t1. pr oblem ilppli(·s to t1m~s or l" lth low <l1lI1 h i~l..." ". ' 6 hr 1 "2-1 hr .·n...11""'1:""" I.1"f I'n 'l' '''' ...'lI. fill" .IlN ' it is lIut n'ahsurlll'li in rln.I... ill 1" •• l'n. n ...n· ". (50 "'It) "r pm"r.. C Hi Ill'l'..1"..-1.id.. 11I. n-nal dl '. 1"""i.·.ld in ' silt· is 111t'f'. "1t " 'It) .. oI. 11" ' 1 ".' 1 ~1.". l lll l>: ....· d ..·.l... "f "111<"idlll1l h I" "It''I )... II L ..· ". rk-sin-d an d undesired.l... n"I.-\.. ". 'n.n"... 111" .....I I"'''l''' . a nd tln-rero n ' tilt· (~ Ill(~ ' II I r<ltio" ill 11.M. II mW] .t ubule.· n 'lIa! d . lilt' h i lld i. K.". iliUm i' .::< o ~:.s ma pmtt·ills is ahen'll is cri tical to ptLSIIM t1 m g: rnuce-ntrutiou lIlnTlitorill~ (Chap. · ly h lnl:kt'll.. ·ar ...1I 1 (~' u r Ihis polar an tih iotk is ('xpt 'l'h'l l to " a V a IO t' WN limit uri ll .1" " J !u........ n-lan....g: - E ~ 10 Plus Probenecid ~~ ~ ~ E " ~ 0..·L.... j o- f. (·..."".1. "..·n·. 0 -~ u ~ ~ u 0.. .. a llol Kunoham..U'C.I. lI"'I...·ftl.. ".1 01 • 0.3 "M ) (. 1.. " I.1....\'....af"' rl..1 a"...ili"tI" I> II . 111i.·n~ I"r...-\' !AJ"..· . J.I.' lL S!)t'(1: s a n' nnw addn-sv-d ill tum... d la"~t·s iu hi lld in~ di n -'l :ly afT(-'l1: tilt' inlt'rprt'l.1 . j.7 . tln...1 eli"...1 .· .l 1 100 Control 'u -. ·"Imh"" ("" I.II''' 1 e zs "fli. 11.".""p'''''·''1 of 1.I ·IM · 41>1 1 <1. ".u K~· > t..IIII: . . I. a.1 0 2 4 6 8 Fl it.. <:I" ·"I<~ I ..li"" ( ." ..1a! d . "1 " f 1' . -n·a" ·....r.... : I.. l lI"rt. 12:27. IS).. I'''1>: ~Il hjo.1-27...."".IllJlll>lll .· a" l i l>iI ~k ) .·f" n· II.dol n.. 1m....l" ic: .d couceut mtiuu . ·ar..f"1' . CI. "..) (~)lIlpld.'. " f Im.11..". " " 10. .. 1\h1 .' 1 .ot..II." I lor I".~ltl i. (-Il l "'0 "'" <> 't: 5 u ~ ~ ~ ~ ~ ~ ~ n".. .w1".·.\tradi nll.1 ' I 1: 12 lor . K~..·r.li" . · ' I n'lt!l ....·n.·f" n' tI 10.U'."n .1.·1f..:i<I . 12-'1 .a" . ) .. .1' .....': n.... s \ \1wl ht 'r ti l" !lol tile' a ltt-r.j" T'.. ini.CHAPTE R 12 193 1.. \ 1) (Dat" fRlIll " Sl.n" li 1\ linjt f.1 n . ...." .2 Control n it 12-7. i• •111.·"••i. 1:I3. tI. tI... Elf of l1I...\killi. Ahered Plasma Protein Binding I\nm\-II'(I1--:I' u r (untlitlolls ill whid .U "'· " f Ii.8 Plus Propranolol .'. FI.4 .tI.. 1.i....'I.1-I.. It: A" I<..... " "r I n M · olmlt" ' .

Lo..w.I'"'IL''' j I ". ali( I ~ Ill WI . U1t't' ilppt." "'''t...'.I IlI lt. C lt'ar.·.1. ~· " I' n'nal fu"d io..... t1 n..1 1.•" .m... lIiKt.Ul~(·llwllt c - COllt't'nlr.. -n i. i.lUs('[u.· "r n " " '.1. O JllSt'flut' lItly....' 94 CHAf'lU 12 Low E :-. 111 \'0 1 1111' of d ise 11 tn hulioll ( h IIM I) and hillf-Iift.. incn-ases tu 011'0111 0..1 ... n it.. Tot al e11'amll tl. volunteers.· . \\ll f nu n fl.~li"n . . This is the hd m\ior M lt! t" I)I'(1t"t1 fo r a dnlg "it t. Io ..".lW .w. "f n ~ I.I ..rt..i..' In n' '' 'nn ' " f "II 1>I. "" '" ~ \. ~ I .. O il n·arr."'Olllt' t'flui\'llll' llt tn .. .i ndllw of pllt'lI)'toin i t ' a fUlIl1 ioll of serum creanuim... t \ 1 \ 1 .. hll l~o. k in•.. 111t" dmg is prilll'lri l)" d imi ll<lh "tl hy lu-patk.. IM 1 int'n'iLSt' \\i tl l an iIWf"('iLSt' in frl. lI:' I" j. tI . n .-".1.('i(' is ti lt' c um. wlu-n III <lndfrl ' art' 0. is 1111 rt 'flu in ' llIt' lIt fur dusi ll ~ rate ad justlll('lIt ht " 'il tlst ' "t·S St' IIllhU1l1\(1 ck-aruuce.In.I I5.\.\ lf ri ll . " larKl' \"1)111111(' "f d istrihlliio u and for wh idl t'l im illa tion Is 1 )I'rfll\ illn ran--lunin.'(..~' "f ''''·· ...t"hnlisllI..al fu · C .. a ' l' .I:2fi. Io~'n'~"'''' "''il l..lrs to II(' Independent of p r o tein " illdi n ~.5 10 0 ... rt'Spt"( 1hl. t"l. n ·. \f . n.lrad io n Ratio . · n~1"i" I". tln.9 .' .p m po rt ionality constan t [wtweeu rod e or input and unbound conce-n trat ion at sll'ady stall'.(If d istri bu tion..IUWt..2.s in t jn.·ly. " ..1 and 0.011 .1 1. 12. II ).ulIl 20 lIlWI.. volunn. C " a ll~(.'5 . ""'. is lint aIT t'(1t"t1 h~' til(' hi ndi ll~ dlallgt'.. . n'lI· t ..~lln • 2 o o 50 100 150 200 SerumCreatinine Concentration (mgll) . . an index of renal function. '...) hll'l"t"L ill n-nul t1ist 'iL ..J 1'1... Fi gun' 12-W sho w s how hluotl clearance.i. u'U .~il .· f is till' n-ual Iunct lon. n·· tiM' .2..w.·.~ .. normally aheml 11. I' IIt'II)1uill is a 1 t' \t r. in IIu rmal l'lJlld itio liS tilus hc. . and th l' nu-t - (I" 1. 0\\' t·lilllinatilln is rt'! ah't l to Its unbound concenr ra non (C ha p ..tl'n. 1!l73. n~II~' "" .1i\"d y."'I W In ::!l l ".. E \ t m l'lio n Rallo.concentratjou. alld half-lift' o r propranolul \~lf)' " i th Iht· rr."'It....t(:l iu ll unbound in slx ht'ilh hy malt.u. gin' lI that lilt' u nhound ccnce-nt rauou n-qutn-d 10 pmtlul't· a ~H 'II re"POliS(' ill till' pn's('lIl" of n-nal di st.d.\' n ' re nal f' lIll1ioli imp'linne·lIl .1iu ll d m ~ r-hmtnan-d by Ilt'p'ltit..pt't.4 n 11 \ 11 ( H. Z2fi.lIIt...·.nn".. 1'" . For examplt-... I'id .. is show n in Fi ~.''''i'.. tl"" "I" ''' 'io..lmll: " f .fu" C • 5 whe-n-III ' and C ' aft' tilt' Iluhm llld rnu:tioll and Intal d m v.tlwra peutic .as thut ill tilt" a h""'lwt " it {" lInw' tl. -' (If till' d i<w... concvut rutkrn in tilt· prt'S('m.. hUI tlll.. The ' \i ndo'>'" falls 1".· n'n.. tln.IIwtaII(I!islII.· ."i<Io·II· . ~ I .concentrat ion .·.3 ill patu-n rs wt th S(.111(' h i~l1t'r tilt' r-n-atinim.. cr. TI. 12-9.' · n l ~· "f l!..J ..lho l\s u f 10 .·. .I..

II .. TIlt' lialf-Iife of clofibnc add (the al'ti"t· mat eri al fonm-d bv IW tlrnl. li'n il...09 0.d ill tI. Although then.. i t""" .n " f 2t1 Ill"..... ..11 Fraction Unbound in Blood ... ""I....J f..(. pl'l" 1 l<"in. " dml(.." "' 101 l...lr"'"." " " I"I . · wi'h ......I"I. it"l u f c ....r .t " n..n-d IInd langt'lt) is indul't'(1 and tha t )" t1t)sa~t' n'f lu in' IIlt'1l1s need tn I~> incn-ased in the-se pa tients. 1.'l r.h .. It is tt' mpling to mnd lldt' thai ll11'taho lislll (0111 ll% uf clofibrtc add is r-xcn..... t 2.(! am! tilt' ('t)JI\"('N'.ur nil dl'lIl~l· ) in tilt' steady-state unbound concentration or till' thera pe utic rt>spon 'ie a fte r oral udmhustrution .1 ( .. VI: l nde p nd e-ut .~ ~ 1 "' ilh I"·nni..· . elin.. Small Vo lu m e o r Dislribution. liin. infu sion l'tllllliliom is Increased w In-n bi llt li n ~ is c!t'l'IT'll'il.....·..1111\1"" " " . ....10". An alte n mli\"t' vi ew o f Ihis situation is to n.. lilt'S(' l'fmd llSio ns an.'it' in ' 1)llIlI1t' of d isl rihu fion . d ofih m le ) short r-ns From tilt' usual Ill..... • 1" '1 . ri. -~ ~ . 1."Ot""'T....r~.lly hy tilt' p an-ute-ml ".. Tbe d" "r~"t... ..1 .. (. M........ ..1. couccntmnon under co nstant-rate L\"..·.I1. 1I"·n . I... as 11ll' fnllIJS\i ll~ sllows.· .' "I "" " KI...1... of ... Id". 1111" half·IJl.&l. lli< N' " f flrofl.. r.1 es te-r.lItt' under ('t)Jld itilllls ill whid l hi lltling is altered.... From a p harmacokinencpoint of .. -ith a hi~h hepetjc extract ion ratio... fn.Ii" " I" pi.di"" 11"1"..lie (h lootl) d l'lll"lllll't' approaches Ilt'pat il' hlo odHe w ( 1.-t.It!tnlni\1r.d 10 dl llll~t· ...n .. 11. a """nil of rLun.. · fr...IO...1 lito ">-1..2 u ~ • • • • A .5 h r I...0I.· I....i th aln-rrd plasma hi ndin ~... . TIll' l'Ollst> fIUt'lI('(' o f 1Il1t'ri ng hillt lillg to ph~l1l a p m · tcins is illuslml('(llw clofilmm-.itm_ ( I 3_~ J.. t1ll'f(' must ht' a l":Jrl1 "!\ptl ll tl ill . ...f· ill lluhOlllld clearance.. (h...41i....... the. .1in 1110-...h'jUJ. 11...... S. 11 pndlct s [itth.".h' ''' i " "'.. 4 • 3 0. ht.ulF "" C L ln l . nu. as M 't"11 Irom E' I_ 17 of Chap... ilK """'" m "".lSl.. i.-tit..0 0. tI ) "..n .35 [l m in 011 aH' m~t ' ) ' 11!t· in l'n'<l. " f p r"p .... l·".. ..f. a n dTl'l't wi lh pol<'nlially im po rta nt the rapeutic consequences." .. \ \'ith th e lncre ase in III and 110 dlllU ~l' in clearance.It inA... "f d1drll..) li' ''' . An iJll" rt' ll. f_ f".CHAl'TtR 12 '" " IM.a1lh" m"lt· \1 ~ u n h~'''' E 5l Q ~ • • z: -c Q o:g >1n i5 E -~ ~ t • • • B • • • • • C :5 . are fo rtllnatd~' Sl" 1tI0 1ll ~\'(' n dmlllil~d. . l ie n ' Cl. it... ( 1I::r"l ~1 C ) .9 280 240 200 6 5 . Silll't· CT "'" I ll. " ill..... lrll>" li"" ( ~ .... wlu-n eL lnI is much gn 'ale r tha n Qlfu...t it"l .... . 111l' 1I1('m Ol " aid 1I100:ld uf C hap..........10 0..: Ili~IM ..~ dt-cI1·. Iht·).. Thls means that tln...I'Cl u in e " . .10". (: 11 ....ond.. I'n'1>r. " fo..oK" "h· "·"'t~ 1 I" iI ... "' ::> <l- - "' ~ ..1 1. half·lif.~ dMmu .-ith til(' nephmti~ s)lldrnlllt' (T ah lt' 12--t ). n "):l'1. . ..'ith a high t'xlrad ioll rati o is exp('l'tt'(l to t1t'l·n·..' IR.. ...uubouml . l' i~I)-' M1r..· C1••".~ .08 0. ibu".. lilt' velum...\t · in I II Illt' n ·b~· ratws tilt' unbou nd ('t)lll't'u trat ioll am! tilt' d rug's (·fTeds.. I" .01.\".r. ""hd · · pod..i lh/u is au ttcipated. 1> (... iera .11.It! S1WlIt!... TI... It! II./...are Illany d nl~s . ll ot is 1I11c1 1'III~t'(l. 'd aw "r In n lfR'lot.l lol l (1). Th·r _ U4fJ. 1.lf·l... r " .Incorrect ...... 1..'l~d llst· el. ......Io-·"r .. 1 ..· fr... K'l.7 1lr ill patie-nts ...... us is tilt' Increase in half· lift'.n "Ii.idl an Increase in I ll.. Ihal l.m T ill II.·I! "" ~ 1.of I"" .D7 0.·IlIt'III!Il·r Ihal \\'11t'1l cleurunce appmadw s bloo d flu\\' in Ihe t' l i llli n<lt ill~ 0~'1Il ...1 of six .. ·n· h I"·rf" ." AI....I}'••'~I ••(in'tI Lttlnjt dnlKt.js of til(: i1d m inist(·rt'(l l"Ill. 111t' oral bioa\"ailabi l i ~' of a dnJ ~ ..= c 1.In'lI: I"'K I'''K In ".li....l<..... ltltal slt'ady-stah' conceut runou is not cxpecn.

is 10. lId With clofibric acid b etng a I. an apparent volume uf 7.- .0.055 1 + 7.. o l F"..tZ I. TIlt" hal f·l ift· is s!tortt' Ill"l! ill 1!It' nephrone pauents because.1111(' \ 1 ")" dust' 10 tlml 011.<'L t1 WII th e 5.7 I...81" "f. lSlIl.aW"'dgt· unbound ttc l'lllK't' lltmtic)IJ in plasma .b IQQJ I a"'ed Ed..5 dIJK. a \". JD e. .III ('xtl'mivl' loss of pl. (0). Poll. S I lAir.<J ddob""''''''' '''. there is ..O'-'<Jddbr"'oco:l . CI."-Y""_Mo<~ . ..Al . 'II/Cl .. S Noooo...Illllllllin. a \11111l' much smalh-r than llt'p.. If otn.of distrihution (Eq .32 S11 lAir in lrealthy subjects.1.3 W / ilL.... oo esc "'CO '"<Al. I i'ln..5 + Constant · Iu Will. 111(' calcularedhalf-bfe (0...of dec re use hinding 10 album in..5 x 2. ·0 "" 'IlI'<I. as shown ill Tahl(· 10. d Unb ound clearance was 1101 cbanged. v II: 7. Ro.mln.\~' extraction ratio drug.qnul to I. .'('n fmm Ihe n·latio lls!tip I-oI'IW ( '('1I \ ' ilm1fi' for a dm~ with a small voluna.. bl..-de. me-tabolism was nol illd u('t'(1.. !XCI'fTlON ". 10)..GokI>oog.". plasma d m~ co ncentration COIll ollly h(.dn"AG ~ TW i al In lIlt" nep hr otic synd r ome.3 6 C lofi h ril' acid IIiL low cxtractluu ratio ill thai its ch-arance.fraction of available hil\(lin~ sill's unoccupied.n. Giw nl hal /"" .. CKA'''''''' CLE"'AI'£f .7 IJh r in Iwalth)" subject s.lIk' hlood lIow." .18 98 :!: 20 44 :!: 0 4 47 0 0<> ~ n0. III(' vahu. .... I.9 L TIll" \-'Illum e unbound (\'ijid .. • ~.. T Il(" Iullueuce of this drop in se rum alb um tn o nfr l cau he l'st ima ll't l From rl'alT.\ p rote ins into I lll' mi nt" whic h fl'SUlts in a tw ofold drop in se rum albumin..'96 INTEGAATICN 'NITH I(lNETlC5 CHAPlH 12 T. III(' coustaut is 6 ..3 WtlL am! for do rilnk add III is 0 . giw n in Ill(' f()(I!Jltllt' 10 Tahir 12-1.7 t / i o kg.11 1A g).' 1 in llt'pl lTolie p atie nts...59 l Air.3 hr.. ) in Ihl' m-phro 1 ric peueuts is tln-n about 9 ....l.·1"\"("11. tln. TIll' value o f unbound ek-arance . thi s is impossihll'.. 11Il\\l'\-l'r. · . IfIII is illl:n'a\('(llo O..hl argm' thai hluod clearance is much largt-'T rlum pllL sllla dl'ara lll't· (also c/e" > I ). namely.g. • '>I ~ ~I c"""••..nlll'l Alb. IS (C hap..7 (1/(1 . . This is ".Jl 1 lll Thus.ln-matocnt).-c~'9¥-.(If #\1 is 7. lttl HaU. · .I... ~rl'at(' r th an blood d rug ('tllll'('niratioll hy a factor o f 1. 0 ....1 ' VlCI.. ..L1f. decn-ascs fn nn 2.k ak'u lah '(! fru m k ' \') is 0 .. (N · 51 Conlfol gfoup IN . of tho Actl Fonn .:".flbnc Acid. or U.I M• • ... is r.n. ~ ~ .3 :!..• ... CUI". 118 10">\ . \'irt. ..anc/P lo.""' NephrOlic g roup . TI \(' volume o f dislrihutinn of clofib nc add ...xr>ot> ~ _"':lrqod <>'dW--"~ 1 ~ .. tlu-n d t'amJIl't'. as ad lil'\l'(l ill pat h-uts \\itl l nonnal Sj'n llll . in this ~roll P is (1."..5710 143 L.69. M'(' Appt> h I. 101'" :!.... :\ lth()lI~h oue miv. O I I LfI.is ('\1)('(..' 1'(1 to illcn·.. I II ' Cl. 19n 1.AP 113 17-125 . AI a serum albunun couceut rattou of 2.. 25 .re " S.7 h r.5. I. .7. A sho rter ...f Cloflbra"...~oIo:>go<:b><J~.69.l lll't' ill uepl rrotic (llttil'nls. is 7. tilt' calculated fml1io ll unbound in nephrone patient s is then Iv - I _ 0 ..c. 1 100 :to L4 13 05 87:!: 35 165 :!: 13 :t 12 1 2 :!: 0 2 ~.Haa>. TIl(' two questions origi nally posed an' now an swere d. lIppa n' nl volume bec o mes 7.O J ... This \~J1Il(' depends lit tle o n ('ha ngt's in p l'l\-lIla pr otein hilldi ng:. ' ..H ff ~.. 12-4. .F. With. ~lfN ~ .5 10 2 . Cha p. ..L'\l."'" .0 gltlay is nt'('(l t'(l in m-phro patients to p rodlll't· II\(' sanu. TIll' normal se rum alhumin concentranou reported is 4...pn. WIllI ..-. Dally ~1.. """'-cJdo.. ~ O OJ . ch-amncr.. tho N e p hrot ic Syndr . S. and tl u-refon..w y all drug in 1 11' I M )( !~' is IM ntl to albumin (" = 0.a ssumes the same un bound d t'ar...lII~t' IIlt'1I1 of Ell.no dlallgt· ill tilt' uSllal (lIlSing mit' of 1. 000 ro-""'BonOI..

r •• V.O D.""W I' -'>ON . boo oq. ltcr-r. U_r N:IlEAStD fUCTION fH~OGICV ~ enec 9APM'f lf ~S 06Sl' ~"'TI(. ac V 01.~ H<>p::ll.. ty....(' .. Tubh. U st 10 t'xam pll"S o f physi() I' ~l' \<Iriah lt·s that alter ph anll..1e I AL..'S.. inhilut ion of 1l lt'Iahlllislll.. ic va riabh-s l"(ms id('n 'll lu' n ' .. 2 .~<n~a<1_ otdot _ 0/ . n ~ d n l.is 110 elJall ~e ill illi rillsk d t'a r:U1I... hi.<:10<:_ ..('"Sid('n'll... ei~b •. OlC IlE~D '" 0000 low In"ow".n ~'eo<ono:...og> Booo YOllabillty AUC (blood) booonoei .. is oll ly elinuuah-d ill ti lt' liver . This chapn-r hiL\ pR'st'lIlt 'l1 «pp r oaches and e xamples tnwun] i lll (..·a. decn-ased h1uotillow . 11.)lllt' al·th .\i tlhilit)' of a t1n1.'9 """ weoc-o NOooo HoIl-·Me AUC (bloodl 001 1 BlQ(MJ. and ill('n 'ast'll ji..1 Se.~r. in bioI 11. STUDY PROBlEMS IAnswer$ 1 Study Problems o re in Appendix 11. .I?. 111l' l"('lIlhinatinm o f l"(md itiom and s o-nanos in dnl~ tllt' mpy M (' multitudinous..l'i(' . oral hillil\..I.h ext raction ratios an ' l.l?...12-5 summa rize s tilt' (·fT "l"ts {'X I)('(:h'l! From incrt'a.. Dr.l?.-l _ I. Seledetl PII.~ "'"'.!y AUC (bloodl H..nooco ~()rlo [)..ooIy"""""'-'l boo 0 ~_ ..•• .rI_.("p tS.mtiun. I "" _ <J>OoiQb.l?. C E.1?.INlEGlI AtlON '<V1tH IONEtI( $ 197 dosillg inte-rval (a llll l"(.s iwl ~· in lilt .!C ll*lod) 001 ''II > ~l boldr."".'it'l i ('n 7....\n lldTwt ic paramet er valu es ... AlltlclfMrIetI. Pa_ ~Sl""'llON .' Iow to shuw It'nd t'lll'it. ty applies.r mainh"n.. l "'ecVi.rrt'spo lltlin.l ti ll~ kinetic pri nciples and physi ol l~ l' l"(lIIl...uu'(' tim e ) m i ~"l 1)(' couskh-n -db e- c.l?.. ~.l?. O/".. 1 2-5. 111(' ('\I 'Il"('tatinll s an ' similar for a dOl ~ l'liminah'l! only hy till' kid m'ys: 1I0w('\ '('r.. ! fo r dt"('n'.. Also . inl' r('awt! adin 'luhub r secn-ttou ruthe r than inl'n'iL'it'l1 t'll 7.. Co nd itio ns irl\'()I\.s nf both low and hi.IU St ' IIf tlu.. and its \l llUlIlt' of dis tribution is ~n'akr than 1011 L.) 0 I .l.. ~~ '...lf'6 oe tNCJfASl'D ""fMTv" ..gh Hepohc I .tfecb ef AlferMI••• I.• onc_ ' 1 "".slln rk lll'l i half-lift' .\l"l.( lInplt'h' th is iu tl'..'roc Otl 1()1.... _ _ . C..lobol.'it'..iulll). d--""'''''9 t " """""""""'""".)"III{' ild i\._ 1 <:Io<:.S hy lIIarki ll ~: T for incn.. o r 1Il1 d lall ~{' in tlu -{'lIIp ty SP. T ill' d m .hly l'xtnll'l('l i in tilt ' kid lll'Y is IlllafT s ('l'!t'l l by dl an ~(' s ill fi ll' ph)'.ly sumlh..Iy . Then..1 for <l dOl ~ eltnuuan-d ('xdll .. H~h HIgh HIgh l~ l~ l~ . and H for Iittl{. T o l..U9 Inltov<''''Ou~ Ho ~~ .o lllp ll'!t' T abl e 12--fi 1ll.

d nl gs an' d illlill alt 't! I'xdllsin '!y by Ilt'patil' llIet"ho lism) 1I1l1 1t ' r the.• in fit): am i <10111111'(1 ({'...I. uf lilt' hm t1m~\.'" a" m I"). 1'1. Be sure that (Oad.1illll ra tio . Tisslw hilli lillg: is: I\lITlIlal (l'a'\(' A): 1'111\1.'Tt'l L'it ' i ll j ll r ).1II01 protein h ill(liu.l-Iit' T G . ti l(" salk-nt . lIiIIH '(! l" w (l'a~ ' B. Gmp" _H igh c' xlnu.'(1( { '... twofold d t '1.. and dC lllhl('(1(e a se c.t is : normal k uo :\ l.fo lltJ\\i ng: ltm d iticms : I J IW t'xt nu..'ul ralioIlS for till' tlm '(' situations ¢H' II for ('ill"1.\( ' i n Jil T). "IlC. . twufold t1t'(n'il'>L in ' Ronl1".!:::" (hull.I. I 2-11. FigllTt· 12-11 1 ~ lll l\\'S CHoIo.. twofold in e rt·a . . twofold jllt 'n ' .i.1 ioll r auo. Draw II\(' {'u rn 'spolld ing: t illl(' profiles of Iht> unbound {"t)llI't.N ' c . Altered Binding to Plasma Proteins Time Altered Tissue Binding B TIme .pmlih-s ural atlmillis - lratio ll u f I\\U d nl.PHi I2 r()lIu\\ill~ plasma d m g: conceut mnou-tiuu. ~ru ph show.' . II.

..."••••••"d Oral AtI.liver .·n•• CUrv•• I....'11 o rally.l!enill t' nh'n n~ tilt' S)1\tt' m k. 11.~tic aJ...'rstood nnlil tln.li\l. am i fi-nu-rca ptopu n ue . 1 2-8.rwte . For 11.fon ' am i aftt'r pn·tn·alnwlll wit h allop uri nol ( 100 1lIJ...lltl)' dlaJlJ... Tlu... l1 w ..g with time? Co mme nt bnefly.. e....-thn'O-llwlhylpht'lIidal t' (Ritalin) shows ('llanliost'!t't1h i l)'....hves. !o. ad ministmlions of (1. A tim?: highly lxmnd to plasma p r o s ifu :::: (J.. H_H·Uv I. 12-7.-aptopu nue was not . rln..tr•• I.. an allt i lJ{"()pla.l)" for 2 days ) f(lIlo\\ill~ oral and t...(' 11 blootl/pla srna eonee utration ratio of n...interaction l...·tW y ('t·u allnjlunllnl.<.... for each isomer I ..:t'III. t' 6 .(' two tsonu-rs. a .I I. C lt·arJ. calt:lIlatt· lilt' dl'ar..I..lt'lhylpllt'lIidatt' is gi\l...Men. ..".dilTt'n:'lIl't"S ill ah~o rptioll anti dispu~ il ioll o f tlll'<. .. immediate rl'le..I.phunnacokus-tics o f U1.\lIe vallies of l'inu-n-aptupn nne. PI••_ 6. 101 4·11 1<XI3 Cnlculnn.. .O l) bas a v tein olume of di slribulion of 2"'0 I jj'O k~. .:0llt...I . Tln.l\e ) dust's of ( + ). AII... I'rmid.iwlI th at Ihe kinetics of t'ild l of the.. . peak umos.) and ( +» of abo so rllt'1:l m.. :\ 1t 11fl1l~h rl'<'1~liZt 'tl for lI1an )1. organ of el iminalion. 111t' )' hepanc hl(xltl Rnw ls "l1 lAir.: 'tl h)' allop urinol treatt nu-ut ..I(')' of fs-nn-rcaptopuri min til(' prt'S('IW of allopurinol.CI-tAFlEl/ 12 INTEGAATICN WIlH I(INETC S '99 featun-s i lldlldin~ n ·J..).._•• Area.. ltI.. Bn efly di st'Is.1' pU'l xJSt· of this problem ..iso me rs is 1I0t alTl'<-1t><...--.'r is the on l).·urs.... TIlt' half-life of f)' l!len..· U MathyI."1..llt't· 2.U1l1· anti hioa\ ailahilil}' of fi-mereaptopu riue ht·fore and 'lftN alkrpu rinol .. nuuole of f). A. cst tmatc til(' approxi mate isomeri c composin on (ratio of amounts of (....ji....ei rcula tiou . and half.. O ral h ioam ilahilit\' 3 ..('t1 in tilt' tn-atnwnt of J.: o mlly Ihn't' lim es a d.. ~SC>". .... is (111 O. nwn'aph 'punm' an' ¢n·n in Tnbk..... Botl....12-7 . (' 5 .tNOUS 110 '"'111 AUC !JJ. Do yu u t·X!x"<.'..I..· arens under Ihe curve. 57 39 ~"'"""'d~ .i~O IlW rs . h. PIo..lMl.n~. Tah le 1 2~ sutnm.. ( .. Si~l ifk~d. h.g h.tilt' fullo\\i nf.~ tln. 111t' "01nun-s of distribut ion of hoth drugs art:' ~rt:'att' r than )00 L .EO B9 120 15 36 <r<lM4o:l. .1 1I.fe (hri ·Adopood ltc:n s.lh1. (10 Il\~) and oral (-i f) m ~.l by the othr-r. 1I>.kim-tk-s o f Iht' Interaction WR" elucidated. U..') dl'~ pi lt' the fad th at Ihe Fractio n in blood that is unl xlIIlld.6. 111 hepatic ext ract ion ratlo is t' lUI.P"eP-rl_ Ce_••"../ l) HaIH. 1-)6CW{ ~ IN1Uo.anti (.. N ~ lAB 60 ~JW ~. ....". 1I0t wt'11 1111' d.' a IOJ~ktll ktnettc explanation for the enhanced t·flk'.' )( E.. \ '0111 111(' o f di ~!nhutioll b..1.v..1 the ra tio o f the isomers ill plasm a 10 dlan.._ ••n A.rI"•• . ....tI_ th.mze s the ohservatlons aflt' r Lv. drugs an' nlll~t1y elim illilh 'tl h)' nn-tahll!i SIJ1 in tln... AUC . wa. Ay.. '.

. and half-lift·.9....lilllillalt"ll h~'IIl 'pat ic lllt'tahO!iSIIl .· ~' l ur pos itioll .s tall' 1"lll\(liti Ol\S fo r bot h d m gs. Pmpnu lOlol is t... 0-1 AVe .. 100' 111t' a uthors SIl~I'st t hil! a ll illl'rease in 1 jl<ltil' hlllll(llI lIW is.lil"l"("t1to Ik' p n kill dll~ tilt' !l<llit'Ilt' S uri nary tract infl'l1 io n.8 .unpk-illin a mi sh'a dy-sta h' l'fllltiitil lllS apply.tissue binding? If so.. . 27 . \\111'11 th is dnl g is in fu !it"tl infm\ 'I'!lou sly al tilt" sanu.t.... Est imate tlat" vulu('s of til(' f()II(J\\i ll~ paramet e rs fo r t his d n ll{: hllMMJ dt'a nUlt'(' (CJ... (\'.. of a mpid llin.. I't'Slll'(. _ Prett-_I.lim s " 11It...oo-.. . clearance (e Ll .. Tl ns value is tilt' minimum inhihitorycoucentratiou a~ainst an alltihilttil'-n'sbtallt tlrga nisllI Ik.ion ami by wha l Fadm is lissllt' hilltling t I"..8 Ddl'nnint" tilt:' minimum orulmatnteuancc doSt. to keep tilt' u rina ry d m ~ l. volumes (If dtstrtlrutkm h.. 111t' effects or rO(x! Oil tilt' oral hioa\"ailahi lity. ultt'rt'tl? c.fH..PJER 11 a.( ccmenn unous in ri a. i . to h~' ~\'t'li ("I'l'I)' 6 hr.200 NTEGAATIQN WITH KNfOCS Ct-lA... the " 11m ' o f ji'l... 1"-1 .lllty.1 0 11 d m j. Use all ll\"(' m~t' Ilrim ' nllw o f I III I / mill..t.. In uremic pali.1. .. . am i ~\ VC o f p m pnlllo lo l art:' summarized in Tahle 12.labil. Is then.llit' n t w ho is and hits 1)('('1\ Tt"t't'i.h ). ld b .1) and in h ltM (l'b).un-mtc sta te alTt'(1s tln. .'· of t h~' ot her d m ~. I ustan tam-ous absorption a nd d i.ng another d m g.stri lJlltio ll of . . th tilt' au thors o r lIot? JlIs ti~. in what tlin.·1l1s til(" volume o f d ist ril m !iull 0111(11111' Iraction uubound in ph\lllil . f..1ivd y.>lhal tlu.1.• P~TlI S .Ic a-_. j~"(:t : F(om ll • 0 . mn'llt ra tio ll (in Urt'f('rs) aho\"(' 50 IIIWI.. Do )1111 illQ't"t· ...'(' ami " b M '!I<. Ii.jtly.. rt'Spollsihle 1t' for tilt' ohSt' r\rdtio llS.1. 26 138 ± OI2< 27 8 ...\"(' m~e phamlal'uk int'li(' pa nUllt'tt'r vallll's ill a 70-k~ sub. Ampicillin ha. 006 46 :!c B..~. tilt" f(}lIowi ll~ lI... 2b 1 (X) . 12-9. pn-dict tilt' ml io (If lilt" Illlholilld < 11:0 rr -nt rations of t he dm~ ill tile prt'M ' ll<...(..In it 1l.6 Ct '"' 160 ml/min V = 20 l Ie "" 0 ....tl ms la nl m it.any t'\ide un .oo. u\'t' ragt' un L and (UJ3. Unde r stt·..ty (%1 4< Cleorooce d lV minl 001 A~ lm g. s)'slt' mic ck-a runce. is 1I0W Icund tu Ill' O. ill Iilrgl' part ..tlf/U 2 1.

INDIVID UALIZATION .

.

~l o R"t I\'\'r. in tilt" remai nder tilt" d iffNt'lIl'(' was insibynifil'llllt . A fail nn' 10 do so can h-ad 10 im'lTt'(. 011 a sim ilar but broade r pomt.nlt'll o f the dm" llIay 1lt'1"(1 1 ht . tedto indhidual d nlJ. tlu. Explain how variability in beccuc enzyme activity monifem j~1 in variability in both phar· mocokinelic pCllomelefs and pIoreau p1a!>lTlO drug oonceolmliOf\s fOi' drugs of high and low hepatic ex"oction roses. 5 . liS! six major sources of variability in d".inelia.i1il'nl is all-important .'\'\lin~.! Il. hUI di ffpn'lW a 1l1 01l~ pt·opl p do exist indudin g tln-ir r e spnllsiv("IWSS to dmb At'(:(J nlillgl~·.1Q response 2. Subsequ ent chapters deal in much gree te r t!l'tail wuh ~t' lwtil"S (C hap.. IW afft'(. iut eracttons ht'lwt"t n dm w. 17 ). \'it'\\'t'(. of 3n pat ients studied during am i aftt' r n'covery. luformation rt·rtainin~ to th e imlhidual!l.'1 a ~ Iidt' 10 illdhitillali7jn ~ t!m. given potent popuIorioo phormocoltinetic dota and the individual's eecsocbe chorQCfefiylO Thus far. $lole whyvariabilityaround rho mean and ~pe of the frequency di$lfibuhon hiSlogrom of a po1omelef ole as impor1Olll as the moon llseif.lt'i(' (C hap .'it" 10 varia hility in d n l. I)l(' ass umption Im. in 'lllt'ra p)' in some )lalit'lIls 1 am! to ocitv in otlu-rs . hUI to Iht. t!ual) is ~t'nt'ntl l)' much smallt'r than jrlt('tind i\idual vartaluht y. tliSt. This S{~'Iioll o f the hook is de. t1lt'rt· is a Ireqtn-nt llt't'(! to tai lor d reg ad mi uhtmlion 'S. ll"(lul't"t1 in these two patit'u ts 0 during Iht. Evoluatewherhefvoriobililyin drugresponse iscouMK! bye VOfiObil. C tlist. oncv w«'1l-t's tah lb llt'd . o nl)' 2 shll\\'("I1 a subs tantial diffen'lIl't' ill rt'SI'ltlllst'..useful as a ~ Ji de. 11l(~ lesson is dear: A\'\'r. 111 imlhidmtl and th e populaonsider. Ht'fon ' prot't. substant ial di fTl'n'lIl1' s ill rt's!'ltmS{' to most dm~s ("xist . Iht.l: tllt' rdp)' (C hap. Because \'ltriilhili~' in rt'Sj'ltlllst' within a subjt"Ct (I" t rn illtli\.! .~" tilt' results o f a sludy dl'sip u "Ill o examine the l'(m trihn tioll of an acmv lion. I Ii ). hut ultilll att'ly.Itit'nls . A bmat! 11\" J\it"'~' o f tlno subj c t is p resented lnthls dlaptt' r. 4. within Ilw hotly (C hap. 10 avofd fl toxici ty . t !()sa~t' R.tt1wmpy.l:e d ata an..01. disease .lyin phorrnocol. 10 the Individual p ath-ut . T rue. given respcose and phorrnocol:. Such /" tt'rind hit!lIal \'llriah ilily is oft eu n -llected hy a \'llrie!)' of marken-d close strengths of It d m~. Suppose.ltit'nls It would. 1-1 ).1-'1 a wl lolt" tilt' d ist'. 15 ). 16 ).l-'i(' wfluld nut 1)(' couslden-d as a si~­ ntficaut SUUR't' of \'ltriabilil)'.ineti<: dolO 3.'It'(.l: rt's ponst' . E~idt'JI("\' for alit! causes of vartatkm in d rug rt~POlIst'. alo::l" an d wt'ilo::ht (C hap. e am i ap proecbes toward i lld hid llal i7jn~ dn l~ I!lempy an' t'xaTllim"ll.n ..l. Sugge$lon opprooch lor inilial ng 0 dc»oge legimen for on individool potenr.l lll{)n~ !). or bolh. IIt't'1I made-that all p('()plt' a rt' ahk e. pholn'lOcodynomia. human s tOS art> rt"l~m ahly lJ(ml( ~t>IU'()II S .VARIABILITY OBJECTIVES The reeder will be able to: 1. a di stinct ion IIlIIsl lX' made hl'lwt'1'11 . its a species. t'..i: of ' pia-una ccncentrunou of a dnJ ~ 01..b 203 . and IIItmilorill.

m n. F.1 (. Fo r example. ' .... ·l ~' . 'i2 :... VAR lA8IU TY CHAf'T E ~ 1J mually little Ill '("(! to slIhs('(IIIt'ntly adjust lila i lJ(li."ri'lln I" " . ti nH' aftc" an i. C hll .1 rn" n ~-hrn ill.exte-nt. St ah'tl d ilTNt'lltly. tl')in~ to lilmh....s("(1 O il di n-c t ul l'il·rva tions of p lasma ("( IIl('('lltmtillll an d rt'sl)(lIl'il' ... TIlI'r . I ). I l. C lear ly... ...o l..' . ·1 T i l..u nM..an " .ill..lI it udl ' of the response. • uf lH l4 "'10<~ . . T ln .k.•....:. s!lows t jn. \'a ri. ..'r. " 25 o o 80 160 Minutes 240 320 ." 1 1.'5 (C hap . hy till' Ii lIli ll~ of till' ohS('f\-ations a nd I lit" lIlal?. il..~ · - . The Need fOf Model.~. pn'S('rilM:'t! only if it h .rl'!ati n ' contribution of pharmal....< Iaily dust.. 1' . i"tmimlhidlla l va ria hi lity ill pha n ua(~ )k i lll'l il'!i ( 'ill I lit.nidt' ran g" in tlu.i dllil]"S do sage rl '¢lIIl 'lI ..'sl'ICmS(' wi t h tim e tn 'l sl'l dl lS(' is M"(' U \\i t h till' neunnnuscular <l~ellt doxacumun ( Fi ~. Io.1. ". 13-2 and 13.l' 11 \\1<1(· tln-rapt·ulk window. EXPRESSIONS OF INOIVIOUAL DIFFERENCES 1-:.s siRJI the n-lative (.1 praet ice. all t' m pts 10 a. to \"a n ilh ilil)' in n."j2~').... of a llfi{..\·.. In d inil'... .. III1 O'" mn...al ('xhib ih a hig l.t-r .l m ~ '" " ~ ~ 0 ~ 50 c. 111'11('(' fo r Inn-rindlvidual di !T n ' Ill" . \ 1. vartahtltry e :lO isls in b oth plraruuu'oktm-ncs ami pharma{. \"D ....1 . . . >lI· D" ni<c. )xlIls(' ('1I111('S From S('\'(' ml SOUrt '!'s ..II..( lil~lIlan l cont r ol.. e \ "ariahility ill till" dosagt· n-qnin-d I " produce a ¢H'1l n ·'poll..s.. a t1nl~ t t. hOWl'\.I<'.(KI)llamil' \' ln a hilit)' ma)' 1)(' different when t ht· e-ndpoint is t he n-lfcf of a lu-ad aclu.. an l'xirelllt' ly diffi cu lt ta."..: Pup uLol il. partkularly fur dn l ~s wirh narrow thera peutic wi ntlows .lh ility ill till' inte llsity llf n. tln. TIl(' IlIaJ!nitmle an d n-lat ive co nt ribunon o f p hanml(. 1 l'l.. .hid .16. 13-1.' nni n .tI.'sl'IC)II'il'!U a ~\ 'l' n t1osaJ!(' wi thin a patu-ut population \ '01 1)' \\i t h th e drug a m i. to a d t·filll"(l {Ia ily doS(' of the dm!?: alltl tilt' plateau unbound plasma concentration of S-wiufarin required to pr oduce a similar dl 'J!rt"(.1)..( K I~l lillll il'S . ..I.. o f .. \ 'a riah ility in phanna{'()killdil-s was al MI Illustr an-d by tl l(' n i dI' sca tter in the plateau pl"\" 1<1 roncentrunon of pht 'n~1oill wen fll lJo\\ill~ vartous daily doSl'S o f this dnl~ (Sl'l ' FiJ!' l -fi.... 100 75 HI:.. ill dnlg n '. C hap . 13. wil lt a uonste r oldal antl-Inllammatury d mJ. o f warfarin m-r-decl to pmdm'(' a sim ilar de~n'e of alltk. till' co m litio n hl'ill~ t rea ted . "anabilit y wert.il-. 1111' lL 'l lllll' llt coukl 1)(' s l n lll~I)' In\sih Hm-nce-d..I<...ll ij' Ii\ IJ l \ \ IcOI Iifi< .111. . c... IlI'n h ' ·. 1.. " I... As iIIustmlt"(! ill Fi~s ...· is iIIuslm h 'l) ill Figurt · 1-.t1l1Sagt' for all lndlvi dual wfluld lit. if i. J.th a n wheu it is tilt' rl'! it'f From chronlc iwilt·s ami pain s a. 10 souu. Im ..·k ( I mJ.m. "f l1<·u".tm in· t1hi dual .(lkillt'lll-s ami plmnllal"lKI)llitlllil'.( "I'~\llallt control...~'}.\sol'ia lt"(l \\i l h illfla n u't l joint s.l a~e and uupn-du-tahle.".(llItrilmtil lll to pha n llal 'flkillt"tll-S and pharlllill'f){l)llamil-s lIlay '"" mad t' ha. which slul\\' frt"(llIt'lll 'y di st rillllticlII h istowmns of the plan-an pt L SlIlil r-nnce-ntrunon (If tilt' a lltidt'pressant dnl~ no rt riptylim' .

01 0. va riation in pl a.1. ltiuIiS millie at C_.I" n" fo( nmltiplt· '''"inl/:. 1 11M) ( "'d" i>t.....·n..."... G .· ""... 'A lh p i crhups a g n'a tt' r a.rf. . L " nf ".'t.. t-.Jit...inn .. J7.. n"K~·n l r.f 25 n'R ""rt ril't~"il>t· "..<\ t ti lt' hight'T close.. .jl 10..l i..nU. ~I. " r... 'lfll...... IOQ scale) . 1 l . "f lI.S.1g1L) 6 B nil:.!.lt·I)' acti\'t" S· arfarill "" "'I(.li"n _( I ".....t 1 "'!o:... A ...il)'.~. 13.<lic >l" ..J ou f'"~."" " '!o:"">mlaily clioln!>" " .. h ut J a~t' vnrialnlity ill hitlf-Iift and concentra no n nt'1'(lt't...~l fnltn <:1"" t: . R. TI. E. : t"UIKLt" K·III.xhn u m n ' spuIISt·.!:. 1""01.I""' .i< "·I~· in 263 poh.lI n it"S . Th· n"K~·n l r. pi"..It~ ..! ill INJlh l't lllt1.LtltW numl>l·f "f polito" t.. 1K' Sj" .(ritIUll ... In cont rast. ..va riahi l i~' ill e ither (''UlIt'(' n l m t io li o r phan n a('otl~lI.1 pLtt...) •• • • • •• • • ••• • ••• • ••• • • • • •• •• ••• • o 2 4 Unbound Plasma S-Warfarin Concentration (J. 1 ' Inal"" l I"..5 Plasma Nortriptyline Concentration (mgll) Plasma Nortriptyline Concentration (mglL.5fi.."h·d .. . u ''OIK~·ll lr...i.a1 I'I>... I"" .. R.. . ( I "'W .. . i. J-e lin..1t IoI M l i H.(lnK t:. t-..k~ 'lltl ..rit"..trio-s ...3 0.1 .UKI Rt. Hr.-!lill lJ 'l"lC'l<>lK·...1 0./ Q ~ " 20 50 il E • • • • • •• •• ~ z 10 o o 0.Ii " 11..y....l b).".l.1 0.tl. ~'in~ mk' """rf. f d Ol' pn~l"min....... .d rrom 'l'u l . .L. a t1m g that displays htth.~~. 10'1) """ >1'1/: ll !U''' II' ... ( ). r 3. ~kl _·I. Th· ""J..n llli of 11K' '11"".un.. 110 a \Jmil".sma couceutrut ion p m d ul 't' s n·lalively liltll' dmll ~I ' in rt'SrNlIIst' ... .llic". 11K' 1". Madu.. H.. ~L l)i' p... In [""Iit. "'0.L...'lCI{..111:' 13-2. Bt"}ta . KI..3.... 1$.. In [) n'j(T"".t1I~· th · h"' ..." '01 ..'i 1". dt1/1t"-· nf Itllllt.1..I ." . lmlMu'l/:h.. 197" .(nnOOl' .l1tra l iu lI a m i M'.t. o as Illustrated in Fi~ ..CHAPTE a I J ." .. AI later time s after thls higllt'T dO su bsta n tia l va riab ilily is uhst· r'\1. is ~H' n OrdUy at 1\\11 tic lSI'S..05 0.ltic ·n .1" 'nlo n. l.. Onto that adlit'\l 'S d ost· 10 maximal rt:'spo nse in all pat ients and oUt· that dOt·s not.SSiIQHllt'llt of variab i li ~' 10 I"t' fo rm er... 'h n. \ 1 .2 0.'h .. 1--1 1 1.h"I0".. · rt'SpUUst·.. ~ l r~l' "' OI l •.. r II. I n><1. nf d"'i..-.. 1' '.'" I) " (.uK!0 011<'.rin.. E. Ohst·n.. I'.. ·nl..1 ....<MlI.' I • • 3 .• "">t~ ." .. .· pI"" . a nd in maximum efTI't.. Here.. rtriIN~IIlM· \..... Cln".J .....llo produce 50% 1Tl.. wo uld SUAAt's l litth..iutr-rpatient \~driah i l i~' in e. fOT 99 30 A 90 B •• •• •• • • .i'ill~ lt n ~"K'II .....

protein hindill~.'..1 """p'If'''' w . Ii"'. IM.. n ." ...'t! hy t" p rt'Ssillj. Inl"'1"""'n l . Tu Illustrate thi s stan-meut l'l lllsidt ' r tilt' rn 'fIUl'lll)' di st ributions in dl'ard lll't· o r . in ""' ".1 · ....-". 13-4.Iho·r C _ .\im um n"'l'l "'~.- CHAPTH 13 large Dose c ~ u 0 0 0 c 0 0 ~ 0.. llw llIouitlium .'I . ki. nib (1 I'lx'm ll' lIl't.. " ". " · tII. .....r."..· . ons ly critical to an IImll'rslamlill p. .. .l."....tit .llt' such Iactors a.". 20...iol. hility ' " l.. ill f . \.....J/:..·n.1I (.02 0 0 6 12 18 Hou rs 24 '" '" c 0 0 ~ 0....I th.pl~.1Illllids shou ld illl. hod Ltr.5 0..lh ilily in rt'SllllIIS(' .Il~ how a particular parallll' ll'r varies wit hin th e 1 'I<ltit'lIt population is importa nt in 11 1 1·mpy..' in ...'.~·I " " " Il'l' n lnd iu n . IUIlI .... .s hut rathe-r ill terms or tlal' pan ll1lt'It'r vulues d('fi ni n~ p hennacokmcncs and pharmacodynamics.·n . ... ll i ~ 1 [.o...".11: .. DESCRIBING VARIABILITY K III l'\\.illll' llS ran hi' r-stuna ted. a ll ~. \'".·" 1. bu t IIUW rhr-n . coucentrunon In aeh ien' . '''' i.I>I. (l" p l: .. 111110· inftorl'"tit 'lll . .111 ¢\'(' 11 dosap.riahi hty in C-.( .is l'tlllsitll'rahll' \'ari.. . 1"('ntra liu n.....n...I st.. is " h. IIR' I'XIX"l1t't l va riability in l"()11re-nt rattou and n'Slllllls(' wi thin the p atn-ut populalioll assoclated \\.04 0....CO Il..........ti<.\..06 0.....hilif:..' td .~". ... ""•..k..1 wit h li ul. rn"IoK...05 0 0 6 12 Hours 18 24 "' .I."ill'l "..-~si~lIllt' lI l of vari..! uri..i ". '"<Iriabi lity nut ill u-rms or UhS<" n. ae livl' lIlt't alllllilt'S......" .......l. CI•. ... ..75 0. )(l'k or li lt" maximum rtOSpOIlSl·.. (ri. .... PhanniteuloJ. """I""'''''' ""'1""'... uml toh-rance. \ \llt'n ' appmp ria t(·.t".!>ft...[110.)lJS('.. .. rn r pl rarmacoktue-tics . " Ii" . I ~..-.25 0 0 6 12 18 Hours 24 '" c 0 0 6 12 Hours 18 24 ~ '" E ..11 Iinn.. ri.li< .'-11" i.08 0... · .ll.fillillg pharmacokincncs and pl\... O nl'(' \"<Iriah ilily ill Iht·S(· pa mn lt'tN 'S is t1"fillt'(l.·.is slill liUIt' inh' rpati('nl va riah ilily ill C.in tlu.11.206 ''''''''"'' 15 10 5 1 0. " .. ' t.l rn lill't Il!~1mll\ it"!i (C hap .I Ill... " . · 1 'M ' " .. then....·....... 1'Mp' " " '" C ...~ ~ ~ '-' 2 c E Q. I .JMlit)c' '" C_ i..lrlllill."li l..KI ~".. 111(' ill"('ural')' o r ti lt' IIltlllt·ls dt .>.-. . ·nlr-.. tha t is. .(l'llllr.....:. am i in maxuuul rl'spc.I.n· pi.1 5 Small Dose a: ~ ~ 0."U" m): 1<1 1_ •. nil dmO(' sud tinu.. SpUIIS{. I_ " n.. 11••• 1.. Ill(' IO \\'N dos" .Jf.(ll l~llll lllit"l. into-.l' rt-p. ee ~ 0... I" ·ftj . i.( IIdru!!: ... ie Her Si" mse-].'1.. " " d .. the-se." .lh ilily is lIliuilll i.?.. .Ii... E 0 :. ' " n .ri.·r.. o r \1lria hi lit)" ill pa tu-ut n-.I..nt'S " l I t.n 'spUIls(' re-lation ship Ior p!l.1 .. "..1 0. ....Il tI 1l .. 1111' steenness or tln... p"_I....... and th l' Factor dl'fininp.1...i<I.~•• .. Inal l 1 ).l '-.

.. O: M ciout of vurtatjou.nl. ...'rva licllls ubout ti l(' flI('all .... dts trihutlons o f pha rmacoki m-tic parame-ters o r ohsc:·.s)'lIl1llt'lri m l dtstnbu nou is ofte-n ohtaim-d with :1 to~?.a ri t i ll nil' tru usformatiou o f IIII' paramen-n such clist ributions a n.oI. in tllC' lU ll.n .r..11 111'lIl' ·.lru~ (A. tI. f.tliz('C l lo till' menu.. examination uf Fi ~.·fin••~. which " "p n'S\I 's \1triah ilil)"wtth n'~ lll'<.o i. f. 13-2A). vari ance dOl'S nu l allow ready ('C 1II11l:triSlJll of .' had hc'C' n 'lTi' 1IIo!t'C 1in l..'C·1I ill F i~ .' . a la rgC' l'C J( o 'il'lIl of \"arialioll llUW iU"''ll~'S SiWliHl's flk a hi~1 1 clc1?. A H K 13--3..CHAf"E~ 1J VA/lWllUTY 20' lilt" thn-e IIHlolllt't il~dl d m~s s!lcMn in Fi ~..I'IrtIl'Y . lllun .h. d ('ar.l' C . 13-:2B.' (F iF. . \\' Iilc' usr-ful to l"lm\"('): va riahility wi thin a p articular set of oh sel'vali ous..SS M u f ()hM'~l ions uf tlif'ts Ien-ut lJla~ni t lltl(' .....llI represents till' 1 )'Pil'al \'al. hut till" \1I.I pmhi t S<. th is is the m . it is lilt' SCllliln' mo t u f va riance (IIIC' ~ lallc Lll"( 1 dc'\iation ) nonn...·filM" lho· fTW"" it .listri""l""'" c B c Clearance (arbitrary units) . Fu rt lw rmcm '..' is bimodal.'lis l·o nficlt'IW thut lilt' 1I1l"<l1l of D m ~ H ap pli." o f \ll riability...\t'S Ihe IlIt'Cliau ..f\'C. ..l )'') ..ItI I t. SIIPIXl\l.found ill Ih h " popnlati.. B..n') mgfl .I''ilohllity an ..' sa id to II(' Ing:-llcJn Jlal .:t4ll11illing: for 1 1 ~-II(1nllal d b lri h lliio n is 10 pillt rlu.• d.' In all indivi dual patn-nt ..~l""llt'1 k.' sc. or 000'25 (IJ lIlinji.t11 is run.c' t1bsc. fur all th ree d rugs is tilt' sa me. . nnd tht')' an' ofh'll \ lc'\\l'C1 m lllt' r tha n normal. TIl(' di ~ l rihll ti()1l is tak en to II(' IOl?.-. 13--28 lnclic-all' s tlmt t ju. 1111 . ~.l..~ It. 11\l' mean. di slrihllli ull ill dC'. D m .. .h \Nd ria hi lit)" alMllI1 tlu. sihrll i ~\i n~ th ai ' the n .lc.-ations art' uuimodnl y r ather than polymodal.... A mon.c' sutu u f t ill' St'lllan. If insteacl dc·a rdlll'l.·s..'C 1to tilt' m t'a n is 0 .Jm in..·. :\.j?. on e has much II. in ti lt' s fn 'C IUl'IK'y clistrilm ticlII of plateau plasma rmrre-nt ration s flf lJllrtriplylil\l. on'n1llllt'S th is pro ble m.'s I......cll .a n' twu major ~n l1l ps within lilt' populatmn: IlIoM' \\i lh hi~h and luw d c'am m'l.r II.I'Xilillplc' ahon' . Varian o ' is a nl(':L ' uf Slln Ihc' (I.5 wul is illliepl.t. ..uf till' lTlost 1I111ill'!\' \'alllc~ 10 lx. \l Ilian'll t1t'\. lu-n.d islri lm lio n is IIllim ocLtI u nd normul .. u see n. .. Ih(' d c'\i at iollllonuali.. ' O ln ious l\'. in this I." Ill'r.hl lim '.• '''''1 " f II". .' h i~1. Spe-ci fically.:l\l'.ri<lh i l il~· about IIIC' meun is \ 't' ry cliffe R'lI1. Ilu. ( . :1IIc1 1 : cut'lTidc'lIls o f \1lri:t1 ioll.lnlll l.'<IIt' agains t tilt' Ic~ari tl llll o f tilt' \<tria bl...(' IInits ofd l'ardlll'l'.1i\" y. e.f Ilon I. ·lf. Fur nort riply line .'r1. Iii••• .. (' .I ll..1.\(' for tilt' plan-au plastna l'C JIll'C 'ntntliu lt of no rtri p l)'lim" III such C'li.1c'(l ill tilt' populanou.l'\ :\ ami H. ti l(' squared dl '\iatioll m m ld 1M' (O.l' B tha n fur I) n l~ A. .1 dll"' ""'IU' .' il . o r \".11. Suhsc'C llIt'IIII" . .atio n is 2SCln (m IJ lllinf. For D m.III(' 1lI1'..·.~IT\.IIIC1' in all inclh icillal is 5C1 m l/mi n and th t' uu-an is IOn m l/mifl. Wllid l is 1 ('Ss than tilt' :I\'('mgc' \1l11lt' o f (W69 IllWI_ A comment o n tilt' quautitnt ton of \1lriah ilily is 1\('C'C lc'C l lw n'.l(' (If c!c'anllll" ' 1...-non nal if lilt' poi nts lip 0 11 It stnU!?... the 1Il1' . o r p ercentile. m ('111o f ll. 13-5.1 to Iht' uu-an value..'s of theS(' d l'\i at il1ll5..\ s lho· fn ~ lt .(1111 1111alin' fn. For D m ....1 )2. A common met ho d u f c..'''l ll'<.nn-dlun 1'C )IlC'C'l1tmlioJ) is n."'I.mean h mnclr grt'HIC'f fo r l. d ifT(·rs [ rum lilt' mean. C) . ur central tendenc y. h igh lIlid lu u: w rl(//J lllty n'fN to di s0"' d tribu tions IhallJa\'l. n'spt'<. .'\i ations of It. tt is dt'fillt 't:l a.~ l':111 1M.cIII(' lthou ' ilm l ll(-Iow wh ich th ere an' equal numbers.uiabi lity "l'"... lu tlu.

ng .itily . chronopi>ormocology Clol!.. an d acti vity of certain l'Uz:. hepatic diso nlt. patien ts \\.. i ll ~('lll'ml on k-r uf importance. 'ood Pot. ptlsma l'tI!l{'l'lltmtioll (Ltta an' 1IS('(1. a .. t1i "t'..f!e.roet>c. 1.J ..l'li.esuiI 01 enhanced d..1 tilt' m h o of n· lt"lSl'.lood a nd mad (· ilio n ' pn't lid:..."" cJ d. ·ariahility.lllty I. 111 uremia am ! hl'lllltic disorders.tools of I!lO!l'(. r-itln-r ht'(."w m . l'crbeps III(' mos t importan t fal1u r is nOlll'timp liallt't·. par1illllarly that d ' n -lated til dOl ~ na-t abolixm . 11lt" modification lIlay ap ply In Iht" t ! m~ ht'i n~ used to In-at ti lt' specifi c t1iSl'llo.mt. tilis soun:t' uf .ri.-ut l''({'t"!lsi\'(' accumulation am i Sl) reduce tilt' risk of Im. h ut overall.e The '0 .. Usual lluS. of this variahility ' is larR y unpn.("5. V.of va riation in drug W'ip oll<.1lI hul also F \t'd ront s.. ~'l\ l millft>slill a] dtsonh-rs.o between p:ll. \\'t'i~ht .nocol procll(e: $OIuhon I. ma)' lx. d nl ~s ~\'(' n l'tml'(llllilalllly.ed to peshc.1 lists exam ples uf ad d itional fat1 0rs known 10 luntriblllt· to \"lI riahi1iI~' in dm ~ n'SpOtlM·..oler~ and WQf~er5 oa:upol. 1Iar h iology (C hap. c. 9 ). ' tlll's(' problems lit' ill tile area of p ath-nt {.t'(.t ' . Gt'!wlks ).on Ofe oflecled by eat'ng EHec~ depeod on COlT1po$lltOn 01 food 5evet'e pt"oIeon rtl$lfodoon may .~ . til(' omi ssion or sllpplt'llIt'ntal iun of prescnlx-d duS('. hypl·rth yrtlid it· patients rt'tp lirt· hiJ. \l on 'tlwr. If!l Illy T.n IO'M'l a. hody comp sition. .':Ilt'1' than usual close n f di ~o\i ll. taken into account. ti lt' I'fft't.l llt·S mani fesl tht'm sc:·lvt·s ill diffNo t' nl't'S in bolh phanuacckus-ucs and n 'spo nSi\l'lless.. A maIO' p<obIem . a mod ifi('.nol\lO'1Q\l()f» Ole Ioeefl in phormoco'." Dm ~ met abolism.n d. Xu nl'tllnplialll't· Includes tilt' l aL:i l\~ of dnl~ al tlu. an d a \'aridy of cnvi mmm-ntul fact o rs.'tIlIlP<U til(' diS( <. K_ _ ..':. l'U rdi al~ Iailure.tIl afft"C.. A~t' . alii) o!l lt'r 1' d io. d ilTt'n'Il("(S ill n 'slxJIlSt-' allloll~ ind i\idllak mud.'i01IS wily pl·opl!· differ in thelr n-spousiwm-ss In d rug ill medici nal pn xlut'h art' s manifold and include..onolly exp«..t' ti lt' p atient 1 1I~ 1lS to fl'(·I III'lh'1' or 11I't'1llISC:' of ' dcwlopmcnt of side-effects that Iht.e requirements oIloOfll& dlug~ d.(' but may apply t·qu all). wf.llion s in dnSlI~t' llIay arise nol on ly (n lln the tlin 'l:t Impairment of a di st·'L o'X."' .mporlonl to Ieod to !he deYeIopmenl 01 a new $i.lblt· Ilsiulo: tln.llJ.20.s 01 d. :\ h holl ~h i ll ht'ril<lll('l ' .. plasma and tissue bim l i ll~ of d nt~ m ay lit· aln-n-d in patu-nts 'ars \\.ltioll.e~ in p:ll>enl ed"'0100n. Tahh. [).lll Ill' im portant :tS IM l'.ml'nmila ntly ad lllinistt'n'(l d m ~s an' importanl 11t."1 of ~t·lltlt ·r is small.alls.d in !he cou~"'" .("Sin hormonal IlOtl'U1l 't'. I Il l' n·.L lUI nhjt'(1i\'(' lllt'llSUn ' u f 1l011l'tllnpliall('t. O('{'. thY u id disorders.(·'lO.___.mtMlifit'(! in ' ly 'a. 111 renal d iM .t.L ('lUI !)(' an addl'll soum.I!-:(' n.• lIlay mx-dtc be modified slIhsla nliaily in paucnts with n-nal functkm lmpatrnu-nt.L siollally.dict ebh-. ~1 ·lll'lil.'l l to other d m ~s lilt' palit'lll is rt"t"t·i\..In :oullls for a substant ial part of th t.."t'.de$.( Il lll sell i n ~ and t't !tI{'.ed". t'..'(mdal)· ('\"tllls that lI('l. !lOllit"nt consldr-rs IIn'll'l. l'Un~t's l i\"t..13..u. S Phanllill'('ulil'.'.. '. "W'. howew r.t'ptah lt'. and 11I'tll'l' t'ut!)'.l \( ' ...e effects ho-. WHY PEOPll DIFfER VAitABlUTV OWTH 13 111t" n 'a.ug melOboIiyn Drug el!ecb Ofe ohen ~ "' w.ug bu4 a ls meIOboI'lE! concenIlO1l()(l~ can change o ~'"" ond occo~11y edenl 01 o~P'.. Fo r example.. iutu lilt..l~ i ll ~ly .\\'n ltl~ time. and the stOppi ll ~ of t!lt'mpy.en l~ liv.netlCS ond on d. 1 Di st·. Cendcr-ltnked d ifTt·rt'lll. 1M (C hap . \\ 'ha te-o-r tilt' n-ason..ug re~loe The!.ug melOboI'$fTl.. to pO·.oe beeo suHl(1efl1!y .lbted. tilt' t l usa~l" o f Ihl' anlih iolit· ~1 'lItam ici u lIS("tl lo In'al a plt·uml in fl'l:tioll uf a pali t'nl must hi' rt'l !LI(''l! iftl lt'llOllit'lll also has compromised renal funonon.. am i (.ll formulatitJll am i lilt' pnlt't·ss IIst'(l to lIlll11ufal1u n ' a p n ltlut1 t'.' tilt" an" )' sources o f \'a riah ilit)' that can ht. is ht'ill ~ IIl1d t'r. A4WltI_I.lllSl..."•• 13-1.en r~ con \lOry on changing The roulE! 01 odmiOl~llotl()(l Not only l pIlormocoi<. Sim ilarly. 1I d nt~ used to imp mn' cardiac emtit' nl'y.

topi("ally. x "" 1 t'l ol i J'~'1 1 h~· Ilt'palk' o\i dalillll. and thl'llphyJlitw ... pa n 'lIlt'rally. IM SlltlrtN lilld 111ll)!.s of(')Tlt's with a lung peri od .(' alTt"Cofs Iht.wl it. Oral h ina\"ailahilily is not usua lly alT ' It"t1 h)' fond .\ t('11 pileI!' ·ts.d rug s. 9. ~...o f a rdiahlt' product . ('. 13--6 wh it-" shll'\' lilt' 1 f-li\" Ilf pllt'nyl bu l lV~ J lIt·. ~I any ehe lllut he rllpt'lIlit" agl'nts ha n ' n' ry narrow lI1al"}jllS o f sa fely lIlItl an ' giWll ill co mbination . h ut then' an' mall)' t'X('('ptiolls to t"( this start'lIIt'llt. ~l allY t'lldllj. hormones. C IIOIllupl. pa tit'n ts \\i lh IWPiitie d ist.<.. a " i ~h pr o n-tn inlake Illay cause t'n7)l l1t' Indueliun .con('t'utmtio ll loeally am i s~~h' lIl il~ally hut also (".lshi(' 1' llI pt~i llg: lind so decn-ases tilt' mh' o f dm~ absorpHOIl.month. T Ilt' 1 'It'riod of till' (.. \ IIJlltiVJlIIt" d im inlliioli.g:. 2 1). illd lld ing (· h lo n l iaJ'~·I'1tI\itlt'.mauufact u n. e .'~' rt"{'t'in "tl ollw r dmWO' a d t'arer pit:t lln ' ('nw rgt"t! (F ig.Lssign eaust' S o f \·a riah ility.C: sub stauo-s. IltJ\H. tllt'Y ('.g.J hr. >li(. sluws g:.11I alh' r tilt' svste-mic concentra tion of IIwlah · nlite l'llln p.i ('an ('{ltltrih uf(' 10 ohst. ConsidN.-clt.t' (Fig.'tl \<lriah ility in n' · SPOUst·. aH tl1t' aIMl\t'-l1wntiollt'(l fol(i u r.'rilll!'ltlst'tl.. Ht.'.. ll~ man)' o f till' \" driahlt's as JXlSsihl(· an ' fi\t'tl.factors ('.{'ll di d .Sof a dm ~. ill g: in the liming o f ud \ miuist ratiou u f e-ac h d m g during ti lt' day m il improv e tilt' margill of sa fety.·o ki. Particular not e of th is phenomo ('1 1111I is ta ke n in cumx-r eln-mothcrapy. Inilially. an' kno w n til IIll(lt' ~(J t')t:lit' d"lIl ~t's ill coucentrution in ptl~lI1 a alltl lissllt. 110 t1ilT 'l1t'(· Wil n '\l'alt"tl llt. pa rtly 11t"{11l1W o f till' fonnalioll of an insoluhh. I'.'nti f)" Slmn'('s o f \<lriahility in n 'S!xlIlst'. lIppmtinmtd y 2.a. d a_~ s i(' dl's i~l is IlIle ill whit-I.complex with calcnnu.Ii J'jllg ('1I~1 11t·S is tilt' likdy (·illlst'. in Iwalt h)"suhjt"{ofs and in l"ali. l\·ailahilily of a slloi.in'd. n \t"taI M. TIlt' menstr ual (')d e and seasonal variattons in tilt' (1)1\('('utrdtillllS of some {'1It 11~t'nollS suhslam'{ 's an.N (1't'll'S Ilj'lt lll whit'h lilt" dai l~· o lle is SI!pt. C i~. EU ~ lIlt' s~1 1 tl lt's is is . «lthough tln-n..·!It'1l whe u If)inR to . Ihat lilt" om! hioa\" all 'li!ah ility of II'l r. ' .11I p m folludly lIffl"(1 till' rt'spo liSt' 10 a ~iVt ' n dost' ur n~ lIlt'lI . Iltltl."{1 in Fi ~. • Varions slrah -git's (~1Il hI' t'mpIO )l"tl to id. pha n mu.'l--fiA ). 11 am plilude of the dlall~e in coucent runon vuries l(' .is lilt' ~ I u dy of rlu. sun ] hy inhalation. Cood Ill all u fadu ri ll ~ pracuce. »it'l lIlay also afft"C1 tlmg metab«llsm. \\i lh tinn-. a on t'(' uidd~· u'it'll dmg.' Identifying the Sources of Voriability III p ral1i('{·.\11 these.n -h-ase charact e r' istk-s o f . day Ill' tlu. apa rt fn llll till' Wit' tIl' illtl' n osl.!l'nolls s llh~ l a nl't's .l'i«' (p rimarily drr h()\is). tim}: it! t"i Ul. is ofh-n di urnal.Ill alstl stilllulalt' S~l l l l lt's i s til' IW[Xllk IlwlaIM t' n ~1 1ll's .s.lIl a~'I It .'llllst' of an imbalall(.s o f whl'l llt'r I h. 1II10 1l. Fond is a complex mixture of chemicals. Houte of u dnuuistration not only can afft"(1 tlu.CHAPTH 13 A wdl-tlt'sig:lI('(l forlllulation d iminislws tlu.'i\ill ~ Till ut llN d m gs..twt"{'n Iht. \ 1au)" 1" 1\i n III llwnlal p"lllltallts l''{ist in hiRllt'r ('{lllt'l'ntrations ill lilt' lily Ihan in IIII' L'tlllntl')'.m'( l wtt h thai of drug (C hap .\·N . o r seas n of tht' )"t'ar. Dm ~ rt'S!'ltJllst'S may the refore dmll~t' with lillw of day.1 11 also thai a SIIMi llg: of g:aslrie t'lIl pt~i n~ lIlay Increase tilt' oral hitloi. \\1WlI. pa rtit11lar ly !It"t. TI l(' d m b alTl"{of("t an ' t'xlt'n si\" y 1111'1al>.. {'<I("11 poh'nlially (". 13---68 ). J) nl ~S an. Fllr t'xamplt' . l ri n~ly so lubll' d m ~. t" ('t'pl for a ~n'atN \"ariahilit)· in Iht' h" lf-Iif(' among tilt' patit-nls uith IWl'atie distw.' nls IlII t·s \\i th l1t'p ati(' diw.t'\lunplt. tilt' dat a tlispla~.arm<l(dlJK\. parti('ularly fat.. FIICItI. Rr-c fnun C ha p. iml u(iiun of til(> dm ~. .ly. O:IIl\l 'rst .le)'diJw is n-du o -d wlu-u taken with m ilk.'pahlt' of Interad ing wit h dnl ~s . Sllllle of till' olhe r dnl~ n n 'i\l "t! ha. l.illllllt'nt'(· of lim e nil d rng n 'sl'ltlll'it'. and m n ' mllsl 1lt'lakt'!l 10 t'llSlln ' an app rop rilllt' t'tllldllSiotl is n 'lu. O f l)lO S{' n"{'{.d('!-Tt'(. r-nsu n-s tln. d iaJ' 'p am. n it.WVt°n l' nh"mlly.. III. d m ~ l1wtalM llislll may 1M' im pi. Rn lllp!' Wt' rt' furt llt'r slllltli\i dt'1l o 11 till' hll~i. hilllatd y dl'!ll'"dt 'nl 1111 protein intake \\1lt'1l p r o tein inl akt' is st'\'('rd)' n'lllll't'1l for p mI Ol I~t'l l pt' ri( ItL~ . t·n S t\m gnlllJls. Appropriate ph a. hall(!lt'(l plll'nylbutX'JlIlt' mon ' ' slmdy Ihan did Iwalthy sllhjt"( E\idelllly. 10 It'sl if n'lI al tlist'a. sud l as wl se(Jfulvin.u'l'Ift> smoking h'm ls III reduce d ink'lll am i toxic efft"{is of sonu.>t. HI' \1uiahilil)' in rlu. wi th careful contro l of the p n K't·ss \"lui ahlt.{~.

• . . • • • • ~ l' • • ..J f.•... 1: 127..~ ~ '< • " ..K ' 10..w-nl ilh t""P'-lic. I.1Will".l....· ) in Ilnn nal " ''''''''' 0 (Iot" ''' IIt'' ''Io) ~ I Kllh"l in I""...is ( ' )11.. ' -'. .·n <~ " K' ..~ ..I:'.wrllhn . . .. . · 30 10 95 36 34 61 Number 01SU bjects Number 01Subjects ""..... m·n l ly .. ....pUllpS..-er t1t'SiP l in wlik-h t'ad l p"til'nl ... ." .". • .(·lderl y patu-uts Sl l lTt'ri n~ Irom St..e.. 1. 1 puinh )..... TIlt' ct )1' idt'al 1..'oj. sud l that Illany ilion' patients are needed to allow a firm co nclusion to he moult' aho llt the l.: 1 . .\ ..:.<."..· di.... l ijf..s-u. 10.L~ S.I<. and n -ua l dh. . ".''-'11' .s ur t'ffidt'llt:)'.il1U1t/tlll o r dose-response n ' lutio nships ill clinical trials. . 130 110 ' • • ~ 50 30 10 '.'••. T Ilt' 1"II'11<I.i<1 ""·I.:.· I""( ..· ('xd ml("tl ca n ht· a part u r Ihe .. • " . (-.. 01 1 Ill(' mea n data for each ".l .... I .Im l: ll .t .-ailab lt· for .-". as agl'...1279.tit'nt' . d t 's i ~ l is often nol pnss iblt" hos\.'1. t1irr.. .lir. 1II1d \1(' a IOIl~ l udilml l·m.. . ~ l r_1' (ru m 1.. " P" ...lf' {lIltl...1Sas his or he r own cout ml. w :. otln-r dru gs. l all o!lwf f a ors Slid.Ii. DIFINING THI DOSI-RlSPONSI RlLATIONSHIP \'ari a bil it~· h.... . 111l' 11llll'fit or luost'n illg thl' dl'sign .'." . ' .. An attt'lllpt to t"Sla blislJ a dO n 'spIJI I"t' n ·laticmship is tlu-n malIt.ill ""h..llit·nls into St...... 197 • • 162 144 •• .1Ii"" In pn"i""" .lly rnr d(..g. Can' mu ...· and n-spolls(' n-shh -s in pbannacoktne-ncs such th ai then. . .I. .:i: -.vral ~mllps...2 10 OWTUIJ A Normal B Hepatic Hepatic Normal No Drugs Drugs Disease No Drugs Drugs Disease • 197 • 162 • 144 • • • 130 110 90 70 .." ' . ur 20 mg.• (u .... • •• ---"- ...' .. :-. h... ...t . .........L'>t'. 1 i". howev e-r. ~ "h l f..1\ 1 1\ ........·.....1<>(.' mlN . Ii....- ....I...11... ( H .·...tudy.· (hu rilJ. g.. t'at:h gnlllp M'n"t'!'i\i llKa <!ifTt' r!' nt dost.· .1"... indlld ing the mn . a re..'" ..' • • . w". d"lI1o" ". Th i.... . ·1· . .-.. " nolo. j. 11Il\\t'\"I'f.. h. 1.1....I<.Lsmil concent rations amo ng t jn....... .>lIlt·.. • J .t\ an impo rta nt I".In.... IIiv.110 li. ... S... in ..nirwli<ltl "f pl"·"Jih" ' ".. and did should 1 he-kl constant.'U".....•: 55 --. In h"... ind hid ll<lls From .".1. n. is that ' lIIany IXlli('ut s wllo might o!llt' rvvise I". TIll' pa ti('nt 1..is 10 t1hi dt' p... li:n" . ...-r . .· 1tJ. ~"· l ." "'. ..:..d Ij". -J. \ ." ... usiuV.t\1·r~· I ....·r... 13--6 . .liIIl ".i t l.. In thi s (·llll-g0l)'."f1. . lif" "r ph. 19 '... ial i ll ~ [rnru such a d("S i ~l is ~n'at t' r q triah ilily wfth lo. rrtmp.L trk I t. 11t1"" .::: . toon.\flr••." " ' h...! I.f" ti M hilf... ....· taken.·n· 'It~' i... 1 1 ' n h.IM>li".). " rxunmou p-oe-dun. ·\t'r. \ 1 ·..·twt'!·u doSt... ..'aring on the " .u .tfl(l~· prior 10 tilt' dist'.id. mlrih lltiOIl or a I actor 10 \·a riabil i t~· . .e. u r dm~ such . T hus.. (. \'arhlhilil)' within ~nlllps 10 h'St rnr k-vels or slatistil'al SiKtlif<''lUI('!'' :\ problem anses when much or the i va riilh ility I". ..~lh.'. 10 ensure thai a suffidenl 1lI 11l111('r or pati t' nts an' ind udt'll with t·11l·1I or !llt' at tnhutes or condiuons of interes t .:t o 'n •• • • -.·mhlt· un'flap in IIU' p l. ..~ ~..or intere.)..: • :... t1l renal d ist'lL'>t' is Kt' nt·m lly not a.. • : " • • .x-ral tliSt'a'>t's am i rt'lilliring lIlallYd nl gs.....:.. in p. .'5.·..t'it· is gl' m' rally ir n -ve rsjbl e .

lt·hiug dilT Tt'nt pt.' pt'r fusiun.lali. nl is is indt'C 'C1st'('11 \\ith p Rlpr.'tlllll:MlulI.(' of a dmg.. \111 dist rihution. ill pha n mlt'tlk nt'l il' paTilIlU'le rs ancl ill such IIIt'<l' lIn 'II1('n ls <l\ p latt-lill pla. is to weaken tlJ(" lIb ility to dt'lt'd : a do st"-rt'spo nS(' n-lat ion ship. group s (111I han ' tilt · sanu.ltit'lit to S(.lIIld II(' m-cded in till' trial . .ariab i li l~· is a ccnt ml issue.sma ('tlllt1. \"arialiun in d t'.n -Iat lonship. 1I .ari ah ility in u ral hilJ.tt1hit" is f(. alllo unts uf tilt' t'U0'11t'S rt'sponsih lt' for lIIt'l aIK )lism o f tltis <.1. T llis t'tmd usic m is lJ. sa ult' for all llt'allhy ' jlltlhicluals. d of 1I0t km J\\ing in ad\"ant't· 1Im\' ma ll)' slIbjt"( \\1..1I11 1111)('r of suhjt'l1s ill each gn lllp to n-duce til(' uncerlainty of estinmting tlJ(" IlW... anclllt·I1t1... lI uwt.-aluuted in tilt' pa lit'nt cohort am l tln-n. h ilt :llso of pn)\i d ing an estlman..'ut rdlinIlS. It lllay n'sllit in palit'nt s' 1It"t"t lin ~ difT .vr.)phyllilw IK'in ~ p n 'tlo lllin.rt's l:M1Il!it n '!alio nshi p and about Interpattent \1lriah ilily in phannal'tlkilll'lit's . of Slll·h a t l n l~ an' IIlllt·1i Ih.'tmtnlSt. tilt' p roblem is Oftt'll omSt. by i ncn·a.' eli..) a t1 nl~ Ilf hi~h Ilt'pa lk dt'a r. I:}. IIl1lt'sS pl'lsma . 13-7).. for a t!m g \\i tl.l\.expe-nsive. II nw SIKh \llriahility man ift'sls itsl ·lf..l.Pil' S t..· lIl'lskt'C l in III(' d eaTllllt't' o f a d n l~ h a\i n~ II It i ~h Ilt'pa lit· t'xtl11l1iOll Tlilio. slIch as Iht"t'phyllint·.1 011 Iht1..\'ailahili l)' for a dm~ . and !it)IJlt'lilllt's mon.1II 101l~ Il('altl.~ i n g vari.. i depends 011 tln... \\i llt sllhst't lllt'llt t1ispnsith m Ilt'ing l'()nl n . tilt' I" Tgt.l'lO illlll lll ptl.'. 111is I. to a lesser exte-nt.ilability (and 'm. ' KINETIC MANIFlSTATIONS Conside mh le \1lriahil ily ill t'llz)"llIalit' adhity am i. Anot he r so lutio n is to {'XptN' t'al·il 1 · p. n~ \ a IIJ\v exlrat1io ll mtio.lhly :L \!itK:ialt't l with \'. it st'rit'S of similarly Shll!'Il'l1 ph'imll t1mg t'tmt'('IlIr.lIt'tl by lit'I~II i<.lind Inw -tlost. prul J.solutiu n is 10 inl·n ·a.lst solution has the di stin ct ad"'lIl1tilgt' of nut un l)' im·f("L sing Ihl' chances of ('s tahlishing u doso-resp onse n-lat ionslup. TIlis is so for p rnpra uoicil ( F i~ .y iml hitluolls..' o f st''o"('TiII l i~ll t ly dt'611("t! b nds .lIl(1.. h('C'OlIlSt· dt'am llt.. Inn-rin divklual variahility in ha ir-lift' of IIlt"ophyllillt' (Fig. l. h. " t.'ma <''t llll't'l1tmlio n ). 13--"i).• thr.1 nn l)" occurs " fiN several months o r IOIl ~t'f into d m g administrat ion.ph sma conce ntration (mul n'spoll s(') .1t'1l d U It·.lgl'S... A thtrd solutiun is rlucono-nrration -controllcd d inim l trial.. i ~h .. ... III this approa ch. wllt' li t1Il1 sidt'rill~ illtlllt1inli .pharmac okine-tics uf lilt' tlm g is fi rst I. )(le mldy hOllnd to pla.. As t1t'S(:ril:M"(1in C hap..r-ral deN ' 1 . Unfo rtu lliltdy. Chill l ~t 'S ill IIt'l"'llk t'U0 111e a(1l\il)" n 'su h in \'ari" tiollS in oral hiu. J'n mp with a high dt'anlll t't' of till' d m g. ~ I a ny orlu-r t11 ·s i ~Il" .of inh''1'''llit'1I1 va riahility in tln. \1lrialioll ill t'llZ\l na tic . 13-7) <''0111 1M' l'~pl ai llt'Cl p rimarily b)" variation s ill hepa tic t'1I0111(' at1h i ly.\rn a and tiSSllt' l'tllllpOllt'llls .1 Ii.1Ilt! t!sSIll' hil1tli ll~ an' hiF. 111t' illll"'ld o f .. can 1M' t'll\isa~t'Cl.lIIolol i Fig:.h a h i ~h d<'''gn ''t' of \'ariah ilily in t·n0 ·IIl. Ihost· in tilt' !o\\l-tlost· gn lllp with a Inw cleumnce and thuS(' in the hi ~h -t lost..y KI 111111' u f illd hit! wlls.II' oral IWllds on tht' inlt 'nd t"tlu\.ttiun·ti llle p mfill's. MUf(1.1II11 tiSSllt' bindi ng exists t"''t'll .III'(1I1. aJl(I I)("i n~ o nly 1Il.Irialio lls in Iht.l'\l. whid l is a1\\"d)"S h igh (F ig:.lilt! inltihitio n.lrolllt't' (aud hillf-Iift' ) mtllt'r than in oral hi{J. ak ('Ull<''t. Ihis dt'Sigll is not lIl\\-d)-S pussih lt" ('spt'('ially fur c1 m gs for wh ich till' full t'ITt't.J\-N . .'. Om.' !'lllsilioll kim ·tit'S.tlk at1hit)" is cxpt'l.td ion mlio. nault'I)". tln. should II(' st"t'll 'U I\U1I~ ind i\i d uals \\i llt \lll)il1~ t'1l0 'llIt' at·t' · ti\il)' rt't. tll' t'wnt sill".1t"tllll h.lS till' ·ts mldt'll t·xpt' IlSt· of an incn-used uuml x-r o f slIhjt'l:ts.CHAPTE 13 R '" till" I. Here. a ItJ\\' 11I'pa lic (·xtr. dUSt'S anaeljllstt't l !itl Ihal tilt' pl. b'L\. su..lIlstant ..1.t'tI 011 th is iufonnation. i ~h !It'p atk ext nlt1ioll ralio.i th a I. . ill p rae· tit'('. This mort ' t·laho mtc . it lIlay Imn ' limil t'tl utilily fur tllN ' n-comme-ndanons. !1('C'llIlst' of a high ~ rst .s Illlwh a ' ' d l'art'r stah' lIwllb to 1M IWldl' ahu lII Ill(' t111ll't' lIlmtion..· h 'm!.. 1in tilt' lin'r . In l't. "I's i ~ 1 t'nablt. III all t.".(1.Iw p. al)i n~ in t'tllllp!l'xil)-.s III lit. t'adl with llc!\1I11tagl'!i and duadvan.lhilil)"within t'adl J'n m p .<l\'('S.ltit' I · ~tmdioll rat io uud m lllt' of ad mmt stranon of the.'i\i n~ tilt' S<lIllt' o ml dost.lIllr. if a poo r corrr-latiou is fOllllcl IM 'lwt"t'n plas ma d nl g rmn-en trution illlt! Tt"SPUIISt .t'!y t'f. In t.. bu t n ..lIlUlIlg I\('altl. limih"t l aml ll" I"'ltit' h llM flow is rt. The overallef fect .Ul n 'sl:M l1Iw at t'..'llt rlllioli .lS Ill ~1 conceutmuon in ('adl patient lit'S in OIl<. ill p lasma .I\1Iibhilily . of c1 nJ~.fTt'(·l...hly \1Iriah lt·.lS \\1.t l m ~. Iw rfusiun Tlllt.. . F ur e xample.11 .llItl)" !IIt't aIKlli7J. ls of ti lt' drug. An -'u n lillgly.

n . .. 2 • o B 16 24 Hours du'>t's In produce ... t:.... · r.d l'a mll('t' ti nt !!: (a..• .'rs Irom o n.. us might 1)(' 1111' ( Mol-'i(' if tilt' tlnl ~ is 101)(' 1I'\('d il-S a _ 'it"(latin ' Il~l)Uf)lk UT In r~ 'lil '\·t' a IWilllad w.. ·11. ()h\iomly. r..'h. > h ¢n'lI I ~' c wln-n. ( Fi~. '(1 nil tilt' follll\\illg n -a.an l:_ ..nl r.'ll'llkilwtks .. li". hIT 'I . . an' substrat e-s of " IIZ\llU' svstems Ihal show Ihl' .." ....in C.l!:h. ·n1l. i n .Iah"·~.uI.n. (I m l hil\... . \'aril 's) for tln. ' h l\\'{'\'{ 'r..lSI'S the...l( .low -dt'ar"dnl. t1ifT. a.~ .·... l"l\...·10 '~l " h..Iml( .u' ill "..(I)(t'\(o/t ) \m uld m-ed to 1)(' lIdjuslf'(! hy III.~"....lsl va riahility alllOl1~ sllhjt'(1s. 1" 11/:< .I" ·..r...1. .s t i n~ do 'it... if ti lt' d nl ~ ts intt' ndt't! for chrmuc 11M'. .or.. " u.... tI... " .uiahility ill an'mgt' plateau cooccnmuton sho uld 1I0t 1)(' illlw n '1I11 diffi-rent )' From that whic h ('sish lilr a dnlg uf Inw Ilt'patk d l'armlt'(' am i h a\i ll ~ till' Soillllt' d(~ 't..ilily i.. h 'llf·lif(. \1l ri a hi l i l ~.' sanu.' ll"ti\i ty. n -III'(1s variahility ill 1'110111(' lId hit)' t1mmgh C/..II"·'It'(·I lf·llf.. 13-9 )..lt'('h. I... pn >.lIl '('h m riilh ility ill 1-1l ~ ' 1ll" adh·it~· thrull~h F: wln-n-as. lrihll ti"" l "l i l~" 4 • ... 10" .. T' M I.. .. imiL..·!" h. . o f major importmll1' is Ill.212 .. '(.-\' r. In miuimizi. ... (wtt h F Of I)...IIlII" ·t.d ~n"t' to maintain a eommou C... if IIwtahnl i.·IIIK-al.Ito.." .. is rt'lati\'dy constant l and pcrhap... mil. 'aria· < Inl: 1I " ".. \1lriah ilit)' in C ..(' d nl~ .rt'!:1. wit hin sllhjt'!:1s.: .li. " " ri ".. Fo r a dn l~ of high Ilt'patic ch-arancc-...1 r.l '''.I....Ii. • .trill !)' ill I. l l i 10 I'r.13-.·(·.. a ...1 pri". hy a nuxnm.ll~·.al .lllC s)"!'tt-m 10 another. and dosill!!: lnn-rval (¢ \l'1l Ilml ha lf-lift. I".· ". 11':' S..t is tin- .Ii"" • . . ' m .J.I i"... '. in ..'" a . al"" '] >li. . ..-"1.variutjon in pharm '...oral ( Iosill~ run.. "'n· .·n u n- B 6 1II. st'!('('lio ll...· p ~ ( ·IIlnd i..'". moh -cuk -s 'l'{ l\lld m-ed to 1)(' 'Yl ...1... 0:'('(1"."'ill.1 3.. pm.r I.. t.. . CHAP'Tfl! 13 Fi" .. 'it llli ll~.·...' l' nz:.II.1 n·r.d· " . 1"11~· i.. fn r it dr u of I(l\v hepatic ch-arg alll'l'....tt....~ ins uffil"i" 111 tn make tI..h t..1ill ..... Un fortulIatdy...i.. AI plateau ....' 1lll( II'r1~ill ~ variation in l:"IIZylllt' '....d <1" 1: l ~ l .....<lil"'..OV • F 'Dose CL· t t1l1sil1~ Inn-real..>l ·".n1 f.I'jo'th . (.·". whid .." "". In UX l'l ill all " .: h ~.:' of v<lriahi lity iu e-nzvmatjc ad h i ty..ju' " .It'(·nl ... till' an'ragl' ('UIl('I'llt mtinn (C .-.IIIT .h •.1i"" 1 M i~ 1! ''''""11. " I"..of adjll..1.. an. ! wluch..lin " ." ' .·h· " ""'I"I.a' "'1101"'1..'1... '''11:1.~1Iu . -•.. Tl us is adlil"\'{'!:! hy adj lls l i ll~ IIIl' doS(' for the Iti..!tin.•• 110011(" "11'-::-""" . current infon n.'n'nl ' '' ''1''(1.. til(' dt'gn"(' o f \'.tIll' Sl U III ' I' IT~'(1 . .. 111is stan-uu-n t is 11.. ilJ.1-('('1' " f tl"'''plo}. (Dat.. lit.n .u" oI....tiu n i.... ( . ..I. In hu lll ('.. . r ..1 . .Jo . ti\..1....I.11' ...1o~·1I " . -.

V\).... ( I · "'11:-'1.11Il'ln~ illk. ...... . I"".... .·· a i" " ...d ....d "'i ll.1." ul.[. ....t . ll" (n l:" I).r..<.· .10:.IiI.j.~1 fur I' .. .. l r..hilo t~ i" "na! hit.1 1 hi"" ...'l~..." ". •~ ...." ift'lt f'(1prim.. k. _1......nol. 11..tit.in d .0 0 ~ 50 25 10 5 0 2 3 4 Hours e ~ ~ ~ £ E ~ .. J . ..h" <of . lu l'" .I" "i . · rrufilr" .. 1.1' •.... . ..• .. ~ 5 6 7 B ~ u 0 ~ ~ 0 ~ 250 100 _ \1"... d)' ...1l '..) o r .I. 10:-1 "fht" 1 · ..·.It'lIt1l11n ro.\ '.1"ri. Io..n... ~i ll1 l1lotlk"....• -1. I.. in tl. ·" .' . n·i..r...Jk.......·. "".. C".t. ~lr.... 11..flIl(t.l it.I....1..... Ii"K"II.rt.j...· t'f1T.-ftrtl"k" 0. 50 !>..1 i n t nn~"': do·..""'r 10 r"ill!>l.u .. ...A. 1".. hou " ". " h... " mli: . .. K~·" tr..lit .tnot ... ........... \ 1. .1. IH : .11." ...... ....l:. -II·.... l .~·"I .. ..l7)' . in lic .. ..... ...." it~.....K. "lIp i' 1 .' . Ear-d .I ...til'n (H).... ho. ~.... "O 0 4 6 Hours 12 0 " lp.....in i<l"' IIo"... s'K ........ ..· T pl.' " mil. 1>t'.j...<. ...·••hll~ i llhjt-e. . !> _ .<.. "'10 0" ..arily in .. ·"I r"'it...-t....... 10..n....... .._~. ·.In.. ~ U 0 ~ 250 100 _ A ~ ~ ~'§..111..9 11 \1 ).... '~I ..n· II..( IIi¢.. r..1 ()... ... . pnrlil.. 0 4 6 Hours 12 Dosing Intervals ..11•...."..1 poLa. ..... .Ik_ inlo: t v....Iml:.! t h".1 . I" I" ..·· ll~ fur . ....·n niu it.... .. ......m.. (1I lr_l' from s l. ro. .ld..--... 13-9....."'" 1....·rfll'it . .i"I .J n........ p•• rt k~. "..·....1t ...l i1.' o r .·.' rlOl.CHAPTEI113 VAA1A6lUTY '" I' i... · . .· itr. .....1o: <or..1 . lbo · ...... ....... nh K·r"ltl .1i" .. .llh dnl!t" ifn' . .I••liIT '''''l''Iln ''''ri"IJil..hihl} (16-tiO'll.. r..• • 3..11".. .il...JIllin i.lf llf. ' ... 1. ~ I.. ·li. 13-Ji. .0_ 0- e ~ e ~ 25 ~ E ~ 10 5 0 1 2 3 4 Hours 5 6 7 l ow Clearance 6 6 High Clearance ~ E u ~ a ~ 4 4 '-' 0 ~ ~ a ~ C 2 2 E ~ ~ c." ...1 ur al l... ~ I 1 1)(.. n-.~I..\11 . . . ill .'I...... I. " r I... .....· "...1 ..tio"·hm.. " "~'n. <of 10: ... (. i> 1 I. II. r...:..] . hIT.Um. fo[Io: _. I..lr.."I. . 1-:. ...u 1'."'.1'" f".. ·....l oI lil> In 1... .I".........I' ''CIi'"' v ...> ~'§.· (. . (I ll mp....ll..~ I I'"~.. In 1 ..-e ( I I / min) ". n..to· f•... d""" ".!l:1 1!J7fJ.m .........: rLt...-r dUll ill .rio.lic ... " f ( :.. p.. . 1011/.LIT.....Iit.. ..t> "ill..1 Lv.I st.-e.....1 Ace. n 1 . I. Pn..." .. 1'. in f. ~~ 'l llIlit .h"ln · i. .IIt....u .lit' (I.. " 1I . 01 .liI: rlU}ll'" _ 1I'it}· .li"..1t i~ 10 ..· . Ih...1121.\·lirn. .. 11......-I. Imioi.

. 10 obtaill tlU' sanul .. DOSE STRENGTHS I'mdlll'" an .h ht'!l.'lh mon. numbe-r can lit. (lllllp ri sill~ it (lllllbinitliu ll of th e market ed unit IltN ' streng hs.. :'\ow. I lt'si~loI h'( l C l ..>111.'j().pm·s . mn~(' of ...ltJwt'sl il\1lilahlt. il\ 50 or 100 mv... TIMt t'r h .mk nlaill h'llalll't· IllI. ti l(' pu tten t r pu p ulat ion .11111.. for a t1 mv.tths.l " hjed iw \\1mlel ll(' lIIos1 l' ffid ently m:h it" . ill IIII..2 tiIJWS Ilw .fn'( lllI. Tilt · a ppmilc:h is In Illm l ' fmlll till' popll lilliun pha rm iKllkilleti<-' par.... is ... IIsually. tl w 10" '1's l ' d mill ~ rail' tha t could hL ¢n'll 10 a pali l'll t witl r 11 dt'i\T..t' . C...i ous ly...'ntl l)o" SUPlll l"l' that till' maximum am i miniuuun d l'amlll1' \"alul' s Ihal 1.' lI. uf dd illt'fl sln·II/-. ".' ' lIl.m... o r in C .. ill all pa tients .'lItly..' ahh-. In p raet ice-... Of im llll..' slllaIlL tlOSt' ·. U1.'(1 if till' indhi dual's de lSil~l' n '(ltlin'lIll' nfs ('1l1lld l)(' <'".wh..('rs ) should ('1IIIW a v.. r tl u' t1l'sin"C...l1l' 1Il~ p mtlll <-1s..t'ma l'1J1lL't'nlmlio lJ r.li(.lk11Iah '<-11H.hl' uUfs lalldi ll~ St.lh'(! hy t ak jn~ tln. Tln-refon -. ~ 2 tlMI lill" riU'~1' of dm i ll~ rates IIl't '(ll" l \\1lU ld hI' sh foltl if IlIl' objt'l'l \\~. if IIII. Oh. sud . whiell a ppl ies wllt'll all palil'lIls n'l jllirc. it would 1)(' n-asouahleto market 11 1n"t..n 'aIN i"tmifl( lhitlual variatioll in pharlllitl'uk illl'fic pa r..' lu allow S Unil' toh-ram x-."111m·.f .' (n nhtllllltl) pl.. th " ll1msl irn ·spt'(·ti\'(' of iU I~' diffen-nces in ph 'lOllill"llkillt'til-s alll llll V. till' Huaiuumbe-r of ...fn'f I Il('" I I~' markcn-d . dtJsill~ intr-rval is h 'p l (1J1lsliml) is fourfold . t!lusc' wit h a pa rti<-11lilrly h i ~h clearance lIIay he 1IllllTllIll()(lall'( l with it Iargt'r-Ih all ' ' IIs' I. whidl wo uld sliffiL for !}' uf tln.'5'1. 111tJSt· \\i th a pilrtklllitrly 'l Illw l'!I'aTiUI('1' \·011111' 1l 1i1~· II(' ..' umounts.t1wmpt·util· .I1 matnn-naruv doSt..lt1 hily (caused h)' a variation ill ( "Il1ll't'lltmt iulI of t' 1I7. al'(:t·pt .uf till' jMlit'l. dt N ' stn 'lIh ll II'!'iS fn '(IIU'utly Ihall m llal .·.". I. O f .wl'\-N .llieut .' th at ('tm ltl ll(' ~\"t'll 1011 p" til'lll \\i th a d t" \T.. Illn~l'sl in Ihl' Illlpll iitiio li. In 'llh1hs t'ho'WlI dl'pl.p lillllli .. till' therapeutic imh-x is suffidl'utly \\i dl.lssnd ah '(l dO!'iin ~ r.". doSt· sln'nj.111011 pmtlll('1 's ' a C••. C •. \ \ 11ile Ihi s idt'al <-"allllni he tot ally 1 nll'l ill pm<-1il1'. t or 1 11I·~· lIlay n'(1'ht' it markelt"C..'IIISt' Ihl' llillf·l ifl' ill Ih is ~n )IJ p is likl'ly to he tI. "" fi · C l.lS uuit do. adjal'1'1l1 tlu. It \" l11 ld then follow Irmn tilt' fami liar f(·latiomh ip F · Dow t . i' .. III~.. % 111.ct .1Il II(' 1J"l'(1 III d l'\i St· all optimal dtl'oil~I ' n.lIlwlt·rs .lim" It' u f Iht. Inhil utors...~ m il. "t"C. . I1 ~ manner for ..p 'l' '5tl opulcnon. CHAl'T E ~ 13 It follows F rom tilt· ror('goill~ tim! then. "\ (11 )n l i ll ~ly.s(l 1l1~.L\ UII 10 1I(. illlt' ll uf 11 d nJ~ for In'"lnl("ut of a tlisl' il"l' in an illllh i tluitl l). t1 n l~' Intended for dm.llil' (':\!nK1ioll than fo r Ollt' o f luw ht '!l<t1 k ext raction .... i f tln. 11ll' hi~llt's l dusil .l do St.tti..lL'1'1 l11l1l1tJtI.1 !'i (and Iwllt'1' 11.1Il~' pnK'tical issues. tl ml is 1. ACCOUNTING FOR VARIABILITY It n 'mains III ht.' current ccunph-.1Il ~c ...IIII1. ..S ttnu-s lilt' u pliulill"1llul' . 11 n lll~h t'!>. (' S s trt '"~" s di ffN b~· a factor of 2 .. sln'Il).. n" lll ''(:t in· I~· ..'lIIls 0 11 1ll. I Il . of IliV..of !it'\'t'ral doS(' sl n' II ~ II .'\ is s ufTi d t·utly wide-.'l"~ 9. A lt hllll~J.ji'n' fltlm lnhlnt'l/! 1 11' tlm!!. ' of ilppm. ami 2f.t Ill'P" I. if lilt.I1l('1' of C l. du d Cl ..\"(' thai a !it'! variatio n i ll (' !l 0 111t' ..i ~ lUI iuhereut n '.l..1 s t rt · Il ~ 1.Ul('t· \·alm ' of CI. C/ . all !liltit ' nl s can " "('('in ' the sauudo">(' stn ·lJ/-. A narrow tllt'nllx'ulil' index I\('('('ssilalt·s the manufactun.. !it't'll how inf"nllal io ll 1111 \llriah ililY (". O h\i nus ly.l"l an'ra~t' plate-au coucentrattons wi thin :!O o f the cptunal \"<11 lit. . allll. di fT by il factor t. 1U1I'1Il ~...' 1ll't)lII l)."' Illal h U. ..('1'SS may II(' adliew"C l hy atlupti ll~ III(' ftllltJ\\ill~ lnll. 11."" is om' lilill p n lOJ Ul't. SC lllll. c alculated ill Ihl' follo.'I('r lostillla h'!'i 10 the illtih i tillal palit'n l's \1III1I'S..·S it e..u is mu.

....s. ...various pharmacoktnenc parunn-te-rs within Ihl' p' llit·nt p opulatkm <IiITI·r..·a r..s. .. / '. .. ."1' ..1h I... (n" I'" "''''' ..·n·... ...... ul'I"'1".ill FiJ.1. ..· I'. ..• nur (7 N_ <. coustdemble variilbi li ~' exis ts ill pl. Ihl'n' is suhslanlial variability in aleorptlon.. Iim" I".It. •. 1II'.. O.1. ·...""it: .1. fil:\.. .h!c.... li e .·". DI'p.~· I ~' in.".I ~' . t ..I.II. thi s m il Ill' .variahility :IS pos-sihl" with mcasuruhle d laI'Hl1l'ris!il'S..i. tlo.l.· " I"" 10. ari· . th " tIt ....•. IS much of tlu.IIlSt't1 hy diffen'III' '!> in the 1·~tl'lIt of first-pass los s. ( 1.. . .. 1111" .· .CHAPll R 13 '" 111t· firsl sh 'p is III i tlt· lIti ~. . tilt' only sub stantial va riahility is in d l·araml ·.clflc DI.....·· r..1......_..l.l"" : thost· willi Im\1.llh...... " f tI..I I:r...w OI . 13-li)...... n.11.olit .otit".II. If tlu. .. .10.lo· . . ( . · tI.• I"tod ~1i''1.t·: IhoS{' who sllln!w and haVt· lu·pa lk tIL "".. Va riabili ty ill tln.. Fur ol lll'f(lm~.tI••.·s ill l plmnn"l'l." " f II........In' : ( ••• )--11 .t k .Ii..'.wI! (0....~ u"i". .1it......mmlt'lers... 11. Fo r example. '1Il""" .li.l'pa lit· t1ist·a<. I" . ""tl ll. y.·..rI..... as shown ill Tubh.. as !Il1'lltinllt"tl p n '\i ullsly ( Fi ~. 13..· {n ... ilhill tl.....t. .. "f . such llSt111'tlphyllim·. ).olit..~·)--t h .. 13. hili \\i !h pr o pranolo l it is 1-.. Po tl..1 in 1" 'P'd k' .Hht. . v + + a + + • • + ......o' it.·n in tI..· I.... 7...1.{ tl.... ."''''litl<l .. . ...:o ril·S: thuSt: who s moke alll ilmn' 111 1 l I... n"I" . if Ilw d h t:n 'h ' d laraetl'ri sties are IlI'plt!ie di Sl a_Sl' and smu kill)...4'1» I" I.. + • + + . I"" I.. \\'itll diJ. ..lnh"u"" n( d.tl fllmllll.. fur dt·"nuK~· in Ih..laU.li."'. .I i w" .t. t· s n il' T.. " I' ''''1" .lllty I. hut fur drffi-n-nt reuson s.. I.i..'d n lilt' variahility is caused p rimarily h)' <Iiff ·n·IIl'l.. Fillilily. ..-l i . ....... ".o mu p mt" in hinl lill~....h" haw 1.· . 4 (..1111. "dlit'\ l-'C I I. I".u . : tlu-n till' populatkru wll ll l tl l ~· tlhi tll"tl into Iour t-.dml·tt-risl ic is di slTl'l l' allli iJlllt' llI'm lt' nt.:..· lw plltie d iSt·.lit.bl.1ht...:I. ..ri<" I' ' lIl. (.slt lon_ and ett-_•••th.... rune and plu-nvtoin Included.J..· -t '" ..i"l: i' .. tI....... .. 111. ll'J. .lit [.... i"f ' "r II.. ..t... .llId io".ltiun ." .. 'I>I"'.". us Illustrated fell' clearuuce.· .tnifiellllt "lIriahili ly exists in all p... \\'ilh ot lu-rs.. tl o ...l. D_g' Wlthl....· .nt Po pul . j "....iL. . r.I" ""t .." tl. . lin' ~1I1"ki nl: . Fur S111111' drugs.IIi l •.... Clearance (arbitraryscale) f"..:u. .AmiodofQfllill Cyc~ ++ + + + + + + + + Dtgo>cin ~ ~onAlo + N /A + + ? + .l. Ik. \\ill(·ly allloll~ d m ~s . I' . ". ·a r".....y partililJll ill ~ I l lt~ 1 1IIpulali till iut o sulll)(lp lllalio lls.... I. .· ( !Yfl'J.· t"t..nw " . .. such as lli~l\ill alll i p r o pranolol.. 1 3-2..~"t"· i.\ t step is to t ry fu ill'-'tllllll llKl!k ....6'il). It..._ lltlJG V.l.. si".t ..-h "m"I. ..... 1"''P'' I....1 p"tit '1I1 p....13-2 for a 1I111 11 1 ~' r of n -pri-se-ntative drugs. . . .· ..•.lll I l"...·ulil-...· Lt..10.·n· ... ".I.... .. s ...."_ In Iht. 111....tnh"!i ' " · .. t P''I'''... .... ~ ...· .i ll........ + • + + + Ph&noborbtol ~n + PJcpolloiol Quinidine + + + + Salicylic cod ~~ + + + + + + ++ Fill.·. 10 1.I Io. tho 0_1 AJ." in·~· m" i"!t Ihat .." . tlwl '~HlIl'ri . am iIJlI.h.). DetI Sp. 10. fur some. tilt' mos t \-ariabll' pa ra lllt' ll"r within lilt' patieut p opulation... 1111" ·r~ · ...d..

..OIl " .... it Illay 1M:' possihle In find a funct jonal n-latlouship with ( JIl ( ' o r more p ha ml<lI'o killt'lil' pa filllwh· rs.....t' who Iw itlll' r 11iI\'(' lu-pat k... 13-1 1). (·.101t.fn 'C lllt·n<.1 (. Ilioliln \ .6. l'a "..1 1. Tn 1' 1l\i~~c lIuw tilt' enti re st rdl1 would work... Ill' p ili ".. 6.uu! creatinine de. lju.." ' dt-1i .L.<1 ill til(' liver ami p'u1ly t..1 (IIIK1io"..L~lI rah l(· l'hamdNhtie is couuuuous. fur whielt p opulation pharmacokmcncs are: oral hi()a\~d..·. . ami t11( )'i.n na.1 150 • T. · h h.or-. . .lIwt'. ill I"' lirf. ~ l..riahih ty in til. ..I.0.il~' Volume of Distribution Renal Clearance Hepatic Clearance "'x 13-1 2.. Ihi" " ''''1>11l..1 n r ... ' porin..·lt.olit". rut! f"'K1 .... la-.11. o f ....... 0 11 tilt" (ltllt'r hand...g. .1 fn r l~' ... . ':ariahilit~. ...otio" . tween the renal clea rance of till' cephalosporin..lr.S2: volume of distrihu tio ll..I>I." ...<t"oIJK.. "f "~-i""t ..'ftaYj l!i ll1l' (and 1II .ttll·h·"...1 an ' four table-ts .t. o r d(·~n"t· of n-nal funct ion . F. ·. wt·i ~h t .o tilli.2 l AIr.".3 I.ik''' < of II lobI •..1Il~' ntlw r d nt~s ) .. of .. {'..0 ItJUltp of 19 ptlil'n ls .J.Lat..1 it.in.hO'd p0'l ">rti"n I" ('W. "ln · f..eli". ..n.u1. ...8.1 d .tln.i l. Sdll·m..... I O n frolll tI. llI lld lan~t .! to the . n-nal clear1II1l't... O."·rt·h...· "f "" n I> . i'l n ·Ltt•.di.r('('fluitliu. Vr>"<'. 1n ·na! flllK1i...597.'(1 tiM" fnM. 1w-. » .' and shape o f tilt' distrihulioll l"urvt' of each suhlx )j>ulatiou deterumn..•• \1tI'Ws i ll . .-s of ./I.i"K.l. T .. o f tI ./ l AIr.w no r slIlokt" 111(" rd ati \"t' si". ill \'. TI..olit.uwt'.....t' " '1.. J. and ht'p'll k dt·ar.. -n-r. pa rtly lI11'taboli7 .d...h. If.. as Sl'C ' II.~' a< " n t...I. n'pn'S1 'll l i n ~ ' n It......Lit" ill Fi ~.. ('t. tilt' 1II( ·..m MIIMI. .flu id i lt. It.... t.'" Eum. l.rio "l\ p.11. 13. i th ro '... 1 n"..1"n.60').UK't' in ...12 fur 1I 1O' d m~.. (.lhil ity... 4/....: 1><.·.of till' C'l l'l.'y distriIJIIlio n for the en tire populat ion.. 16." .· n 'P"'""""'. 1..."6 C HAPTt ~ 13 hu t dn nut M Il Okt. i lll hnpai .. 10.t".' p.1o'W'. • • •• • • • • o r •• • 50 100 150 o CreatinineClearance (mUmin) • • • Weight Age Renal Function Oral Bioavailability n. (-'ollsidt' r tilt' . nil' ("" rtl"" of ti ll' tal LtI.1grade dmeasure of n-nal function ( F i~. such as il~l'. 13.

Il. il is sma ll a nd il('t't'p la hlc' .. urun ce "hou ld Ill' 1U11111.11 Fur Ihh t1 n1~."l it~ fail to al't'tlUlll fur mllt'h o f IIIl' \Ol ri ahi li l ~' in p ha n n at 't M I~lla rnil ~ . tllt' n ' lIIay hc it ( '..w " 1-imt 'll for 11ll' 'f1.. 1"l llllmls l ilt.: pl. a rt' I'lllplnyt'tl ' d init·aUS'.lSIlI'. 0...o f di sl rihulio n and fur SC llll(' o f tIl(' \"ariilhil i l~' in Ill'pill k ch-u nmce. a in vnluuu of dislri h ulioll .lIIt't' alltl Hllu lIl" of dis lri llll tiHn. St' pam h'l:l fr om its inlhll'Ilt't' 011 Ilo d y SH'i~ILt . ' l lIl" (If lilt. a1-(t'.aJ.gn'a tl's t l't lllfitll' lIt't.gl'. V. an d Ilt'p'll ie ck-aram-e.: ast' .t. Frl" l l ll l ' ll l (~'. if requt n -d. .o f tln. 13.\ for IILl' wllolt.~ilm 'u .:.. dlafilt·It'risl it~ illd udt't) t'tlliltl atlt 11l1atd .'rls lil". ~ an im lh i d ua l's do.a!-. Ht' nal fllll11ioll alsll ac counts for almost all tlu. Thl'". SC I.wnl" of ~t 'ndil's . A.t\s llln ptio n th"l lilt l.. whid l m a~' ht· fa r fm m t hl' illlihidllal's rt'l:luin' mt'IlI. I" ..llic'llfs mainlt'!I. lIf1wjl al k i atie-n t . HI 't 'l m i ll ~ III till' ill" lili"I'MI IMli" III. 16 ).:i llt'lil· s'aria h ilily adds Iilll . r.lssi. IImn '\ .'u tit' indt 's o f IIII' t1 nlg: is sllllieicollily l lam'\\". . t't lm'(1 i n~ tilt' l'H lp'llal io n plllln uat'u khwl il'S for tlupal it'lll 's s\"('iJ.lIJt't' .gnilll?: Iht" p opulunou vakn. C lt'lIrI.dsts in a.m ts for mo s t of ti lt' \"a riahilil)" in volunn.'.lsma t"l lllt"t'lItmlio!l aft t'( a si ll~11' dose. ~ o llt'l llt' lt'ss.vuriahilitv in n' na l d l'a r.. lll.lIll 't' tlOSt' n'f!Llil'l' uw nts . \\l'i!!ht.t\ S l h \i f''l:1Ihat'k h. a nd 111l'1I IISC' tilt' im lis id ual"s dlamt1I' risl il~ to p rt"tlid his or hl' r inil ial dos. Surprisill~I~'I'H:rh"ps. 1II11li1 of Ihl' s'ari ahility in 1'1 " S('H IIl'\(' is dILl' 10 d i ITI 'n 'n l't '~ ill pharll1at'tM I~l l. II UWI'H' r. sudl . tilt' filtio f /Cl.p auent populalio ll.'fI' ri.. COIII't' nlraliotl \lo llitu rlnl-(l.Il:C 1111' pmhabilily of I ll'i ll~ ah lc' tn " sfi malt' tilt' t'tlm't't d us. aollllini'kriul! 11ll' t1nl~ is ha ". exrsts in . .t\ il.ly 1ll'lplo .. Ft··w. volunu..:I' n 'gi lllC'lI Ill.uia hilit)· in Ilt'patit' d t'a l'.: IIlt'lahnl is111 !taw Ill'l'lJ t1I'\l'IOIIl'c1 llml he-lp 10 I·.uni( ~.' plain much u f tilt' inllt'rltt'l:l inlt 'rl nl lisiduill t1i1Tl'rl'Il('('s in hCpiltit' d t'a ralil't ' of ce-rtai n d ".1( sillt't. les s t1mfitlt' nl 't' t' lll Ill' l's!'N't ·It'l1 ill I'sti ma l illl-( tln. wd~h l at'l'tl. IIIl' hasiI' sll'lllt~' slill holds: 10 d l'lt'nnille tilt' rdati n ' I"l mi rilllltio n o f Illt'a \ urahll' 1·lIarat1.lIJt't'. I.'sisls.. TI ll' appm. tht.of oral laoil\"ait lhility In Iltt' IMlit'nl .l lly.:s tin this (lOlfillllt'!I' r. tlll<lllli f~in l-( ph an nal'tlJ.:hl. 0 1' hioa \'aibhi hl)' is tln. Slah 'l: l d ilTt' n 'lItly. <I~t'.I'M msc'.ihll' dl.gn'at N than Ihat IIII' n-nal d c'MiUlI't' . Xom.Insc' 1"'''' '11 l UI III. SUh""ll'lt'lIt adj IlSIUIt'III in till' n 'l-(iIIII'll is mati" l"ISt'l:1 o n n " I'ltlIN ' pn Ml m't'd .q' fo r pn '( l it'l i .m urll'lt' r \"a llll'. of l'ildl lahlt'l is it measure uf \"ariilhilil)' o f l hal parumeter within tln.lp. atij uslllWlI1 ]d (C hap . T ilis is not a lwuYl.\(' h pn'St'IIIt'f1 a lM. :h tilt' IOlti'l F/\ ' " l rc lll ~ly illllu t'llt" S ti lt' )waJ.-r.of l ilt' m rlabi lil)' in lJt"palic d t> rdllt:t' a nti . If tilt' t1lt'm p.'lillt' d in C hap .ltl' r tllan u"in.s IIlt' ntio llt"tl..wailahi lily is .Itit' nt pUp llt ltiOIl. as l ilt' pOplllaliull slIlm-' fo r Ilt'p'l tie d l'al'd lll't' is much d t'a filll('t' 10 IIIl' p .lst t'tl1lfdt 'lJ('t.Irla hilily ill oral hio.llit"llf S 1 linJ' tlost. if til(' d m ~ had just Ill"t'li l'xI'n ' h'( l lult'h all..1l 0\ \l'\ ·.l'\t' fo r lII()n i l (l rlll ~ tilt' p lil\ lIl<1 .' inf"lflllalillll p m". .siZt.12 ~ III II I ld Ill.l(.s t1t'sl. am i 011\1'1' d m. ~ClI 1t'I Il(' II ' ss . at't 'tlllllt\ for sonu.. aH'fil!-(t· plat eau coucentranon.. \I o n 'o n ' r.I~1' n 'gilll l' lI. ttl n 'spcmst' \\it hin t ht· ().:lll lS\ill~ tilt' llll'an phannat'tlkilldit' pamlllt · It '~ of till' dnl l-( 1I1.II'.' t'tlllt't 'lll lOlliOIl 10 aid in adjll"ti n~ tIll' lIlainlt'll'IllI't' t!osillR fillt' Ih mu!!h fet'(lhat-J..of di stri bution.'\\' of a IlIIM he lps in doSt. Fil\. a lltl Cl ' H hILt Htt lt· l'tm (jtlt'llt't' in tilt' 1'~ lim alt· of CI.'J't'. a. ~ol llllt 's!lt'{:!t'dly . ami n-nul Iuru-t iou should ~n' w aso llilhlt' imlivnlual t-slima ks of F. Tlu.II'il\1 a ml lll'pa lil' d t'ilfillll 't' is tln..Ila hility tn a('t'tlllllt for most of til(' \1lria hility ill IIt'palk.uK't·.~ (C h. Su mt'l illll's.fort.: a..I"'l:1 iu FiJ. lilt' ('sli ma tl' of lIIainl('II. hu l tim !?: d h l rilm tio n a nd md"I Mllislll eau Ill' aln-n-d iu palit'lIls wil h renal flllletinll Impaimu-ut (St"t' C ha p ..lllt'l'. I "i (Co l1('('111ration :\1o nilori IJ~).CHAPIE P 13 217 o ra l hioa\"ailah ilily.'r . 1Il1"1Il l). d is.1). II andlu-ucc totul d t'ar. II I'n'. n -ual fUIlt1iull lu-lps to ex plain SClllll' of t he s.lIlusl \"ari" "I. n-asonabkt't III fid" 1ll't' cnn Ill' I" Ilt't iI'll in I'sl imali llJ' tln. 1I1I'n' is liull' d Ulil't' hut to start l ilt' imlh i dual (l. A lt lJllu~h J.. 10 a II'sSt' r exn-nt. 1. account for Ih. in!l'rimli\i l illal \1Iriahilil)' in phan ual"l M I~l la m i l~ ."si~ l i ll~ lilt' populattou \"alut.t.ll:t' am i \\"d~h l . Ma rke rs of ~l'lIt'l il' control o f ti m . IlllpulalioTl .'s plain Ihl' ti lllt' t"l llll""l' in n ".'(1 011 lilt' .glI.cl. a mi nl llt'r 1II1'. r patit'lll \n lHltl han ' Ill'" u IIIm ·h h i~l lt . renal d c'a r.' inll.!l.UlI't' wit hin li lt' popula tio ll h also hil-(h . 10 lilt' a hilily to prt'tlit1 im lisi lhml dos.tlil'lll on tllC' 1~1 1il"ll t hKa~1' rq. \"aria b i lil~' in IOla l d t'a r..1 1't't1l1ll1c'l1 for h ut.\. . lilt' II.\SI'(1 o n ph \ llla ('tllll't'llt m!io n.

llittl t' wi thiu Ihis V..1'. admiuistratkm.1s at a consta nt m it' (If 2tl lllgtlir for 41'1 1.(use till' rml/!. llow it dm ~ is ha ndl("(1 in thl" palit'nl p opulat ion.3 L.f16 11111in . was i ll~t'sh't1 o ra lly. \ \ '!lal h a major l-:IIISt' o f tllh \'ari..I'IIIl~ '(/11 as YUill' illllt'l{ flf \~l ri ahi li ty ) o f tilt' follo\\..\.t" least vanabh. "I1L IIw ra peul i<.5. 0 .lt't lll nd l llll ~I'tI . is Ul... alltl \". 7. w llt'll the. "'' ' ' .' major SU lI rt't·S o f \-ariah ility i ll rt·spem.lItltolll o f t1 nl~ coucentrattou hil i di d n u)' ' m llell\~ tilt' subject s. W('n' l'Ullsid l' rahly diffe n-ut (o utsidt· till' 99% (.g.t.dala to id t' ntify tlu.ll lrd(1 .n/v$1QIl HoK~. L t ..:WIlJl of I.(' ofa "thl'm lx'utic" l'()IIl" 'nlmtioli ill ti lt' \-: rio lls sUhjl"t. th rt'~artl to tht' rai l' of .('. I1 ~ p.·12.l' tln. l to tln. S lIggl 'st why \'a oabj lit~. t11 l''Ophyllillt'.lbi l i t~' ill dll-.obt ail\{'tl ill a siudy o f the pIHlm ml'()kim 'ti<. 511:. b . 13--2.lmillisteR"t1 t' d ln lllie.W) . a.211 CHAPTER 13 STUDY PROBLEMS (An swers 1 0 Study Problems or e in Append ix II.. stable ill till' ~. am i half-life . :2.dt·ly a lll(Jll~ patients.wtioll liIlIMIIIIlt! ill liss\lt· (fr 1r )' US(. \\ 'hat characterisne or a l" ltil' llt should IIt'!p to tai lor lus o r ln-r dOS. andlittle i s excn-ted tlJll·h all~{.' \\. ).· vl. D iM 'uss b'.lt lllt'll l of p at ients wi th manic depn-scion.. a " nl' of 39 L. IISt'(1 ill till' tn '.t~l' p hilnllill11kim 'til' p arameters o f Iht' jl-ad r('IIl'!. a. tjn..) I . IM pl'a k pl asm a concenltt.Ull.riahility of a d nl~ tl ilit is pn. 10.(.Ultl lllainh 'Il.sed uuder the 'i<t"t1io l\ " Al"tUllll t i ll ~ fur \'ariahi lity" l'o m 'spo lltll. wln-n tIlt' pharmac oki m-tk-s Hf tilt' d nl~ w as stu t!il't l in ti lt' potk-nt.( 1. T he {I m ~ is lipo philic'.S2..(' hll. a~{·. am i ihllp m ft·n ? 2. tilt" \\"t"i~h l . I )i'Ot'uss l. S\l~t'l't wlJkh pharmacokiru-tk.1e lh'l F'OCIIQll 1 15 14 4 0 1 1 '0 50 015 3 30 47 000 4 15 00 01 0 5 13 81 001 ""bound a. m low of thi s d nl~ is na rr ow (0 ... 2.II1m t l\ndl l.1s.I~t.llIy.tl n lV.pa nUllt' ler is mo st likely to {'xplaill tht' va rianon ill the plat eau ccuccntrattou (If lIo rt rip tylinl' sluM" in Fi.trlillwh'n: llllld d nl~ (C 1.lIy tilt· 11lt' r.ric·lIy why 1I1t' lUi plmnna cokim-tic parameters alllil t' art' 110 1 sulncit' nl to cha r<I('h ·ri. aut l C lt'ara nl. 4. T hl ' rull owin~ data (T " hll' 13-3) wert."t' is much ~n'alt'r aflt'r elml than aftt'r i. in the observed pt L sllIa ccne-ntrunon-tt nw l'1l1'.Wllp .v. t\ naly.lllaillllll'nt . 3.. 22 I.!)(. rt''1uin'lIl('llt ? Ii III a J. h. .alul':O.1s. its fi' is l .a~( '? II. ant! " .quirerm-nts \1 11)' \\.II)('lllk' illlp !im tiolls of liteS(' tlata \\. 1. \\11.10 L: clearance.paril nw!t·rs val'''' till' 1I10st ill tilt" pillic'n t populatioll (or diKt)xill.• 10 <I m~s .t'.llth y sllhjl"t.l\ lmill h·sti ll. TIlt" tl nl~ was illfuS('t1 int mn 'llo11sly ill fin ' slIbj{"t. f. vnhu-s uf ti lt'S(' parall wlt 'rs t1ilit' n .1 pbarllliln lkilwl il. AfiN Lv. tnuton am l /\l'e varied over a fi vefold rd ll~l' .(lIIfidt>Il{'(' inte-rvals] from til(' popula tioll value-s uf F. its alld t1usa~t' n . adtni nistraI iOIJ.¢ l' hl (ll'kill~ a~(' lI t alpn'llolnl.It•• 13-3. pht' II)1oi n.. whit' '' is t'!illlinak d allllos t t'xcillsi\'d y hy ht'!" il k lIlt'taboli slll . List tim . Yet.. n.ht' patient . -d 011 lInlM fr. fi' = O. W('J'(' Iound tn hI' vohune o f dis tri hutjou. Lithiu m. ti lt' a\'t' r-.. ) '(' 1.4 10 IAmillit'(luinlle ntsl Ll. By {''Oi ndt!e lll.'Odywle ploYTlO co-c e-e once Img!L] PO$I. of P. ami n-nal Iuncnou of . T Ilt' fraction unbcuud "-:L~ fonm l 1 01M im!t.p atient population \~a hn-s. fracti on u nhu und in plasma (fr d .5 h r. discus.IOInillantly t' :u'rt. Hril'f1y di scu ss how tlJis (''Uuld ari sl'..

1 0l ~ within a patient p upuh&lioll is I. ral i('I1I ~ an.ScN".\hi li l~' ill dl. F and \ '. IL~ ill ~ a deloiW1 ill ""hid.d Ol~.'> In .1.'fint " a I.'i% n mfldl"lwt" Inn-real o f l'!"ara. alKl lKlt tiM.... 11IK' n litt"'\."(1 11J nm.~~ .... a I.~ . Other pharmac:ukindic 1 l<lr.t>ly \\ilh tilt" d rug.'aralll't' on tl H' <Ith' mpt In 1. or :200 111 ~ {lai l~' of the.. n~ .rarKkllnly a.i~II.lifTt"n 'l1n:.l.i\ill ~ a lllllhipk:'-tlt:.. 111t:' u. .W!iPOIIst' n "liti olllohipwit hin a pali t'ul p"pUbliclII.~mllp' n"(. me-n nf t"itlK'r 50. .h. IUO.. of fin_ 'fold. 1>i'>("\I. \ 1U)' 1 "1J I."ntlal illlp<K1 of thi s \-ari.. lilt" p lt."S I"U:'III ~h.Ilwlt"n ....OWTE ~ 13 2 •• !'t.' md.of three.5 [A ll. l1lt"rapt "utic at1i\ i t)' n "Sid..." u f a 1.I(.

is IIl1t' of two til' mon. An individual pt)S st'S Si ll~ a pair IIf identical alh-lr-s. lw itllt'r uf which is m il. in wnich generIC po/ymofphi!>lTl con be demon!>lfo!OO and lisl I'M:> examples01 each.anti.lllt"l1 t"llnd itiulls ure uf'tt·n dt'h"l11"l1 as a drnmatk. \"c An til/a t. idiosyncrasy. that is.('Up)' l'()rn's pullf li n~ positiuns (Iod ) on p aired ch romosonn-s. opulation stullies hy a POIYlllfMlal fn'( llit' lll) ' t1ist rihllliull o f til(' l'hamd t'ristit' ur S OIlIt' 1IIt'.tnTl. homoZ'f9OU$.. 5. 2 . genorype." 1~ GE NETICS OBJECTIVES The reoder will be able 10: 1 Give e.2 list ~t' l \('t ie o uuhttons th ai alTt"l1 rlupt. (. Define the terms. T ah lt·s )+-.ygllfl. tI elmg Idlw'Yll cm. p n K"t't 'tlill l-'( til t1msidt 'r spl"'l'ific csa mpk-s. ('itlw r dominant III' n'('l'ssin' is lumw:. nhnormal t l m~ n ·slxlTlst·.study of Ilt'rt'tlitary variatums ill d m ~ rt·S p OIlM' .. Ilkillt'l k s and phannal1M " I)1l'Uuit'S of some d n l.lilt! slIhtll" t1ifTt"n 'Jl('t's alllOll ~ Individuals.~ ll h~ '(1.I ami 14.dt ·finitillllS an ' im po rtant 10 all 1I1l(1(' rsl alid ill ~ o f tlU' . utl lt'fS 'lS ran.'ssin' alk-le produces u ljI 1('n ':.~ for lilt' gl·!It' .. phenotype. .' " snail)' dt 'h "l'!l'(1 ill slm!it's of twins. and hUlI\lrl)l'0llS imli\idllills \'oi tlJ n 'l"l'ssin' alit'll'S may St.difh-n-nt gt'lIt's l1mtaining SIX"li fic inl..tl. allele.st"l1 as POl)ll1l1'llhisllls.nwl Ylw is th e fundamen tul asso muent Sic of ~l'Ilt'S of all imli\i dual.vartat inu ill n 'SIXJIlM to uu admtutsten-d dm~. phOfmocogeoetiO. llIilh"lllll(JIl( ~(.. illcllldill ~ mu ch o r tlu.t'st' condmons arl-Otrans'S. genetiC po/ymofphism. saUlt' pllt'u lllnx'. l111'y 111<1) ' also 1M..y.:I'lIe tlcs is tl u.l la~(' part or both lilt' ~ t ri kill~ . 220 . 111(' modi' o f iulu-ri tance is r-ithcr lIlm ll ~t 'n k (I I' poIY~t'"it· dt111'lldi ll ~ UII whetln-r it is trallSlll itl t"l! by a ~PJl(' al a si n~lt· lot'lls or hy ~t' I WS at umltipkIud on tilt" chnIlIlUSOlllt·s. Built homozygous ludtvtduals with do minan t ulk-h-s a llt l l l(' lt · n )/.. tlu.lSIII't· uf it .cole the eoseoce 01 generic po/ymofphism . A union u f a t1nll1imml with it n 'l"l.nor mal pup"latiull ill at It'ast two pla-notypes.ll il·ally.' pln-uotypes.omples of mherifed IIQriobilily in pharmacokinetics and phormocodynomics.' (It'SS tliau 1% ). wlnh.' t1eh "l1t"ll ill p ...ou. sonu. C ern-tic polymu rph ism dd ilws Il\ll1llJgt' nie traits tllat exist ill tlu.is domin ant if it {'xpn'sst's itself and recessive if it does lint .L.!. l/wll OfYIH' is till' ou tward (:lmral1t'rislit' l'xprl-'ssioll of 1111 ind i\id llal. luhe ritance accounts for . Describe alleasl ""-'0 ways.t·ritahll· clraructerist ics tha t Ol. 4 Stote undef wha l circumstonce$ pher'lOlype ~lus is 01 therapeutic votoe. !Iolall)' an' t·xp l1. orhet Ihon twin studies.y~ollS Individuals lila)' sltow lilt. and hetefOzygClUs 3 DemooslfOIe how pccccrco studiesand sludie$ in twins can be used 10 ind. All alk-h. 111t" h'L hiol(~('1l111 Ilil nflw rt'tlit)' is till' ~(' IlI' .I'W ilIlllt lwr. " (·fort. !Io 1 ()llI ~t' n i mlly t1mtl1. 1'()ly~t'n it'lIl1y controlk-d \'ariatinm W rist· to a ununod al fn"<llIt'lIl'Y distnbunon ami all.bhu-print. 1'11(1'" ' 1!I(/ l'f1/.y.~ individual fur tllat dLamt1eri sli{'. All o f t!.

. .• '". bod. .14-2..' 3-5\ CO'.. G.. ~Txuk:J' C'''\" USA popo!a"O" ""e'c >~O'j oVolignant h.. A. -~ Ueccoeo l<><i usc -.". ~t's1 ~lc 'X '" 10 O' eece .CI C0 2 .n a~I">e" l~OO'_ls VOfious aneslhetia... f< " .'.'O~.. I"1 .9" ocelonillde."...vue Il""~ '"'cr" CYfI'2D6 .1... l'Illlklp'oIoI.tlcally D..oc-eosed Y' ~ -]'::"0" ~"p... '."'7\0'. pimo- NO'ld occv'.t. " .j '...s' "Cl ~old> "-'VlOl.... 1"0'" 'g' .j.«l\. e. ~'CW 10'" 'i 00% Ccocovoos . «..'0 's . .._ o.. ~ :. A .. """'. O'I()I1fi~ine..e Slow ond loll -" Poor '""""'"1OC re .. .~ lOin.>()')O' . 3 8\ Bkx" OQ% O~IO:S I%A. !.. IkM "'""!tlyIa. U 14% CQl>CO~Kln~ .ol cb-oe-or ~. ' l' '" . if<H1()1> ' "C·W. 1G6PO _I b vikJmln K Awo "'1"\0 '~ 100 phole dehyd'O' "'11100<' c'teoed . V. .. Warton" re\lS' .. .' . spcY' reine.. ..J'v''' '" -n~\Cvl..-'.-tIc. "Xl ~V 5" 'POn<.11yhhrM.~ . ' hal> g.000 """"' .vh<o<e "'010..~ "'0-.o""'" .hO.cI Yarlatlonlln Pharmacokln.. Pot)< .../ ' .d "''''''. I..... 2500 .O"S Gb<~ AonOt""l' 'eo- App' o. oagJ!a" '.' I....xtr0' melhatpCll'\. CYP2CI18?1 s. ond chbom- d. ~.veind\ICed he- rrdyric onem< G<""""" Un~r'IOWI'I '1''''J' . "..n.('''.. tJu " .fTIC5 221 Tabl . ". .i .10'0<1 ""0...~.. 14. . s.sonlOZ..< 'II '. de......" ' " 'I ~(JVIsm Of d..o<\S IO%O-'IOI~ .fl. rimoIoI.~.. ..-'.'.oO<' $-e".... .'-1: v ~ ... co P'oor and exlen< ohon oI5-m& P'oor and exlell" >w """""" !lOll 01 &mtorcoploput"'.~ de!ne.tI_..'"'O!o s.... '" -e soc-so '0 C"...1.. lIecoonid& bohoIoI.o~ Enco'nid.' .:J" t' """ ':h.. binding . 5-1 0% Co<JCo.....~.n '2 Ialge ped-q-ees wG'bin liver witl in~ol"nlty ~moI i l .~hyd.enlO's and Es.. " "")1'.""oc 80 bo c~moColfy .. L"'J(.o- .CHAPTH 14 GEr-..rnllnat..'>1 """"d~ or enzyme .d """"''''' 01 1o-zos Or.n hogh f'eQlIf'rIC'. ... ...mmtcQn' rTIQ(l d'lOIdoo< 1 . Som. " .Io'QI~ ma . and perne.1" ~<.'OJ!"~.. . I 5..../> c) .- ApprO> rna~y 1 .n Votiely of d"-'9'.. i l .

\ itliu'(! \\ith \\i ddy difT('rill~ (·llidl·ndl·.. 11lt. ind uo:lilll-:: TIlt'l opmlol ( Fi~_ 14--1) ami tht' untiarrh) 1:h mit· d n ll-:: t'IK.pn. For 1·. \\itl. " llIltlt·.' ' n 'lIt1:ioIlS (It"l'umllg: in a d islim 1: ~WIlP wtthtu lilt' pop ulatioll h'nnt"(1 puor IIId aIM1i7. illl all tih)lwrtt 'lIsin' agt'lIt llow Ill) IOllgt' r in list·.t )t tlioll (T ahle 14--.. primarily 10t'ilh '(l wi thin the li\"t'r hul alst) round r-lsewlu-n....xp n-sv-d POI)lIlOl"]lhi l'<llIy. IIId aholi sm o r ' Ihis t1m ~ in .')O mixe-d [nne - ttou n\idatinll S)"Slt' IlI.1: 011 a S ill~lt.h nllll (' )P(4. St'\'( 'ral ~t'l wtit' llt )l)l n0 'l)' l i s ll\s or drug meta bolism have nil'\\"!1t't'1I kk-ntlfied. n.t·rs. t'il(.lll st· il is mpidl)" lIyo:.lmlyt.Iwill l: understood.GENfTIC5 CH. < til(' ~1I 1 wall. !'-4. d n l~s aft· sU" jl"(1: tu u\io:latitm by tl. 1-1.'S lIlallY t·IlZ)-lllt' S. . ~t' n l t'\ululiOIl o r tilt' ~t'IIt·s . lilt' at)Vit'il! cholinlI1t ('slt 'TOl"" h'l\ oulv 1/ )(1 0111 o r tilt ' usual affinilY for succiuvk-holuu-.ts n-mained 011(' or tilt' la_ major unaccouutcd sources o r \'aria bility in \t pl. )" 11t't'illlst· hydmlY is lIludl sl()\\"t'r than IIsua l.fid (·nt. tilt' renal rh-arance.<.\1 sevr -ml hou rs arh'r s l opp i ll ~ tilt' tnfuslou. partit'lItlrly CYP3A -I."l )\"t'I')-. am i 0 an ' in tilt' "<11Il1' pos ition 0 11 ulh-k-s.·r . Ihal tilt' '('n ' h . rt':('. ~ I os l wen.') Sllh rlllllily or "II I. 'Ml" th t' firsl d m g Shll\\ll 10 t·\hi hil ~('lI di t' Ilt llYllltl'lJhisllI ill m:itlatioll_l1lt'rt· is a t1..\PTH 14 ~ I ll rl' thuu Ullt· inlll' ritah lt· dlilnleft'ri slic llIay lit.ist in atidi tiull ttl dt' hri stWlnillt· h) t l n>~tl'i(" n it' d('aT.ly n -sl n d ''ll 10 d m~ 1I1('la"o lislll _ Henal "xc rl'ti nn or dOl~S diM'S 1I0t apllt' ar til show ~l'lIt'tk pul)l norphism . is <li\i <lt"(1 ill 11II1II'lI\.:holillt'sh'TOlst'S_ In an occasional pam -ut ...')(111.t't1 to inat1:in' products.<1.lIIt"l' \lIlu('S ..ar m an ll illl'l it'S_ Althnll~h 111I' n ' has long IM a st n l1l ~ awan'llI 'ss or IIIl' illlllll'lJ("l' o r '('II ~( ' lId it'S 011 Illdaho lislll. under ~t ·1 11 ·tit. T )llit'a ll)".h dt'lt·flJlillt. eoillst'(l by a t1 t'rt 'C. am i il 11t·1. cholu«. a wholl' hos t or t1nl~s. " I hmll ~h E.1 1a. hl"('11 a lmost l'xdusi\'t. pn'st'lIt 011 till' same pai r or allel es . pilmlpis w t ' urs of]" within minutes or d ist1 111 ti ll lli ll ~ thi s lIt'Uft)IIl11st-lIlar hlucki ll ~ al:t'lIl.\ d ilTt'n'nthrWTII lin ' l)lllt'ili dl(l!ill('sh'rol-st· tn va rious t:lIZ)l l1t' illh iililur. \\i th \\.1Ix.011 (·. Sillt't· Ih is di st.sud l a _."li llylt'hnlillt' . mlls<'I(. art'h('l)llic tlm JtS _ A Tim ' p lwllol)]lt' is st'('11 with SIK.detected b)" a<h-l'N. whid l t11 risc.:! hy a di fT 'nl ~t'IIt· . ~ bllY dfll~s an ' o:l. o:It's i ~ lill t"( 1 C Y{t.tl st'tl ('IlZ)'mt's ( ~t ·llt · pmdm1:s) \\il hin ('il('l1 slIh ramily. nl" d. dt'brist"l uiut· h)l lm \ )t l. 14-1 ) han ' h''('n rflum l to ht' suhs i rolll's rOT this t'IlZHIlt'.y p l:l~ lIla and Iwpalit' pst'lIdo..:n't' 10 wh ich varia bi lity ill t l nt~ uhso rp tiull und di strihlltioll is .hllt"(1.t· t)1od lrt>JI\(. > rollt)\\ill..\1Ullpll'. Ct ·rtaillly.I\. ~lt 'l ilholi s lll h. t'lIl" rurther h t1i\id t"(! int o Sllh ralllilit'S.1:s a IlOlrti ("lIlar H\ ida lin' 1·1IZ)'lIIt·.ill p h u n ml(·o kilwt il-s !Ia \"{. hy Iht' d ifT Tt'ut ronm o r t' t) 1o(-h n llll(' 1'-4..2D6). ea ch var iant ha \i nJt a d ilT rent affinity rOT e basic compounds .' i ~h t ­ )(' matched. an d ilt't.OIl is lilt' ('\islt 'Ut"l' or an ill)]lit'ill "iis t' IIZ)" ' rather Ih...t.al varian ts or " I-alid l lrly I:lyt"(lpmlt'ill t. it is o nly rt"( lly.' (C n h .lind 1Il011( ISIlt"l'inyldl(llil1t·. Ik h ri.l: unfilial dust's or til. T his SUjlt'Tram il)".1Il a lower concentration or II\(' typical t'holim ·sh ·rol-st·. Iwallhy slIhjl'ds _As a (:umll:uy . thl' ~. Tht' C1 1'3:\3. in Ih(.'llinitlt· (T:lhlt.· IIt'S roT h10UII l)llt'S A.)"" \('S..') 10 10% or C:lll tMol-~ i "lls.')()) I. Ilt'u n llllllst'u lar h ltx-katll' 111.lSit' 1Il("('hanislll s involved art. involving o\i <bti ou . d lrt)JIlOstlll\(·.. I. INHUITID VARIATION IN PHARMACOKINETICS E\1lll1pl" s or illht'ri h"(1 \"aria bilit). t1nt~S Ihat an. o:IilTt·rt·J)n 's in otllt'r ('l Illiit' ~rt>lIPS (Tuh lt..:lo m illan lly t'\t·n·tt"(1 uuchauged n-ml to vhow 1Il1l(:h It·ss illlt'rim ih idllal \~I riahility ill d ispos ition kineti cs than cxtellsi\'t'!)IIll'la IMlli:tt"(1 ()I 1" S. S'Illt'l hylal it)l). 111is 1I0 Illt'lwlaI1irt" is h:L 011 tbt' d i\1.(~.. Amltlt' nll lllt' mis ilT(' IIst'tl 10 n·rt'r tu illtl i\i d ll.lllar hinl l'1t'-. there an' st'\\·r. intn lllp Ih rt"(· lllaj(lr t1isl illt1: ralllilit·s.1). \\ilh ad\"dllt('S in 1II0 lt'C..for :my dOl Jt h·lltls 10 1 similar in a~l" ami \\1. Ilt._ ~lallY aberra nt rUTlIlS or th~· ('IIZ\"Ill" ure II flW know n 10 e xist. t'f( Oxldatiotl \l osl slIIall lipnphilit.. is lilt' 1Il0si ahu no:la llt. 2 ami 3 .contr o is P(M d(.1). howt'n 'r . Ihal a fTt't. It is a rt"('('\Sin ' Int il.

..' l!('(· pn'Sl.. S · EU I:I"...· I" ..In'K of hi~1 Ilt-p.· tI"oJ .'. ... Althou !!..I.l ' in .I"i'It..uw (.I. ·ln..substrales for till' SOUllt' l'1I0 11\(' (Fig.1loy I" 'r' "..IYilI.1 GlNETlCS 223 a.sso dah"tl \\i tl.· . 0 6 "·ill:. 14---2 ).&rtr...J... Yet.'s am i 10 calculate..mighl ha\·...i ".. ~ I nrt'f l\"t'r .' it· .·"~ K~· I.·.. AI· tbough III.. I .1 alltl 14-3 an ' striking..... imliedlillg that thl'Y an.w.. concentration after oral ad miui stmtioll ilUlllllg Identfcul twi us is mill'll k-ss than among fraternal twins or..· nN1 .~... om. p r'Ol't'SSt-'S is gaill("ll from 1.. oral do'i(' (F ig.t<.3. H . .all in . when II.· of va riutmn lIIay ht' tllt'n1I)('ut it'lllly impo rtant.nl.iJaloilil~· . There is also co nsiderable overlap in tilt" strucm rul s!)("l'ifid ty u f SOIllt" of tilt'S(' ( ·II ":y IlWS .clearance . lnt\\~1 r"""I .lJrr'·"·IK~· in . Sit.. 'i nfd..f"l" IN..~ lt.ti. E\itlt 'Il{ ' famring g('nd i(' coutrol of IImny of tilt'S(.·" 1".• Lal'):t· .~'.. ..·ar.....'nh'tl in Figs..' .. a pri ori .U1t't' lIlay f.ul 10 d t'lt 't.'''r...p"""".. tilt" oxidatioll of certain dmgs n lSt~n~att'. d..otk d.linl1 p rimarily n -Hects uhsorption rathe r than elitninatjon..·.~ >1 " ""'f'n t rnIMIt'~ af" 'r >(". L.. r." IIt~ IIN'fal• . I. !lj'):!. Om ' dOt's not kno w.·\itl.1 '·~l .". if tht' measurements Ilad h('t°ll takr-n at 2 hr ..' of \~Iri a hi l i ly. N i tk.. \\i th till' (" Ilt't·ntr. TIlt' himodalil y uf lilt' frt·ljlwllt·y distribution his!ogmm of the s.... I W Illustrates such an ilJ\'('Sligalioli with tilt" antid t'prt'Ssant dr u g nortripl ~'lillt" Variahility in the plateau pl....t.." '1.1t1 l"u m. \l... 1 ". Examinin g on ly half-lift' or total dt'u r.It>l i' ..· ohlaillt'fl a unimodal frt'llllt'll('y distrihution nnd t'Xdlldl't lll1ulltJgt'" il' control.F.It·.·. .: h subsequent ('\id"I\('t· coufirmed that POI)lll U'lII...i.StK "ll with for1ah mat inn u f ... 111t' m-ed to nu-asure both dmg and nwtalN llilt's umk-r tllt·S{' dn.1: thi s gt' llt'tkaJly contmllt. ~i h·'" i . Similar data ('xist for otllt'r d m gs. Jt!7: IM't..) . C c c 0 u u ~ z: ~ ~ 5B E ~ ~ '" ~ 200 . ind t't"l l. .".S. wle -tlu-r a low coucentmtion n -Hects poo r bioa\"ailallilily. C onsider... studh-s \\i t1l twi ns. anal~""ii s !lll"''ti sol.:alt· lI .. " 'k l W.....• " .t-:." 400 .. T. alllong auy r. o r raptd elimination.lt·eh '(l.lf-t·\i dt·nl.''.·..·rht.t! St llln.. 12 Hours 0 18 24 .." llN · '1"I'".. for t'X<lmplt•. agl'-maldl('tl gnltlp.. ('fII\('(·ntr.·lIIllslam.. if tilt' uffecn-d ml'taholih' is wry polt'lll or toxic.. liti..·ly on 1111' 1II1("hangt'(l dm g ill phlsma IlIay hI' misleading. s .. II.... '·.IM ' (I "'WI. "' '''y. ilION'" l...] uf \l . taken us t"ideu('t' of polymorphism S umh-r monogemc ('(mi m I.l~lIIa Ilort riptylim. A cetylotion Imlh i dllals \'a r:' \\i dt'ly in their t'limination killt'lil's of tiK' antitube-rcular t1 n lg iso niil7j d . idt' nli~'ill g Ihis SC llln ..jlQlt'r ill I". 14.. Fig.... .... 1I1t'l"I'" . ".L.. GT . ~l"-"'.: ("MLI "~ p1N·'.CHAPTEIl 1." .I Ii'k'S i'kl. Fn.·aell mt'iaholit(.jt . k . 1t 1'.'1 ).. o 600 '" -= ....!ion r:llling...·· m......I"" nr n. slllw ahStJ'l) tic)I\. " f 21 _1 "' Km''f orml.... till' use of a singlt..l n lll~·LI"n " f ''' ·'''... M! ""'1""-... 14-t) W<l." .! l. •1. such tha t a dmg may 1 a substrate for mort ' tha n )(· ( lilt> of tln-m.~".7 ". a dmg that is d iminah't l hy St'\'l'ml mt'laINllk pathways of wh ich only a minor nlll' is under gt'Jl('til' control.r (0) II..in fi"'I.k tI lirr.. i<' isoniazid t'limination t'xists. J II . J I...... Iimt _point meaxun-ment could han ' ht"l'n misl"ilthng.hr plasma ifotllliazitl cont't'lltratioll follo\\i ng a s i n..lI1domly St..n! .'1.tI I...·nnilla nl "f . \\i 11l l)t·rllaps tilt' conce-ntrat ion still rising. n. is St..lJrr. 1...

latoN an' ~t'll l't i('all~' !lu lIl0 I)"K US 'lith a I't"t. "I" tl'll'" '''If1 IIn.66. t 'K'l·tyla to T...: Cun ' ll .tj....1.. so that II + II = I ..1lt.·h " "zy"'''. in tilt' dllta ill T alll" I4--..Im"..L'i(' NAT2 .1it.'i. is 0. \\'h ic h s h-ads to d istrihu lions for h l'lt'ruZ"~flllS ami hOlll tl0~um fast <!('l·tylato r.n n.HI .t..·ll"f"'1'...· ph"rmo..fi% of Cnucastaus haw 01.e:..folloY ' . As sho'l1I ill Ta blt' 14. I h-nce. W. hut in (Irtr-ntal a mi Eskimo populations tilt' Ilt' n.... f"r .III' with lIiff : .z> SUBSTRATES: S-Mephenytoin Diazepam Tolbutamide s-wartann Phenytoin Niled ipine Erythromycin Cyclosporine Desipramine Dextromelhorphan Debnscquine C affeine Chlorzoxazone Theophylline Ethanol 2C·Meph 3A-3-5 2E-1 Sufphapbenazole INHIBITORS: Fu rafylline xeteconazoie Quinidine F i.J... lM·rfin.oss CIT s.. .'S h' lIl s isl i ll ~ o f a l11 11lhinatiu ll of tilt' alld t's ) art' + 2.. .lapp.. ifi.I. 1. 2 . . The results <lispla)"tt l ill Tilbl t ' 1+-3 fur t'lIt:11 d hn il' ~mllp an' c.·. "".234.~ 1I1!H. then till' frequenci es of tilt' Kt'lIutHlt. Fo r example. kinrt ICS " f .r:. "" -..rk-ulan-d in the.. is much w small" r. ) .".S t'xist in tilt' di sl rihll liull of ill't'tylalur t' ' sta t us...l(' ...G{NETICS CHAl'lU 14 houiMjd is prilll ari l~' i!('t. it is IXlssiblt' 10 calcula te the fl't't lllt'IJ(')' of llt'tl'TU0 Wm s a mi ho mo0~ulI s filst iK't.1o'f1"ho.. 1I "1a. a e:. Sprin. ami 1)(·0 cauw lll't't..I.lalt'tl in tilt" liH'r to S -aet1ylisu niMjd .J... 0.... 11 2 (fo r tilt' 1 hOllltr0 "Kom slow an..t.s« .ulic t'IIZ)1I1t'. E.p"tl.tim ll.c. tilt' frequency for tilt' fa. I" 11".t" lators F rom KI'IIl' F requencies...<. .. i" l. I'-&.'t'iy.I..> of 0 ... l a ~t ' gt .... tlifft'I"\ll l.... oI<i'..: 1101... ..'il ) k i n' Io'S ) in IUIlU.h.·!)·.. for C.·nl. 111(' Slllll of tll('st' fO'(llIl'flde. n( Un .ihit"n " f th. 01< "f F..·r.m lo'l{' .10'..".L~i ilIlS a nd blacks !la\"(' ap p n n illmtdy t'(l" al nurulx-rs (If slow a nd fast an·tyla toN... S low 11l1..t..... l't' 2"~'J. M oth Ca"('l.I I'l.1( 1"" in ..I...'it) ''1I~'' ''· . a p n 't'u ('\()r o f a ln-palolo\i(· l'u lIlIX)\lIul....l l"h. I I ~ ". . It..... is LO." r..-" 11. 1) . IlU ..~.'t'nt of slo ..9'l a lll i o.illf!ic"Io' '. ll l ati. .' 1n"''''' '1 .'('ssin' allele pai r..fJil...Kt ' I"'fifio..•. Ih" 'fl " ".or_ l1l.Il ....·ltilljl... rt'sl)('(1i.% .lt"'.·n·" t 11f..itj. that is.11. "10:10.Mf'·Il·"t ("01" " f l~t"d' "..11 •..Lllt'lt....· '-"1:)1""'" · ( Fn U ". " n' 1i... I)" · laton) is 0.V. ..~pt'ri .('s ill III(' 1 ' ·limina lio n kim-tics o f lscmiazic] rdlt'l1 po lymorph ism lIf a particular ~ -a('t'tylt rallsft. AI. so that II = O. 11.·Lith.." " f tl lf' .illK manner: if I' a mi II art' the frt't! ut"Kit's of two '1Ile lt'S..lih." If ·. '""'" c1n.I Ih .. \ '. n.... a m i q'l. ·" IA i.l r.u1 " 10·1 l'-&..l('('tylator.. latoTsta t us is umll'T mollt ~t'lli c co nt rol... ..tI..1 ..12.. ( :rul'hic nl' n.l lI<~as ian s ......(' slow acdylatoT alk-h.350 (21 /(/ ) o r 3. of .I· ( :. · l'tJlllrIJllt'tl t'lhnil' d ifT '''IK't. n"'I"'f1 In "".2 (f...11."'"...d...I.

.· I'L. \' ."ltJl' ...t"oI....... \I . II( ' l 'rt nI'I~ I .1 ~7h"'.:" -\..1'1. 1'lh'J ) 25 . F.. . It· i" ......'I..· I.. :5 ~ tl 20 15 s .. Il. -C f ..tl " .. in ... n pL&-..""I.. •J tI.""".J' . mud... \1. l lt.. lII ll nll'. "".1 " hi'III "W ....1. It ...OW 1"-5' .I" r).l lt (n wn E' ... ".'o::Jdn» .. n. l t 'n"" . . (nwn • • ~t... .. " ·... L.. <.01...lIh. ILo\... \1.". l .1 .·"ti. ~ ":. ' 7f>. l II I (mh·o .1 pt.I'~· ' Il r . ..1I ..r " 1....&.rt ri pl~~1r"· .."".TQr5 -.'I... I'nn ·· t:..~ ......· I>." I"·".and \I (.I'h Ind-on~ C~~ .oaT'>1.w: i<o .....lm . Irn m~~1 ~ 20 0 ~ ~ ~~~~ I>.. u !! ~ ~ ~ " " c 0 40 20 0 40 ~ ~u HI(... ( Ko..1'J"'1' .o\ P...I !o:' ·tl"'"" I>I .ur \an.......3 11 \11...... 356 350 386 43 8 45 3 408 54 55 08 45 7 42 7 282 .i.I..· ... 19fIl11 f" ~lt... It "".ln" "I iJl ".It''l'..n l'''~Ii .... I ~J.... .. 2 ............flrr ~ ~It. ' fl r ..I t1now: 1 1"·n. F".u."i l'I~· in "1.. 1-'-4..1.( 10:" '''''. ~- .. J.....·r .. " · III ""in" I"A . nIlK" nlntl~ II' or 'K .n .. !I...Ct-WTE ~ 14 ce-ercs Identical Twins 225 80 ~~60 es t: Z 0 ~ 80 Fraternal Twins 5 ~ 60 E ~ . ' nl" 'I.~ ...uitI nll"l...I.'1..g c ~ e.. 10·". " <~ ...t..I. 10·..I I"i'" "" 111·. ·n (Ill iol..1..II.·l'hltt . .. ..'' (. \ : 0 (:'-"'1.....').0\ .1 I" i'" . 11.. ... .1"" .. J.. E ~ 7.m in n.: • ":?--J' Bloc'...~ ......j" t ...... Soo.... It'K I Sjo'Io(\·" '.1 .1 '" D " 10 .1.. - z 5 0 o 4 8 12 Plasma Isoniazid Concentration (mgIL) .·.....· ( 1l~1 ' 1 ..·...Iorl......-l..'.. fII( 1....

lidefations Sl'\l'ml poinls nr-ed tn lit. knnwl('tl!{l' of the ('x1sh 'IlI't' of lar J!. Thls is ll<u1 k'ula rly mn. run limi t t ht' liSt' of both t!nags: it de\l'lops mon.t· d llllic <lifT n 'III't's in p ha n mlt"flkint'til-s .lsso l:ia h'l! with d t'\"a h 'll pLtsm.(lIIlri hull' In lK"thi ly a nd lu.(' nf l ill' "fTt'{1t'{! palh way to t'li minatilJl1 ami wllt't1l('r tl m g.. l.{ lrtiingly. wnh o l !Je f Iact nrs .l"'-·S tilt" fn "fjl ll" ll l'y of I M rn"lIl't " of an alll'll' is linked :t:ll ll~ ~t ·Jl(lt ·r.('li fmm slIbsl mh 's o f th is l' nzy' IW (St'(' Talilt.t.1poft'nl ia lly 1t'W IIlt'mpt' uli l' a~I'Ilt. po te lli ially mu re frequent a dn 'rst' react ions in I'MMlr nwlaI M IIi".idly. d i n i eaJl~' relevant.lI '(. l"lSI. ilm! elmununon is al mos l l'UIlIp!l'I""y via tin. :k (.Ii"j 1 · l·n:l. ilS ilt'('lyla tiull is a mino r pa tllway o f <IapSlJllI' d im inutiull a llll :'\·a{"('ly). Ill lit. suIJjt'l '1s tldi cieu t in dd lriSl Mluilll' hydmxyhl'il' lIlay d l' rin ' Il'ss . part of lilt' la rgt' inh ' rinti hitilial \" ria hil ily in III(' t1t'gf'('1' of tl n l~ illh'fill'l iollS i ll\nhi lJ~ inh ihil ioll a lltl intllll1io ll (j Ill'n'ilSl'l1 s~' I t l lt'sis ) of dm g 1lU'la IM.. the dn l ~. St'{'{JIltI. Part of its an algl'"sil' al'l i\i ty is due In morphn«(u nTIl'll From I'l'M !l'i!1(' hy tlt'b riSlM llIilJ(' hyl! RJ\) -h 'i(' (. h ul tlOt'S "ppt'ar 10 1>1' . Tilt' uu-chanistu n -nuuus o bst'lIf'('.ty]lbpSlIIll' h y S -at'l"lyltmllsfl' m'i(' l'xhihils l-:t'lw lil.'l! inUa nllnallll)' f1'SpUIlSt·. l·lll. \\i t h lilt' :tlh 'llda nl O llt(~J lIl t'S . ~l a llY o lllt' r Sl'('llilriOS {.t' r ).UII tlm g-n w laI M ng . or tm. \' 1'2 1)6). rivt'll (·th llidty. al'lhily rt'sitll's p rt'l )mnim llltly wi l l.uj tl am i sonn. llot\\ilh stml(lil1 ~ tl1l'dillkultit's ill makill~ p n -d o. unk-ss lilt' d lls{' is n-duced.)·lI1t' d t.ing t'n :l.pOI) l l1 nrphi slll hilS 110 dil1 il·a] l'l'lIISl'llllt'llt'('.(JIlI. t'll\iSil l'l l t1l'llt' ntii ng 011 g tilt' f'('la li\"l' illlj'Mlrta lll. Hnwever.'i an' stlld il't! in till' t'a rly phllSl'S of di n il'al l'\'a lna tion llf . Fo r tlnags SII{·I.. SUIIII' o f tilt'S{' Sl'('ll<l rius arl ' sllIlIllla rizl't l ill T ilhll' 14-1 . fluillitlillt' is a ptllt 'llt il1hihilor l lf Ild lriSlMluine hyd m xyl'lsl' alll l lhl'n. Itdo". il'isod 'llel l u i t h I'le \1Itl'l l l'olll'('llt rati u lls of isonlaz hl.22. suc h AdGrtiollaI C1inkal C . For b oth d naj. is l.K'('f) '1 t1l'ri\1lliw is the msjor Ill('laho lih '. In must (~. l'ilSI'S. QlIi nitl illt· I·ffl'(:t in·ly l~ lI\\t'rt S a nonuillly ('lI. il" lhl'y ap pl' a r til t1ifTNill their s llS('( 'Jlt i hi l it~· to adn'rst' l1.t conceut rations of hytlmlazim' a nd jHlIt'ain alll id t" Hapt d iu'('lyla llJl'S a lsH n 'lluin' higllt'r <IoS{'s of hyd mlazim' 10 control bypertenston.I'" importance of II. sud l . IIII' chnical imllislII d l. Also .lIlall-:l'sil' " {'Iwril fm m l'l'M It'int.. 1-1-1 ).PO I~l l\0'1) lJi slll .).\(' (If d OlV. Ihe S ' .ft'nsiH' mt'l aho li". Fi rst .r lli".b pSlJllt· l'(mt rilmlt's IiUll' to ad hity.a til' t LUmlgl" A("( 'I~hlion pol~1Jl( 1I1. all ill1 jlflrta nt Slllln. RS Wt.d l.ll'(·tylators .l.ts pn'S('rillt'tl \\u rld\\ide or 11M'll in a Illllltimdal so(.for d m j.t'r 10 a n a ppa n 'l1tly t·n. S)l ld ru nll'..a lft'{1t'l ! path w. A l~ lll i filsti n~ a nd illh'n'stin~ sit ua tiou is St"(' n wi th l"(M!l'i l1e .)lt'ml nil whe-tlu-r al'li \ity lit'S plicat ion s of gl'lWtil' pol ylIlU'1)hislIl ill d l1.c1t·fit-it·1l1 lIlII' (llfM IIlt'l aIM ' .id y.other dmW.ly. llS d l'h ri.. TIleS(' dTt'i. suhjl"t.(' ('<lit-illatio ns." Lsin~ly p rt'tlil'l ahll'.. HI'latin ·ly f(". llIatll' ill ad dilioll In t hllS{' matll' a ln 'ady.l llli. several sul'l-:rtllips within till' ~t'l lt"ml populutlon a n ' uflt'n o f a ".fjt.illdudill ~ desip nll nim' ("'-'t.ro n ' inhih its Ihl' fOl"lI1alitm of all llw lal ltllitt's Ihat a n ' pnltllll. A S~"'h' llI il' lu p us ~ t'l')tllt'lIlalosll s -likt. is d l'arly im portant for till' n ptillml n.Ii". : Interes t in :Il't·tylal ion POI~lIlO rplJisTII is lint [ust am d l' m il" Poriplwrulneur oputhy.lS iSllllia"j tl-ind ul. 14--2 ).('1I )lt"p. . AU1Ul'II1'SS of tln.h ism ilISl' 11t'('111'S a mi is important fo r scverul other d nags.)'go lis rapid al'('lylutors nmy ilISI) lit. T illIS.l("IIl'l' uf hm no zygous aml llt' It' m :l.Sl Ml nim'. a gl'lll'm li".(llllila lllly adminis te n -d.t' rs. o r IM ltlJ.Ylllt. ge m' lic IM JIYll10 rp his lll lJ:lS ill1 p lil'aliolls ill di ll il~I! lri a ls tl uring tlnlg t1t'\'I'!opnwul.. palhwa y tn ovr-rall r-liruination. occu rs ilion ' p n'\'al tollily ill slow al'('ly' lators uuh-ss a n adjustment is llI. SlIl'h its hyd miaz illl' an ti prut~ti lla lll itll' (Ta hlt.. 1I10n ' pronouncecl a m) sus num.'· is \'(' 1')' low ..:ls ma ke il lIillit-lIlt 10 1~lkll l ak the ~t ' ll ol~l"l(' fn'(jlll"Il I'y . 1I0w l"'-I' r. W'lw til. In slll' I.'lIl"tiollS. rnt'lah· ulill' .ra pid ly in sllIw ruthe-r than rapid .lI ilS II.)'lws is tinder gl' IWlil' l'l'mt m l mI(l inl·I1. TIl(' l'l'lIl\"l'rsioll of lilt' a nlilllllt'n'lI]a r tlm ~ tlapSl lllt' 10 :-':'. if llll' ff'('/jUt'lll'y o f all illllM lrt. Al'n mlingly.pl1.l~ 1llt'lal M \\i l h tilt' a fTedl'l! snhs l rdte o r tilt' IIlt'lal M llile."'lI. G£NE T1CS CHAPTER 14 Isoniazi d is au ex eept ton.S. ki ly. stich i t S SI"l'1l with e i<..'{ u f inh-rpatit' ut \ '-i1 riah ility in p hilrma - ..ull' in the d m agt' o f iSllllia"j d or \i la mi n H..ffl'l1s lIlay IK"(:lIr ll ~l'I llt' r \\i l l.

. Potential Conseq uences of Generic Polymorphism Invotving Drug and Metabolite for Poor Metabolize.tIIs migh l ari'\(. 1I11t" famil it's.- ~ aled reponse..CHAPIEI1 l A GENETICS 221 cokinc-tics. prt'('linim l i " dtm S{'n. tilt' dmg ranl x..('(1affinily or tilt.~t'(l l o e. n .. Figurt· 14-. At IIImt. prodnccdustng hiol ('('hnolo!(\'. atlt" ILlalt' anli('(lagulant control. '- o • M o D M I . warfarin rt'~ ist a n('(' is not found ill all kindred."L~ill~ amilah ilit).(l'hit"\l' a 111t'r. till' variation in d{)S:I~I' n-quln-meuts is fivefold . III ('{ lIl1JlLOII \\i lll rulu-r ~t' llt" t k traits..e ral ~t' Ilt" r.l' lilt> 1'1l1. If tlu.'(1 fesistall(. \\ith the.'!Mll islll is irwn.)1111'S primarily n 'spollSihll' for nwtahoJjsllI (If a d m g...lt i(Jn s i nd ic..l.. Anal)".~dh's that Iht. however. with which warfarin Table 14-4.haradt>ril.. duri ng its sub'\('(!1Il'1I1 use .known to d isp lay gt'l ll'tk POIPllUlVh islll.is o f tilt' frt" lllt'Jl('y o f ti lt' n-sistancv in Sl. palit'n ls n ll'Y in Iht' dllSllgl' n-qutrcmcnts o f warfarin 1 ('(lt'(l to pm1(' (hll't.Hudmgs ill h m familit.. Fortu nately. ami rt '~ I)( II l\(" may Ill:' lI\isSl.lpt'ul k ft'SPOIIW.( ll\S C IIll'Il('t'S. lIIiL\. wit h polt'lltially St'riUIIS (. In sr-veralnn-mbe-rs of Sl.'(' I1~ art' hq~illllin ~ 10 1M.ln~rnillt'd in a single gt·llt·. PQIllI"IliaI lOxicity ..'(1 unt il tilt· dm~ 1)('('()JIws \\idt'ly prescribed. A normal phanmll"llkillt'lk pmfilt· o f warfarin in tilt' n -sb tant sllhjt'(1s p oints to a phanna('()(I)lla miC'illly !J.('11t'(l 10 .. o f pun ' hu t' man t1mg-I1lt' laholi zill!-! t'1I0 111t·S. n 'sistmll't' is a domiuaut d laral"lt-ristk t r.(·.. INHERITED VARIATION IN PHARMACODYNAMICS :\ ~ p n"\'i l)Il ~ly 1I0 !t'i.sin ' closes of wa rfa rin an' 11I.5 Illustrates tln. A p rnba lll{· Illt'l.'ll<..('t'ptof for vitamin K.s..' illl'rc..1.l"nzyll lt' invulved is one.' I I.evaluated ill a pn-seb-cn-d ~n lll p o f suhjt'(1s \\i I1l Ihe t'1I7)111t' dl'fi l'il'III'y to ecunuuwhetlu-r St·rillllS pmhlt.

· ~" .lin~ "f tI. » t'sp itt.t~ t1i.n i' I""1 kiu. 1 \ ..· 3-1 nM .. ~' il . to lilt' overal l vari ahilily in d nl ~ uu-tabohsm in tilt' p ark-nt population.'. ·at.n 1 n"a1.l] n .· illl" iu. 2'..illlt'll of a dmg: n-qnlred in an iudivklual.. positin's thai an' elm' 10 otllt' r tl lm ·ntly adm inisten'll dmgs.."" w" .l \ ". ..rt" l'OllI(X'k s 10 produce Its ant it'll<l~u l<l ll t t·ff('(:t..r.tnlllysis of a small ~u Jl rl (' of " Il u l or all )' other IiSSUt'. luee-d Oil D S A .11lt1 spa rkillt'.lSt situations ill whk-h: Ihl' therapeutic iudex of ' olites in p l..:-. " ."I...I 2.1 ing uri llt'.t<...... IIwtalltllit..m ... ....... . Its appt... which contains a Ihiot) "llnate ~mu p .nt'". I ' .· tI. ' n . ldndn'tl. -ll \..i" '" "n pllillTt.Ltnl .. Ti ll' iU<lhility of appm\i lll at d~' 3()~ of c. plu-. Om' is tilt. for lIlany reas ns.s. STUDY PROILIMS IAn ~wef$ 1 0 Study Problems ore in Appendix II). ro. tiM' . .·aJ is gn'a l('SI ill Ih.st·ast' and concurrent dnl ~s . 4!'l I.mil an ' c1illk ult .t" W" rn ll lln ll'" . G in· twu t'xmnplt"S t'udl nf inhcnn. "ft.t..to. lil I..~)(:ia lt'( l with tllking of lilt' ma rke-r and o lulll'<.. Curren tly.'W II<. PHINOTYPING Phcno l~pi ng: patients for a p articular IIIl'1al Kllk pal hway.hllllill C'''lK"'''' So·n.lI l1 it'S are ¢\'t'll in T ah lt. il..(ari" .... 1. ·ml h ! ..· "f IltJlI.&. :I.... .tst'..010 11. Other l'l:uupll's of gt'. ( Ho.....a)' t~)S ts . I>tI.'(' n f '~dri ah i lit~· l lt'n· . I. PI' .. t'a')' to measure.'('lylalion and dt'h ristIClllilW h)'(IRJx~""ll i(J n in 9.1i<.....! . thl' aual~~'s o f dmg am ] its meta b is relauwly s afe..... ilh II " "..(.. ·ml nl.: .. ' . n .th"S the importance of ~t' l lt'tit... mconvenk-nce a<..lillli 1l"I"m . I ~.)lj . 'l(' ·' lit. f.. " 1972. . ·nl tlM !N'l ( .• T Inlt-no..0 . I".. D ~A tests have pn-dicn-d lite pln-notcpes for IKIlh :-:.. .t. its llppl·al. E""'1 Jt.o.'S a....5% nf llt'ultlJy volun teers.ih' Ian h "f ""lit~t.I < to p lw nolypt· for slow 'K'l·tylalion..Ld>ihh' l fn ll n n I.'lKly... am i ~l't unot lu-r is ti l(' Ilt)Ssihilily of faist..l. till' tnarkr-r tilt' d n lg: is luw. Iltltn ll·. wh id l d t'ur ly ind it'.' U'\l'rloo kt·d ....&K'..Importance of such sou n -es of \ll riah ility in ft~SPOUst' should uot h..lpplim linll of pbe-notypi ll~ to pn-dtct d(J~lgt· dept'ntls till lilt' n 'latin' t1111trih u tion u f otlu-r factors...certain dnlW' sud l 'L~ prupyltlJionradl...m.. prior to d m R administration has b een p mpost'll ll<t">t'(l lll'ltlll til t' m ho of dr u an d Ilwt a!ltllih ' g conceru rauons in urin e follcMing a si n~lt. .· -u " Il"\i..1lu "f ~ n 1'n .. TIlt' .5 mJVl<K I..... 11-. sud l .. a('(·tylation Of oxidation.li'''·1K li"...... 111. ..t<. ~·'''1it'S..'S . pllt' lIol~l)i llg is 1101 \\i dd~' t'llIpIO~l'( l in di nk' ll p ractice.UJ('ll~iam 10 tusn.1.l il1ing: 1J1I'1'lho!it.l\ing:dt'hristKluilll' 11 )'tln nyl. 11Ih·rrul...f2.'5 III 97..'1'11 II ~ . .wt kally dl'tt' nnilll'li variation in pha rlll at'l K I~l l ..Iml:' in ' o 100 80 60 40 20 Percent Reduction 01Prothrombin Activity at 48 Hours o I"..IlI<... such .. I. lr Tl f..~ ... such us cl" inid int' .. illuslrak s how ~I'llt'l iC'S also t'lmlri hult' s to \1tria h i li t~· in tlu. :. anor lu-r is .'j " f Ih ' 26 I1M . tln. holds IIII' promtse of pn l\iding a ilion' direct approach toward pft't. 1-1--2." ur"! . tilt' major sn u ft. hM1i"n "f 11.u". . Although the number of exampl es is t'u frt'll lly small. Ki" 'I1 II. inlti!ailing: tilt' en0 11W. namics .d variation in pl mn tlat'llkinl'l k'li am i ph arlllac..to·" L n. " f 1.1. and its pl lt'llolyp k d litnlt1t'ristit· is h ighly com-lated \\it h thai of tilt' d n lg:.t'u ot)llillg. n"'l""" '" i.ln. G'·.. hin ild i. in 11M n"'I"""" lu II.tpo'M of lI " m"" G''TM-tit. 1.ih ' . for slow oxidation i..· ur...1.:-' tiM . SIIIEllllt't! 'azilll'!Ht..· ti.: S~~"I ." w ."I>. II. H.. ..l] O:. tl Ost' of a markt'r. (.'.. II-.< ~1 . 111is app ma{·h aims to lx-rn-r antieipa h' lhe c1osa gt' rq?. I" . lklt..' f..C HAPTE ~ 14 F I"...10:. ( rH"il ~'..

.. Ti lt" fn "( IIll'lIl')' within ti lt" population of an .terms: ~l'nntn)(" .l'ut (ff' "" 0. pmpr-dllulol. 14-5.7 fl.l'it" \ \ 1l:lt an' thepotential im plications of this fi ndi n~? S. "'". 3 0 .. is" suhs tmtt' for Ik h risollllil1l' h). If slllw o\idi 7.Lssol:iah"(l .-ith debrtsoqnnnslatlls was weak or stmnV. li lit'fly diS(1lsS each of til(' fullo'\1nv. Tahll' 14-5 list s the 1Ill"..t'nettc POI}l llOrphisllI in dl'<U"lllll't' n'ad ily appan'lli... hUI nnly fur lull'im' is there a pnh 'lIlial ll ll' mpl'ntic im plil-. t nxid i7.ilil'nt p opulat km. ' . stan-nu-uts: L F h-camkh-. l>iq:11SShrit'fly IXtssih ll" n'usons for lilt"(l1>""'l'\l"(l corre-lations. SlIhjl't1s p!Jt"lIol)l )l't1 a('c:urt li n~ Itlllll'ir (lehrist llluillt' OxilLlion status (11l1l1 or t>xtt'min' r llwla!lllli7.. . lIlt"lo p ru lul.t'f'S o f substrates of dt'hristlllUilll' hvdr oxY!<L"f' 10 pnor mdahol i.ellt'ti l' oli¢ n.4 3 1.I'l\I.m .. }l't nnly in IMtie nls '\i lll seven.st' (C YP2 Dfl).ric hllll. Q llinidi Jll" converts t'stellsin ' mt'l alll)!i7. I>dilw lin. ill ad d ition to lIlt'topmlol ami tillluiol. am i wllt't lu'r till' ('orn.fl)" how lUI inht"rih"ll S Olln '(' of variation ill ph an n.'king d m gs: iltl'llUl()I .idi 7.. 3 ..t'rs) inv. h .n-nal d)'sfulll1illll is V..l'lll"tk p morphism.t"ll h)" :o. 4.t th slow oddanon of a d m~ is O.t't1 and that f'xlaih il V.'t's~in' aUdt.ll examples of dnJv..an·I)"ltrallSfl'f. .. Discuss brit.btin ll .t"stt't l uue l.xlJihit ~t 'lll't il· p ' olymorphism. an au ttarrythmic aV. 2. oly 3 ..1thin till" !).~ that fnnn m inor nw lalllllih's \ia palhwap llial (.I S...l'rs .. of dmv.lmX)-la.. G in' h \ll esampk-s.0 <03 4.... and j:.a-rs..Ilt'Q..t'rs in tilt" po pu lation? ASSUlllt' lli at ll\iclation status is und er 11l1111(~l'llk l'(mlml uud that " II tilt' ' 1Iriah i!ity in ol:itla tio ll wit hiu tilt' p opulat ion is of v.1('(1 frt"(lllt'nl1t's of slow <Inti fa. a. whal a n · the t'\lll"(.1II \11 11ll'Ji of va riou s pha rllIal"llkindic p aranu-n-rs for l'ad l d n lV...U1 tifit"lI .CHAPTER 14 GlNEOCS 22'1 2. pai r. fuur Jl-adrt. ph ellol)lll'.\idl· u.' is Ilwtaholi.tie p olymorp hb m in the-ir clearance.s that an' m.K"Ilkiul'fics lW he idt'n · ..f llit' follO\\-11lV. 50 63 0 50 0 31 0 38 2Q() a 280 150 .Ition .hOl1lm:yv. und tauolol .tllt·lt' .. •.. A <Img: <!I'\l'IUI)l"l1 for \\-lIrllr.ous \\-ill l a n"(. D apso nt' and llldl'illl' an' I.

-ncv.td it'lility didalt' ag. m/o/f'!o'C('llt . is likely b be independenl of age. 11('1\1.' o n pllannatl 1kim 'tit'S. normalized for body weigh1 . Cesaibe the likely changes in the pharmoce*ineliCS of a drug Pfedominonrly excreted unchanged. given the volume of distribulion and fraction unbound 2.of varia bility in d n 'g rt'slxmS(' and .1 cri tical Ilt't'tl of d rugs. . state ments made in tlJis d l<lptN p t'. based on age and weighr . if opt imal tln-mpv is to be achieved .unst tilt' \\i tll' UM o f IOllwtllllinal stlltlies III indi vtdual s to examtnc Ill(' influ('II(_ of a~. from neonate 10 elderly polienrs 3 Adjur.is made to tilt' "( usual] adu lt dnsag. ' and pr.L~ a res ult. It is rt. pa rtkularly in t ht· Y()II I1~ alltl tilt" old.mildl' in individuals o f difft'ring agt's. that this stmHfi tM ' dtiun o f human lift. singlt· OhM'n.of tllt'S( characteristics .'0 )"'-~. It is alliU n..(1~l ii'.'SSllril. a~t' dot's not Ilt'("{'ssarily define fUIlt'tional ertain ttl tht' a\'{"Til~t' pt'rson w hiu u a. .~ .lrs of a~t'. . bypcnods of WtM1h . agt'. Hather.I~'fon' procecdtng.l 1)'l'ars and 12 )'('ars of a. Desermire eose drugs for which Iooding dose. is dt'f1llt--d as that rt'¢IIll'1I wlJk h when W\l.t.gt'. Clearly. this ph m_ needs to 1 ddillt'tl.'0 }"{'..Irs..lilt! '\(·lIt·S(.L'i(' IM'i n~ treated..·(·lnp lllt'ul.ttl ti l" typical ad ult 'i(' )(' patilont\\i tll ti ll' disease or condition n't illi ri u~ tilt. "( u sual] ad ult dO~I~e rcg tnu-n" g.ll)(·utk S llt:t. n-llect how an imlhi d uill may d l. in/ mit .i ll~ do~ge adj ustll lt'llts fur il~t'.g and lIt'{'t)f(li n~I)'....lngl' wil l. A ~II ~.(1.. ht'I\n'(' n 20 and '. Furthermore. ' Expt'tli('IIt. h{}\\lH' r. the charact e ristics of tilt' adult patit'llt p opulation d ifTer with til(' t1i'i('. ciukl. 11(' 1\"('( '11 tilt' a~('s of OIl(' month and 1\' " )'('a rs. L fe is a coutiuuo us prt K'{'SS with the dhtillt1iou h('I\"I"('n 0 111' period and the next oftt'n illdefined .(1~li zt'( l thai d lnlll olu¢ t. III th is bo ok tilt" various sta~t~ nre t!t·filw(1 ali follows: neonate . chsracn-rta-d A POINT 01 RIIIRINCI T lmm glJolit this dmplt'T n -fen-ncr.' '( '1\ I\1..1 <lN than '. it is the. is a n additiona l souro. TIlt' word at/lilt refe rs lu-n.rinw ll llIay I\l'('(1 10 l)to modified. tilt" a~l' b racket rather than to tilt' ind i\idual. Th e life o f a hu man is eonnuoulj di\i dl'tl into various sta~t'S .n 'I)' ) 'OII Il R and IIIl' ag:c'(! wiln IIftt' ll an" in 11I1)'. The infnnnation ohtailll'(l then-fon. It is a~aillSl th is 1). up to om. . is arhi lrary.men for on individual oIdef than one year of age. ° 230 .'lltlOIlS '(' an.._' 15 AGE AND WEIGHT OBIICTlYIS The leader will be able 10: 1. tilt' usllal ad ult t10S<I~t· rt1.l('K g:rolll ul ill whkh un atte mp t is mad t • ill this cha pter 10 dt"\"t·lop a [rann-werk for lIlal.l.· n'¢ IIll'Il.'l1 to th is f)llk'i..l p atient O!t'hit°\"(·s t!le r.'(-s. t!t.p ertain s tu 1 the population ami doe s not 1II't. he l\vt"{'n the a~t~ of 13 ami 19 years: mil/It. and eMI'''. d r u n it. the csool adult dosage reg. AgtOis t'(ortlti lily om.mon th I Hld IIIl' m .

.... dmj.. all ad ult ~ d " I a/o:t · uf 5..uhtailll.h ·usi.. fo r Ihl' PUrpt N 'S of sllh... PIl. 70 veers . 70 30 20 10 o 15-59 6lHi9 70-79 .J ph. Ilhan nal"ukiTll'l ic data a n.p ll· (If all a~. nloin. .·1· 11 ohk-r... .·r ltwl th. UutpaU...CHAPTf ll 15 '" 111t'(Lito. IIIt·1I1 ('".. The... IU7'l ) 20 15-59 6lHi9 Digoxin 70-79 . ~"I>.. ­ I~ Ihcu..nd S.-. p"lti" IIIS lakin ~ di ~()1(ill .·a.ntl. umpUon ..tt-d an' t'Sti lllaft'S "f tl. IIfM. !l I M I diffen-nt a~e trends for tht· II ~ ' of hm d rugs. in('fmlin t·IK"l...d. ..u m u nl ....ally nld" r th an those takin~ nitrofUrd... IUln~' "(Jlml l.t· p" pulati o n rhanmtl·oki'll'tit.(·lwr. I S_I .... I...· disorders...-tiolls. 11111\. elm . a condi tion m" n ' ''''' '111)' alT('<..llations..-tin" JX. ..• 2 "25. 70 to Ml )'f."..' (If lli ~(ltill in a ~JCJp uf )1Mlnv...ln~mnoI .: I). S. It·lltll" hi· middle-age . S i IK 't" O K..~ lulri" .' C" tI•• lnh u l lOn fir tlruc ...·ars. 15-1 ..It'...d iull.J.·N...inrhc pli nctp lr..1111)' a<lulh ant i in a Nitrofurantoin 50 t·l lt.\ -2~3 . .' lt.um"""lo:..nlo in . 1 s 11".') wars is iL SSlllllt... <: .. are ~l'll(' r. ' c.. 11.(' ad ult pa tit' nl po pu l.. .... .· an' V..1.."" t. oIo.. Li.. in Fi~.ntl cJ.tlaia in T alllt· 15-1 illustrate a point ahem! a~t· and tli..........l.1 al the mean a~... 1 to In 'al urinary tract infN. trat'lr tl fr om Borlhiu• ..· o f t t.ally '.. I... tlm~s fo r which t·. h nc nilrofur..I patien ts takin v.. than IhoS(' with cardiae disorders ..d.. n an' ~... <I( . .. there art" ft·. . Tll rr.n ll In 40 30 I. l'atit>llb "'i tl.. IISl"(1 to treat l-an lill<..

.t'. (. E\i dt·utly. th e ohst'r\'t" inl'J'('il'it'{! st' llsiti\ity o f t'ltIt'rly Ililtit'llh to tilt' d ceut ralue.l br during till' (.1st! IIlllch n 't:lul. 111(" int ent tl lt'rt'by is tu permit a la -tt er estimak to ht' madl' of tilt' initial tllI<.t'iStll.uno c l 011 ti lt' hil'iis of di ITen'lIt't.. PHARMACODYNAMICS l1mmghont this chapter..' alst! st'l'n ill till' t'ldt'rly. lU pt~ill ~ is alstl p mlougt't:! and pt'risla lsis is irn.mtr-dt1: ions... is al1.mtl lltith d iminisll('t:1 inlt'sti llal lllolilily and hlollti llow an. 111l'St' dlilll~("S telld to he It'sS apparl'n t ill tilt· . ABSORPTION D n l~ absorpnon dllt'S nol ilppt'iU to dl a n~t' dmlll"ti('lilly «tth i1~(' .' l111l~('st iH' e.. ceooc 54 68 476 3.__kl_tl.!It" di lT t·fClIl't·S in till" values of tilt' ('sti malt's .. Fur example.' value..l'it-'S. ill pharmacoktnetics of this ~n lU p of d n l~' .tl pati t'n t or in a p atie-nt poplll<ttioll whllSt. a ('(mtlition of n-hniw adllorll)-dria persists for till' Ho t week (If lifl'.. Pa rt . petI. and 1II11s<:·I(' (.. s k(...I_ Y__• H_. c•• UUN Young heolr+. which It'nd to p m mlllt' hoth "'"ol l llo\\' .'(i n .1IIt! sprl'mli n~ o r an intr.:t'. :\'llIw tllt'l(.'(J\lS (.. art ' rt'!a!i\'I'ly rt't·hlt'. Thus. and u nly aftN 3 ~'('ars o f a!-:e titit'S ..ulminislt' n't ) dnl!-:. h OWI'\'N ."l.lSt' in .aptt'r ls to SllAAt's l IIwan s o f 1''OTTt't'tillj.!. e uuurrent d iSt....lditI Il1 IlSl. .11I indhidll.l'i l ric p i I.232 ACt: AND I/VElGHT CHAI'T£i 15 . O il(' ohjt'C..'iah't ! wi th s lll.ruups is ill'(.. An t']t'\ll lt't ! g.. all tilt' fadoo tIiSl'lls'it't1 in Chap. Difft'n '/lt'('s in n 'sptJllst' with iI~{' an ' likt'ly tn (''(ist fur certain drugs. Fur alltie pilt'pti<' dnl ~'i alll! t li~o.ilrly months of lif(. t'stim :lIt's ill till:' )lll lllK Iwahhy Kmlljl an' of littl. indud ing ~.(" i\. 2B 71 40-70 7t/J 85 -.y ... l\'ntit" ..Iem ... With .nx ill h t'! WI't ' 1l tltt· !\\11 g..ulllIsl'lIlarly .fTl't:1:S of be -nzodluzepim-s cannot 1)(....ss.. dmgs lx-fon .. it~l' d ifft'o suhs tillltially from till' 1Ilt' I1I a~t' of til(' Ililtil' llt populat io n in which ti lt' usua l adult t1t lSi1~I' rq~i n ll' n was < es tablis hed.·Idl'r ly than in till' .. and other d m J" s-.ere J5 14 """""~ 10. an.ltJ.tlTl phan nill'()kinl't k s are assunn-d to lit' indepe ndt'llt of a/.('t:1.. TIlt' intlm-ucc of all other fil('to rs..wokhll'!i(: 1)<Ir. alt h(l\ l~h cluhln-n "PIIt'iU tu tulerute a " i ~l ll' r c unvntra non of tilt'st. ~il"t ril' 1'1II1 lI)ill ~.I1~ d i ~lJ\ i ll for tn-atun-nt IIf s('w n. 15-1 .. do d l<lll~t· with a1-:('.tI_ PIIa. h_ rs .arly fm n-na l dt·ar.I.y SUbJe.s of phann.. tilt' m ngl' of unbound plusmu d nl ~ conwnt nuious .m lial' [ailun-. or ' r it is il'iSnlllt'{l th at tilt' i1~t'-rt' lah'tl t'ffl't1s ('lUI lit.l'it riC p it..1)IJ nlt 't l for 1Iy aj.s d .l' llemlly.Ul~' tone mamfestanons IX't'(IIll(' ilPllilrt'nt . [l'util1ll. ucoumted for illdt'pl'Ill!I'ntly.t' .('t'5sfll l t l l<' mp~' is assumed to hi' indcp-nch-nt of a~t' . \" alut.u l1l'Il ' r. l. hp...1iw of thi ...lIll. Part o f Ihl' difTt'n'!w(' ill renal ch-arauce of t1ig.. DI••• I. C. expl..· tln-ra- PI·uti<.. for a g.l~t' n-quin-d tn tn'<It a t1iSt'. a tlday ill ~a'il ri(' ('U1pl)ill~..I(' llIil'iS is .HI•• c. l' fft't1i\'t" plasma d nl~ t'UI\('t'ntm tiuIIs aplx'a r to hi' the SiUlI<' in Iltlth chtkln-n and ad ults..g<l\tril' alit! sec ret ion appmad l IIIl" "tlult value. dl'IIl~('S ill nllt' mtl lt'r than ill exte nt o f ahsorption an' found . (. 9 that aITt'(1: dm~ ahsorpttou..5 ""rnmll uf i llpa til'Il t5 rt. J)ifft'n 'Il('('s ill t1 nJ!-: ah"" 'lltio ll a lll(Jll ~ ad ults.!. and hlood f1 uw. ill till' ncouan-.:::tI" InPciloenb . ht·· IWt't'n lilt" two ~rllllps . llIl1ll'd for h~' the t1ist..."tril' (. iute-snnal lIIoti lity. tIll' \'1'1')' )Ull ll~ ilm l the t'ld NI)'.su dl as diSt'll'it' I x'i n ~ tre-ated.' thl'n'fo n ' I'XI)('(1:('(1.-..' lL'it' ..

CIlI: I'n~.' n~lI lt'lI S uf dm.I. allll ltt... ~1 .r-ar to a h:-Clrb d rugs il-~ t"l. !towt'wr. (1IrTt't'ting the' <ad ult 70 60 50 "E .I\.l i~ a.. t1urilL. so too sho ul.'t" of a~n..!w(' d nsag<.~ ~.li" .P.Ii. U .'s rapidly in l·!Ii1d luKltl 1 and atlo l" s(1' nl1' und tln-n d t·I:lint·s slow ly in tlw t·ld t·rly ( Fig. jll ~" iU"'I ul" "1(' " ( 1). . (·!Iild a nd for tilt' ad ult who is p e-tit e-.ll ld~ FlK· 1. ~ l lldl t1t·(lt'llds n il li til.~ l lISt'I M lt ly «un-r '1 ). \ ''' ' is fn 'qllt'ntly IM din'l. Ie"."nCo'r fur 1I.".uf d i. K..... \'.h l. ...). e xtent of absorption ' is .ill g .high fjf'i l. o~all IIllM ltl llow . lil's: 7S-~ 'o'~'on ..1.IunJlI( p'..gs. clea nmce. 2nd ~ .. WM ilM-n·.cn.Ie·r..1" illo "1..l: is IMKly wt·ight.-.2..1 volume.Idt·rly. for u 111111111(' 1' o f tlm. in m-ouates and adult s.·Jj('t· ill w<.f lllah lt·... l'lJlat'iatt 'd .1 ... .".St.'I ll'lIli(~11 PruIM'rti c's tlf tilt' dmg and Oil tln.Jlllpll'lt'!y uud. fmlll II.... J'I'..I-~s dmgs ~ n 'n III till' .'5-2... I~. I. 111(' h st 1\\ 1) Ilill" Tlll't <.ti..' ·h~.\a !o' In II"..c.·. 15--2).2 an. musck.Cf'i.'ll l..: .f'i m In prat1 il't' .· rs w e-rr.'" (.. IIl1lM lllllcl \ ohunr. '<'.nli. ~ . p.I.. Show n ill Tah ll' 1. tli ' \ 111IIioll (V)..\i ng to Ia~. \\"t'i gh t..·."..(If t1isl rih ulinll 11. Ii " -l. Wal" "I.c -LIIl' 1.1ly lth pn lport iun al to Iltltly wt' i~hl a nti il1Clpllt' ndc'nt o f agl·.n'usou for IIIl' di!Tt·rt.·. St. ural hin<availahi lity increases \\i l h agt·. o r ullt. in till' .~ 30 " 40 20 10 o o 2 4 6 8 10 12 14 16 18 0 10 20 30 40 50 60 70 80 90 Age (years) ~' '''''I:. HI'(....AGE ANDWElGHl 233 n 'ry yo ung.. 3.n. ~ rdrmU~' in tI. i( . ol" f ... in subsequent calculations of tlosagt'..cfJ(l'r. .. ... I!f. .I-~s u med not 10 va ry \\i til agt'" A major exce-p tion is for souu.~: 2tj.<1O il unbound dn lg.. mljllstlllt"lIts for wt'i .·I.'" 1I"altl. h ig..l-sp.~·. a nd organ [unction art' related to h'ltly \H·ight.. 1 " ....ght an' ma de o llly for th .. BODY WIIGHT Om.. f cue 11 "".111's... It ' Ie. fi n l ~" "r Ilf lif..go. if an~t t. II t'Tt." I .mass.\ Ulnlin" E' atnin. n"I. vnlunu. I " "-~ ".1-\1..r"I:" " " il:l.' valm's for d t1'"'1' u f plasma pmh·in hill cli n ~. mnnra pid ly than adults... E. a nd percent o f drug in tln-litltly unbound. (.liu.igltl.'!1f t. Id.. fmlll' U-2t1~ "..' \"aliahilily.'i---.c.calculan-d d Cli ll i(·<all~ ... LOADING DOSE huling dose proporttonally for Iltltly wt'i~h t appt'a no n-us. in "". illl·n"I-St.' ph~ . .·. (}.of e1isl rthution (\'11 ).[" nlll( II. l"uhc. a \\'t'ight adjustllwnt is ~ellt'rally thou gh t 1I<''(.ti".5 kg at hi rt h.S.. then.'" .) . 2. hilt no t alwaY so . I ~.'5.1 EcI'I.fce·r ." S"rw'o'.\ \t<.. At1:o rtlingly. I ~.t'SS<try (lilly if tilt' ' wt'ig hl of an intli\i tlual tlifT by more tha n 30% Ir o tilt' a\w:'I~I' ad ult wI'i!?:ltt (70 k~) " t.."j..of tlist rih lltioll .. Clnldn-n "rtt'n app.. The vuluuu.

s.distrihllh "l. DI.a!t"tl from hntl)' wd~llt alone. is d imil1alt'(l almost enttn-ly 11)' n-nal excn-tton.2 "'" '0 r-. if no n n:ali7 for l'N kl)' wt'ighl.32 0 . ~" 1... Ihe data di spla~1. . t'~llIpl(' o f c reatiuiue is chosen 1 1("t.tth total b ody wt'i~1lt.1. I.. plu-nobarlutul ami tilt" two sulfouamides .u nsid('r tilt' va rious parts of Fi~.n SuNiso_ozole Phenobo<bolal SuWa~az. do ' 1101 part ition well Into fat. conskle-n-d for t' lIladalt.80 02 t1. Al. (If aJ.. Taki ll~ inlo accou nt di!T('rt"Ill..-Wllwns for age.'mllly al)(J\'(' IIll. for example.lIIt'(' IX ut! 20 ~'('ur.._ ~ . 15-3 furt her our lIlIdt'r.. As co mmo nly Found. whidl di min ishes al a mh' of al'Nl1ll I II pe'r )'t'. DISPOSITION KINETICS Fi!!:llrt" 15-3 shows d J:lIIK('S with aKe in half-life ami dt':lnUll.'('(mli ll~I)"..3 'O 7.1 Body composition is important.' of either ' di~oxin or ph t'1l)1oin is unbou nd in thl' blxly.ll.. TIw n 'aftN. In l.1 1.tll)" too small. Du rin g adulthood the \"alue of Iu n-maius uuchauged or tends to ri w fur thl lSf' d m ~s hou nd 10 albumin.'On' sidl.''(~.. for tilt" first tlm'(' dmg.'(1 do~' produces the S<U1 lt" unbo u"d d m~ l'(JIIce ntranon in b oth neonates an ti adults o r in any otln-r a!!:(' !!:nmp.t()N.·rtaillly st) for e n 'ulilliut' dt'ard ul'" ( ~l mJ1(' n l ­ lar fittmlio n mtt·). 0 . TIlis is l. Let us l. Creunnim. ai_I.. if n-qni n-d. \ '11 . wt'i~ht· norlllalin'(l dt'amnl.l" a d('amnt'(' equal to IIU' ~IOIne mlar Hhra non mit'.couceutnmon of which falls sli!!:htly wit h ad\"a nti ll!!: year.. 1'>fON. th nlll ghollt d lild hcJlI(J.1 ill Fi~ .. Iha l in tilt' :u llllt.. l.ar.. plasma binding is lower ill neonates than adults.l man )' flllK1ions dl. is dc'pn'ss("ti in tilt' IJt'(lJIatt·. tion must lit.(' (If l.ulliltlu l(Jl..0 063 10 6.llI~' must of Ilw d m~ is unbouud in Ilw Il(xl.ne 068 "'" 0 53 0 16 0 38 0 .. .. Yet ..It•• 1 2. :\ du~' corre-c anti oll('S(' Il:ltiI'IlIS.47 "'" 0 .I. tha n .'f' ill "indi n~ ( 111 lK'CIIr'S )..l" gn'at as anl idp. for tllt'~..·i ~b t-(. into total b ody water sp. 1 by ')lI ' .·.4 1. 10)."· in loatli n~ tIuS(' ilia)" uot lx.. 02 6 0 from III am i \' ( ~'(' Chap. falls h ut still n ' llIaim..'(mstiluents. 11lt.loH -" Digo-.t th a!!:(' an' well understood .'('s.' n '<llinillt' t'xpn's~'( 1 pt'f ody w('i!!:ht. 15--H. to plas ma protein n 'll is virtually tilt" same].pt'IJ(L . 10 warrant au. \n'i~hl.(x'l1('mic:a1 properties o f the d m~.' ·n'!al('(1d lllu!!:es ill dist rthunon. <lm!!:s... \ 'u co rrelates b~. should sufTk t.o. fo r IheS( dru gs.l"t1 r.. on the physil.. N A41.43 to 0 .0 0 63 is 65 1. however.Ii IlIl.tter with lean b ' ody mass.'n 'a'it'S . blll irll. Clearance.t. am i h.. s corr ected for hod.·a\l~' dmTl!!:t's in tola l lickly water ami glomerular filtratkm r ate .l.·S(' anti a\ 1."'- ceo .1.all II(' llpp ruxima h.::t' l.3 t 12 '2 es 1.. conskh-ration of dosc" adj ustll lt"lIl.(mlr.l0\lA1E 0. IItM'eH 'r .. is lltogliWllly kilug fUm of b b ound to ttssue or pl'l'ima l.. Even MI. an nftt' n forgott ell l'N linl is that t1lmuglullit . Di~oxi ll am i polar t!nlgs..>.a \\1. tlu.tpitU 10 l1'aeh a maximulII . 11w tIiITt'n'ul. a d i!T('n'lll.'ra~t· pt'fSUIiS o f III(' S<U ll(' ht'i ~h t and F rame.l llt"dlangt· in ('n 'alinhw dt'lar.tandillR o f a~l.:n·'l'i(' (FiR. which is similar in nlN. 1I111eh dt.u.. as wit h a!!:l. 111 (' dlan!!:e in hi nd illK is Keller.16 0 24 3.. 5.'SOhst'fV('t1 iUlllalt's and ft'males._ Pretel. and SCI a \\1...56 72 "'" 5. Clearly..'i~h l ·n(J nn:lli7J. Also .n'l:a lt"tl ch. Pl.' :adult m ille ... ' 15-3 ill some detail.( l rn '(1 ('( l lo'lI l i ll~ dose. is the same IN.ItwtI_ D.... To the extent Ihat creatinine mnmcs ot her d nl ~s.55 0 ..altw at 6 mOJlth s.70 010 . wlll'1l it is almns l I\\i <'(.. .CHAPTE R15 T.lrl!!:l's in phannacekine-rics and 5 11~esl a means of illd i\i d llali7j ug dClSa!!:e r'l.

-uTrli"n . 11M' ........ 1$-3... .~" ... f" r a ~pK"\ ....• 11"' .'1' '" I" .·n (Sit·n ]..·r. in..... ....M' ill tI.. r bl<".'.. n" n nR d'il. I II.k~'I . J......".. Age 55) ( ...t "'rth.h .. .. inlo I".li.... H~' \:I. I n Ltl...".T<"1Olirn '.tly 1 ~""t1 .. .jnl: 1...'tin. 1II". """.".1. llut...ing nil. . Ib lf·llf.. II ha lr.j' lllIlu h 1 Iil-nl.'i ij hr... 1 a'Hl lHllIo d"a r"'I(~ ' "'HI "'. it twk't' II. II~· mullip~i nK Ini · d...] . I' h. .. .· i ''. 11 " f 21-29 ~""n... " c .4.:"io:·I."".. "n •·n-...lif.~ · '. ".· ... tio: II' " f ......" I.") ~. ..~' .i .........lf.Jo:hl " . I .·r......I I ..· d .1 rno". I"h . inu lin <4<...4tt' lOr Ix. In.> :"." da..... i• .. An. .lir.. ..'u" . m. ~" tH ·mL. \ '"1"....I"'''· ... I.1 i"'p"' . ~ .· "l(l"1. lij.\.'~p"'in ..... · anti m l1tll 1 .1 po I ..... H.__Cal d."...1k ~·r in I h II · ." f I.Ii"" of "" f"'''1it"...: Ch. W...1 .".i<../'1 "lit"'" nlf't..1"'''' "f I " ....".l "1U)" . d . Age 55) or Hatf·lifel(HaIHifein Adult." ..0 0.. lij'j ll.I" rinl: RR . 1.·na l flllH:ti"n." .5 0..•."f I. ." ~'''llnM'' "f di. .h.·n· ...... " f Sitonl"" ·It.·litnlflllt.. t!w . . M. 55 ~"..l..""" h:alf ·lif... i_ 'H" IH""HI ill pL.....5 2.. . .".'t' fttt 1iort tlf s."..· .....n ~·ltl ."...· . tI. . n"'.. ". 1 .· "f ....· d'~"""'K't'.· " f p""" r."N'tlli..~ lik..Iull. ·n · < ..'">fi )...lIh"" d nl.... !'i... ~"tH... h:alf . 1.·nli~~· I~' n ·n..t.......·n.nt1 ..t" "I: IIa!f-lif..dr..n 'lIl1inR lhat It. All"'''' ¢> I".1U ~~. .. d..... (S" p".'>-~.. i..."· f".... hy I ~" " .·r I u.. .. ..1"'''''''ip: Surf"''t' ...I.H. rnM..5 .. ill d...5 .. liI.~. n H' "'..uIl<.. al I..... " " Iwlf·lir.- " 1."' 11 th"' '' 'RIH".. .I ..ao:·It· S i.l rihllti<.. Age 55) (- ) 2. ~· .. I.1.· tlf d i.... h. in inf.. ~l'ioU 1 .nn ...1" l nl.m · ...I f.lI 1... '1.· id .. ths..li" n nah-.f lnlR miw.. II a ".... n.. ~ •• m~ 1.tHl n. t· . . in I ".....0 1.')...·n fi I 20 ~~ k"lL... (IiW'1 ..·ar.I ·T'lOI:'· pl"I""" unl. loy I ~. 229:6'~ .I .1W ~....~' .I•..f" '1.CHAPTH 15 AGE AND I.rh·r i Fril.......5).t"'... 1" ...... Sd...1. ) (Clearancelkg)/(Clearancelkg in Adull.." .... . r....·. W.MRi'1 ..5 0 o o Infant Neonate 2 3 4 5 6 7 8 9 10 20 30 40 50 60 70 80 90 100 Age (years) Child Adult I~ Elder Hit. ~-iRl '1 1tl.. . I ~ ..i lo _A...u·ntr.. ill ' ...1.....n l f"... .ril"lli<. r 2... . 01 11..: futpio: l ...·" .M.I....Iiminhl.· n-1."i. r"l"' Uy .· i" lUI "''''''Jo(l' . 1 is .\.... .· .rantT-Mi hirt h. . 1 fil l'l "f I. I' 1<"'I:"r i" II...·k nt1.rf.... J .... lI ..lli].. in I • l"lt .l wilh "lot...rf. . t. .01'" ..Jo(l..TaL 711:'1..._".~ ........ t 1..-D.." ~' with lQ'..·limi' WIH >1l i• . "l(l' . I.1.\.~' ~1 . 1:1133.1 ilt)tll d. n · .· .1 lir.1f... I.i ll. " . ·n· " . n r Ii.1 10"'. I " .. 1ij." ... ''h ....·tt... -. ''''''I''''J'I".J..0 .. K..aI...'!tin.lif... .. I) m.I.......... I. W ..."" l lind .) Iff" l -ffl.. ~"I"' i . .I........ ..r..\ " . .dini'M'.r liltr... h h~'..-h 11....0 1. CI... .• d.1MnlOlin.llih." "I''''~ nld "R III .n .]' M .· " f .1.kllU... n . 3 ".~' ""ltl...11 ' I..tI" .....t i\ hiRl"'r in Ih... 120 rtrl/ml'Vpl'" I.J f" .. · n ·.... rnm .n.... · II ~ ...I tI.I... <It fi n ...113-1..' i• •......· "\'".....'oI£IGHl 23S (Maintenance Dosing Ratelkg)/ (Maintenance Dosing Ratelkg in Adult..~. I<"' R..l tl.')..' .I'..-".~" ..] IH"~' .• K"''' I>. " lwIf I.· ..·f\lU ...... 1 1 / y' i .I"n.. '''1 . I.10. ..i l h ....I«'f.1.·n 31101.. .·." I.liI" main.n ·f" "..1 i i...1 f" .4i"h ·n..1iRl. 01 1in I.·_ ..." (\ \·MlI..~.. 1 ' _M ...· a r. .... " ..n · [Wl"iKt..·ld... . s "rf.. p n "... t""... r . 1 Kri" . (I.. .. hy ...~.· " .Olk~ ll .....------ >)" _ _ -. " " ..· ""J:.......~· ..

tn}iu tl 5. 1'1'. wh ile t lu.&~. It-~ .'1 m l J min.d iu irw p rod ul"lioll a m i n-nal excretion .· 1.half-lift.IIl ~" S ill di sposition uf d Olj.1 • .. 16.'5 TJl IJmin.•. BI'l'iIIlSl' to ta l lMMly ' S 111N a-s II percem o f hody \\'(' i!-th l. dmll!-ttos rt-Iatin-Iy Iitt l. ""tI. "" In m-wlsorus.." · <lr llio..1 (ru.ITli 10 increase l'xIXlII('n· tial'" bva f.1d !). I. sw. rst:' I~' rt'fI'"(.'r . n . I. i ll\'(.J..'ar'lIIll. ill d .'. 2. l'rt'.' t1Urilll-t lift' ..c. fin.kJ' ad ult ( 120 mlimin .·. C n'a linim' dear-lIll't' aplx '.Ulcl 40 \\'('t'k.t11 ill fllll-lenn Ilt'tll mli's. : j(" d liUl!o:''' ill p11~"')O:oIo ~"'] rllllt-t io. illt-n-.')-yt'ar+(.'U T.. 11 rt.... Weight 8S 2 when." " t-. ar t' WVloll ill C ha p . 20 0 1" 0 30 50 Age (years) t"i!t.ph .' ltlN I)' p a nents . iO. .t(itl'o(..(1040 .lhl in dicate .-.' s1l1l\\1I ill Fi ~. . '1{\ "f . Clearance (mVminl .io.'i4 l-~ ) 70 90 .l(1n r of S !It'tWt't'li V. . hio.. 15 -.] SC..." SI.m'"wI"'" 100 ~ p ~ ~ "p .VU]II('S ill a 20. l·i~h l i ll k~ .}..1.·IIt~ 111H1.·iar.!il1t'tIIl)· comx-ptlonal ..tI I". st't ' lll In (){'1.11 1 (" . .old.~ .' is ('\"( ' 11 IIInn' depres sed per l'. simila r ago-n-lan-d dl.." . creatinun. malt's : !02 1111 J ll li n .. E " 40 e ~ ~ • - Cardiac index Glomerular filtration rate Vital capacity Renal plasma flow Maximal breathing capacity e.1I1'1.Kluha l rt'latinm hi ps that Incorporate scrruu cre-atumu-. 'l"<· r'''.I'i l~ '''' .a~t· h cxp n -sv -d ill )"l'ars und . tln. .. ill .~.Ag e) " . Altholl). ((' malt's ) un.. ill an lIn 'raKe UO. mall' s. . \t ~. i"iu .l I ~' B IR Sl rd )!..Ull-tl' in cn-at lui m. That Is.11 40 .I()~ralll o f hu(ly wt'i~h l Ih. Wll-.~'{'ar ..1s lilt' dl..&]...':h t'xli'llsi\'(' d ata an' lal·ki ll ~. Iht.. il is 101l ~t'st in hoth 11' '''\'''0 01 alld . . (('malt's ) art' ()"'5 tlnu-s those o f tlu. ..d("lr....di. ck-arunce-s (4..bh'l..Imlf-lifl' is shortest unnux] I )l 'ar o f a~t'.~ > 80 2 2 ~ "' j.old..I A tum-s tllt ·S(>values . n l<' rule· .Ulll. t1lal l'~'alinil\(' d earalll't' dllrin~ Ill<' first few weeks aftN birth is pn'1.. hl.r Ii. k~ adult ..'36 Mo les Cr&Qt iolM CHAPT 15 U .' ~ ~ ~ 60 ..10r o f hotl. anti ~1· lIdt· r. .0] ... (l ...i .-.. Mon... e.(. dllrin\( . i LS wd l a.:h.Ilit' n ls... I ~ . 11m.p..s a~(· . und lu-ncc d isl rilllltioll. " ('ilotht.&ni ul.lIl ~(.~· pt .. 1111' d. oI"l(ic..It'ric.Agel " Weight 70 Females Creotinlne Clearonce (mVmln) .._ •L".

.. " "J""l('k.ux.I. . t ../. 'II' II.111 kIC1~"\t in tilt' .·1T.. " '~lm l p" . \p"' 01''''' '.. .l.. 'i. particularly within the first few da~~ .'tl't! hy creatinine clearance..1.37 3 .( m lJminfl.ln". 1I ~l f·li f.... · " I'. IUrTt"l-1... w.linn.. ami ill adults older th an ."..I. llln'<i t. jtTl.Inll "'li n.'t" all'll.' . ' in 80 60 20 o Premature Full-term Newborn Newborn (3-30 days) (3-30 days) Infant (H O months) ~ Child (2-11 years) I Adult (20-55 Years) Adult (5H O years) H lt. n Dis .. PI' . Conceptional Age (weeks) .. ("llllsitlt' r th(' duta 011 diazepam .... "'p'.. I)usill l{ requirements for a d".uN1.li".. f"or tlx..... ._ J.d d......._ h" m "llCl lh."II" tI" ...'(....l..: n . J:.t" Ill' \ 1" ".I".. 10 00 k..L..8 ..J in . or ..J ~' . ".0 Il l ' "«' a nd C I.S : 3-& '. I.". Sp' ..h""._ 15-. Cwa tini. n tl . .. :'\(' xl.L : !>nll!: !>L iti"n !>llrinj( 1>. I ~ .. an' rapidly (:h a ll ¢ ll~ and must IN.. RS rt'll('<.1 or '"!.·r...) Stim".... l.. '111..1<.f.......>. t:.. Sl. (AtLql'l .d ) ....1.n n Il d prt1t·nn .. p lulI• . Infants eliminate tilt' drug most rap idly......oc.of' l.I. R." .<lU i\ ..111 rn"" II.'iij. C hant 1 C o..:. 1 .')6.." !: for . 1100 W ilkin.I.. G."pl.11 •• 0. tilt' Inll!!: half-lift· in tilt' neonate is caused by depressed renal (UIIl1101l.:.lm in} _ IU M fi2 .' (111\tillually updated.. (Ad.."5...1 28 32 36 40 44 ' n 2U ' .. ('("It~'fIti.. 0 1111 .' . Sd ll '" lw r.. fit of . 73 ".".liN"" . ( m l.. rt"s!"-clin" > H '. 1.. · " " till' Ui' I" " i til '" li min. 19'13...~ that is primarily excreted 1I1ll'hangl'tl d l\ ri ll~ thi s p d lllay b approximated Imm knowledge o f the conceptional erio e al{t'.. An"h.'~1..·."lial ''<Iu aliun to till" .. clo:'ll flUl("l' i.1k". li'lI'S "'P"'" 'nt Ih. IM'r1."'... ( ... ..1 n ll" !>uhlil....'io'L]'1..' tl...1 (n" " AI·Il.L.·r .R. HI. " rf..sinn ' l'Ulll't·ptiu u). of Kk>l7 U.('1. S.. (m m 6 11"". a d m~ IIll"taboli1.limn I" M'..i3 ml .. which 100 • • o .-ct''l l (o IM' n hla('k circlesl for IMIt I} ' ''''(..1.....Iianl"'m in ".. "" I"".n .. ~I"" Yorio:. " .'\ . diazepam half-Ii fl' is If)II~('st in the neonate. (finn . 1l\-6..J.... Chilo!.111.5.. n.lI lh".I u n · ('()u . I ) • 0. .. <1"...../d... 3 11_lfilh 'lI l l'_-&.1 I'rmu tiM' .. ..'>-fi.hnillt· d .. . o "'''IM. " •.d U ll 120 mlJminll ..:.l'n . With cn-annhu-.. ..tk..L I. ~ .\.55 yl'a rs of a~l·.R.ON' "n·.1 11...... · h.."\1 in tiM' inf"ut ....nCL..· cor rIi e r ('<"'('< 'p h" " al "It" ....'lI l liwr IIi. .. G .231 a~l". (".... .. In" "\t .. nal aJo:l'..'Jl. ·1 " ...· n . 1977..t't p rimari ly in the live r.· .~2... As S('C-'II 1 in Fi~." r. ' .. hul IIIl' n-quin-ments.( .

u ht"('n tK'mollst rolt('cl li. ('...I ~..."'io lt' of diu~i"' rn .Ull. . t""pt'liall)' ill Ilt"Ollah-s.\ a p"..: aclnlt lu I.'r. H.IJt)1 . a.. holi.... Cn'C'C.kl l tiw d C 'il.-. oliflC1k"to of ..11'11I. \'oilt. .t11 i nln'. .liJ'-I't..~: (.lII~t" ill dt'ardlK't' or hal f·lift' "...·. 1.'i~h t ..rly !lIIIMl l to l it-. Unlil lIIun' data hC"('OIUt....1"1. Ctmju!:tidht. n lt·lwJ(·!lf. J~ I .' n\ '(.lIn i. in dC-anIl K'l' pt'f lilll)..._ . '1 1:5-1. and \ulUIIlt... F: .:x..~ KI"" .". t'Spt'rialI~' t1KlSt' e hn unan-d prilKil)all>'I ~' m . l"M"r >l ~. tlf o. tl K' all -important IInholllKl ck -ara un' is " "(1 11("("(1 (Fi~.. (CC ltll. 1. . S M.lij. ". a point 1II'lllt..t' ....· .. ("'''' 2u 1 1~1·"".. \ t·.. ..1T". The· '· fT....rju!t .IISt.'U... )h.. .. aIKllx"t... prohah~' J't>At"t inJ: dilllini slK'tI C'" lp<K.1.III 1I1111..tr ( Fi ~... tlt"{"'rt' il. "'CII~...t h.."\'(... ~t' ma~' C"dpt u n ' nll l~· a s mall pt ' n't"nt o f tilt' hltal \Olri.lIl ~I 'S n .1 tlnJ~ .!. ege..._.tlx.l<UIl thl" km~ 1. pt . lIN). ... its d l'ar..:n l(' . r . a~' from 20 In MI ~"iln. tiM. s... "" 11M' . J s .0111 Wf" lps .pnrtinll nfl:XJtly \\1. admit Of KM'I"'ltrM:iiull and lary:" \'oIUlllt' IIf I li ~t rihu tic lU .."\\·101'("() clnl lt-lIlt·t.1..t t·MI·rly ~ml l p . .. ...K1hit)'..~\ol"'!> lI.i a h "(I.'5. l-olpadf)' also dec n -ases hill I~' a It"!>....· d t'ar..6 'l ilt 00 ~l'an uf a~.·. l)i.tat u. t i llit' n'clllin '(! (ur Iull matu ranon varies " itIJ tilt" (·II ~lIlt· \) 1.· (If tlia:t. lI . nit·.b•• ... 111(' further prokm!talilJlI ill half-lift' in tilt' 11l )'..t.. 1-\t. Iht .. >1 ..uK.... . ZJ..11UC'w.. l'h .lio '" ..i t~· for 1It'Ilatic ult1..I.w..1 . httl" ".t~ he-t'n nh~ 'I'l'( l in t h.ult"t'in the e k.231 lalt.. \ \'ill . ( . IIo·" t.'i()(.. I. dl·:.. \\it1l all t i l"~Ti IIt'.roUK't' o f I l n l ~ i~ lI\u.I. <:.u" .:'·r1. R l : I>i. S!i . uf tli!>t ril mliu u h ilK"n'a"'l"(1 "."('".'\t'r 1'\lI'nt than mt ·n..... 15-i).fTr n·..I. ..iY..~. . IlJ. a5."'(' <llKl \ 111 1111)1" IIf I li~t ri hl)hol1 art" dt-pt'mlt'nt o n pmh'in hill(lin~ .u . .M" .11I1' lI\('t. IIwt al. 111t'S(. 11 .tc...'i. a nKJtld t't)lIIptJIIIKI Il_ 1 tn a.l. .m"... Md ahol it· . illI""lI-'l ~ .) . That ti lt' pn-mnnm!It'ClIMh' 11. in part .·.2 lAJU in 1.'1"\1'r.' StJ'. 11j'. IIcM'(.lk-tion ts that I1It1ilhohsm is I. l ij.. 1 C I. . "" " .LI.fT.t'."It·.(' ( P""(lc ll ll i nan t ~· nn-tabohc} o f lIntiP:oTiIK' .Inll J eli" 1" ' .m in tlK' hve-r. For t''-I lIIpll'.....K1i\it~· llla~' t"k" lIIon l h~ 10 rn alu l"t' .. A .li..idatiou.\ lle·.' ill tht.rI~· (lalit'nl h.. \1 n. Gil.h'H7~1'1j. no d '.ith a~t·. ' for KM't' r plasm a himlinJit of dnJ!'t.."1•. "'~1" n... 15--JoS).n ..1. "<"'t'ml IlIlIllths In mature.<iot'S hy app rn u ul<Ift>I>' 1% ' .ilt.ow' ill IIl1lxM UKI nlt1a holi<. U.'Ci .r". thl' d t'ar. from 2..·tc.( [1 ..) d e.1' ." e lm . H. "'I(I Wi l ~ i " " .. tilt' km!tc"".... icL ti\1. il\'a itahl(" tilt' I Jt~t current I"l't. I .:1 1"....1l.:xl R.(' o f Ilatiw l'4lp. li\lIl ..... lJ nl.ttc.l1 ...·a. bill nll l~' IJt'("auV:" of tiM' 1t"lJ(It'IK.5'1 in the >' )111I).. \ullllli(' uf dhtrihu HolI of th is d n l~ is ap"" p m \ illlillt·!y tht· SdIlK' 0 .M.. dlan Kt"S llIi1.bti\t. 111l" shnrt N h... I5-H). \ 1 n. 80 • • o o 20 40 60 eo 100 Age (yea.....lll(...l\i ll~ numbr-r o f tl m~ . M" ~' . (OI.\<..lIl't'..n ".L h.. dtl..I>L..... h.(I(·li ((· ill tilt' IIt 'OIlOl!t· rt·flt"(1s .·.. "'MISh.".·rly.b•...11 ([.llI> LlIl~t" :11I11 a.. requires !>C)IIlI' Ih!>l-m~tOIl .... fn...f7lf-4 'l3. t1ia7.·I" " I.. t1 t"( ' tilt' live-r. TI. Fur \( .. 1111' IIl1lxM. \t o J ' N O .lUd \tllulIW' uf I li ~lri lolll iull dl.\ cll"(·o 'a..1.. II ."" ). " " II pI m•••. . .lli t~·.y 1)(.."I .·U. I I <:. It.....llf-li(. i " . Iht. ."ic·1IIll")" Ilrim. II cJ'.r.u1'N I..I· 120 • • •• • • • 1m".n -Iate-d ( Fi~..'ardIK't' n ' lIli1i ll~ t'S"'l'llt iaJly constant . :'i ..lIf·lif(· of diazepam is flul s u rpris i ll ~ and :'> In""..' rolll \1lriahilif)' in U1I.tril~· hy o \ icb tion .. s... b. ~ I . : AK'" "'KI K"·..t'pa lll in tlK' infant than ill tilt" 20· In 55-)l 'ar-uld ad ult n-llects dHTc·n·nn.itllt'r dt '(:n 'il-("(! or nc" dlaIl RI"(! in tiM' t'1dl'rI ~" Tn he' nil th" n )IJ!iI' I'1Iti\t' ~ille uud \ . "1<:1'." "'M Ir.-IIt·"t.... t' 1 So·ltc·" .. J ( :1".:xl Ii..U K't' ill d l'am. 1.. ph..arlit'r: dlR lllul(~k a m i flllK1icma i a!tc' must Ill:' t lisfinJ:uhllt'tl. ('C .31 1 1 ~1 1 2...

.m >fv.. s tu :!... " f ~.."la"I(.. 11"..... t1c·!t'rllli llt"t1 alit·r ch rome oral t1( l'S in ~ of S(.'O..tz. or 1 a l'tlll ."i f1llflh C lin l'ha n n" ... II...1. ... ' ... 1 5-1)). .....l ·...!!!:t' in childn-n ( Fi~.w lillie.\'. IU. .ltie Illd aho li(o ("I Il<ldt~ ' Ill'r uuit hnd y Wt'iv.t!t't:lillt' fur IlUhllilll<llllt'talx llic d t'a nlm...t'll. d'·llr. : I>i_"..tI( tI.: A nli!'~Ti ' ....=.jt'l-i" Io·M. B II..Iilt.1""0"1"'''' ill II".t..1in . It·rIy IlooI....."h..... 3 it follows lila' tht. « 01."0 "".... .(·.'.. . ' "IlriJJlihl)' in d "OIr. .. i n~ . It.."b.. 2.:30 1~."Ii~-n..l\".. ."I... \ \ '(·igh l-t.• ill..'(.... .-ial. allt! in 110 11(' studk-d tlc .ar.> u D '" ~ c 50 40 30 10 10 0 • • •• • c 0 ~ :::> c ----:rb • Male iY •• Female •• -1L E ~ ~ .... aI... '(· " f ~ ~ ~ '" 80 E 70 E (13-37years) • • i.\ .. . • •• • •• •• F emale •• n". I S-It.·r...im plim t("<! in tilt' Y Ollllj. . f."m for il pn . fn'''' (..... . il!t'r1"t llo 1)(' lilt' Sa 1l11' as that fnr n-nal clea rance.I". eli". i ll~ ratio IIf platt·au ptL\lll<l couce-nt ranou In do<.'(·" 60 U .I11 1ll' l'\itll 'Il('(' t ha t hor mouul statu s ill wnmun muv al<. "1 . . UI':"S . i.. r .compk-tcly hio. an...) I Z. in "'...Ultililly ht"tw('t'!l th e d ifTe n 'nt age J?:n mps." ".m". "" • ...'(. 1011...· " f .10. •·. tln.".1.""l il~1iIlt· 1...1 "'i l h I"'" Ini"it".ht is tln-refon..\ po tt' nt optoid.". 1 1 II: .1"'i lh ~"" ")( ...Jf.. J.. ..e <..lr.... h m..1 A.·~' n..Ii""..1 "'llf'JCin..nna<l.im <l ck-arance o f <llft·u ta ni!.pOlll' llt o f...... ~ .Ulotl· "'illli" .-s pr otein himlin!!: appt'ar to dian!!:!' \ uhs l..'("i\.O[I Il1t~.. >ln \' .. Ikoll. ""'iI. All lh('~· alllit'pilt'ptil' IImgs an' (·\tl"llSh-t 'ly 1I1(·taIXllii"...la pl ."h l..S. n. ' "."LI1..... 'C'r g. 1 .l""l 010. "f "...-i..."... • i.. Male 80 flit... n . Finalh' . t' llI..ill~ r..is <..h..\"..llt' pt -r kilol-!:r.L.1half. . (A. ....) 1 o 10 40 60 80 100 Age (years) .r. 1!:H1.~..l it. C"I.."'i"ll:.• Tnlli".. ~ .. " a~c should h(' :'\1'\1 (umid!"r till' ilwn '.... III P r annum.ll inl1l1t'lIl.n ·a.. ~ 1I ."..tlll."".·n. p"p"l.. ~ .. ar.H I " nl.1in " IeIc'rI:-' 'I. llk"'.t:.'w'S tilt' rd at ioll slJip )(· 1)( ' 1\ \'1 "1' 11 p la. 1 . 2.1lI sht..·.... .·"I..·.. R. Fi~lrt· 15.. ·a.. S ...Ir. n.('(1.. ..J . and age .Iii..107 I"-.... d l<lllg" S ill t1n1g killl'lil'S with ag.-i. 11l':42>- o 4. n...11 ...... " f C .. aiI:-' wilh II!:.."... n J.1i"!.....1 sl.. \ t o . 1I.m .ti ..'t' \\il t./ kglh c. A SiWlifk a llt t1t·(. "Ii.-i."...1. n. ant) on.m llp ....n .. .~ c ~ .1(-!o·" r.... All till'S(' 11m!!:...." I " R ."lITn '1:1:l't ! d l'. mar)' . tln-n .l<. . t f.. I ~. M"."' I ..lIll't' llIust lit" higlll'r in a )l Jtl n~(' r and smalk-r child . J-Il. 11.....· pri. and since IDo.· n..... ..a1"" .Im~ ..ln.1. !>iIT.erel anlil' pilt'pl ie d m ~ with i ll('rt'.1.."9 i L' a nm~b approxinmt km.. 1f.. t I. ... t· in ' " Young Elderly (61-84 years) tilt.W.l ..Iif.. R.('... G n-ater I..'''~ of ...".... 11I..

TI.olf'''' '''01il.1cin-J.C:... Th."r· mj" jo.. .lI.. .tI. .lmpIl' ... ..." (}n~ 'ldl '''' 'd rmm e 15 c IA 'm"IC'''o. "':-.• in (. then. G.. 111\1..° is d t' ri\l"lI from dinil'ill silld it's in a lIlist"ll popula tielll.".I.0..I• • n '••• 1.J ..1.-.\· ('x. (" " '11 hLot'" cin. fur .". "'1 "~ ....(hl.-"..' wit h a!-tp... .it'S k" I"." oak.. "l.. . 1'. tlifft..10. CClIl... "1:1'. As \I....lllhl' ext re mes.. in )lIu n~ ad ults k-ss than 3.-l I6-l 22.y to aro( lld wnuum is p mhahly on ly 6(1 kJ.ltLllt'S.."....:t· 9()..: Ino..1 Bl.<" in 110. • • pecte4 e-.I.·. eli".p. I.)-) l 'llr-o ltl p. . fold Imm t hill of a ~j(I-YI'ilro(. ..dly. . l fl.). A 2<).llit'lIl is 5..•.) • 20 40 Agein Years 60 80 <:!1· lr.·ar.. M. \U' I' . E.' r ..· ur ~. MAINTENANCE DOSE THERAPY Adult For musl 1l.ft'n n ' lIlay wt..11.0 1....• Ii" n .sicI" nlt illu of adj ll\ti n~ for ~t' Ilt It'f IM 'l'tII1lI' \ ilion' important . ".1.. . AGf: A!'IO WE IGHT CHAP1EI! 15 Jo"I.... 15-3.. 11 1(' dt'("n '.·. dilT K 't'. {\(lSitlol.It. a ..: in si.Jf·nl.rs nnly t\~~. "...I!!:I' 20-yl"tfo()ltl man may Ill' do\( ' 1 7n k~ in \\l'ij.in.. '-H-1.t.)'l'a r-nld woman ...• I'llMIn.. E ... .P is lIut dm lllol...I~· I n ·L.l_ .kl Ad...r... n"....."' .. 0 0 • •.'11 em ~t· lld.o. iol."l'Tt'''''.: ~"'I" '1"'''''': l1.J-....ll i" lIlS a n ' fair l)" 1'1 0\1' .n' l. l'f('atillilJ(' clearances of mall' a lit! ft' umll' . ....1o.·'. 1II1·noll.. 1.ltl mnn..' ..5 )'t'a rs o f a!-tl' a nd ill Ihost' im!i\itlllals hl ') l md i5 )'l'a rs o f a~l'...· "us ual" ad ult d u'il.. TI l(' di IT .>I<it". . .. 191 111.t"il . 111I' a\·..·. 1'6...LX lilt' awr. I fU. 1-1':.).l('lIn· of ho rlll lllJ('s ami . .lts 20 55 Q() 120 85 50 102 43 n ._ .. "1 . 0 t..olin.n" '''''' I<~''l1 in f."\ will......\l'a r-old woman a nd a 20·\l'ar·old ma n tlilT" r 11\' threefold in tl u-ir t'n'atini m' d t·'lflllll 't'S. .is g:t'lIt'mll)" 1111 m-edto adjusl t111s a!-tt· fo r ag:' ·' A 11(" '1l lllay . J...III('(· occurs ill " 1mW Il h ut lI o l ill nu-n. 11.." '. rdakt l to Illt'ir . -.... ("' Mil (.... isl when Ilu.I(~· of 35 30 25 ..('. ~ ~ o o tl.. fu r ddt·rly wumen and )'l ll lll~ 1111'11 .(I\~l1 in T . ..uKI 110·.1 r/.>I..l'i(' in women lIlay l it.ltit ·uls. IIo·nni. ' i. 1 n n" .-\ <..10....-i. wln-n tIlt' I)pil'lll p. I'.' nlJ. bill a ' 9(). (.. A..!!:1'lwm l h ·m lt·lJl·y fur mdahlllislll to <!t'1'n·.!. l.at" • .1l1rs O il tln..e.. .'''l! ha'il....'·r· ~ 20 u ~ • •• • 0 • ~ .. "..c·mor. 15-. i.. ( ..n ll * "a. .thlt. Furt her \~~ Jrk is 1I1"l'111"11Io t!e1e n nillt· l ilt' inll... (:.d ifTt·n·!H helw("l'n t hl' indlviduul a nd tilt' l)lli(:aI path-ut t·\(~ '1"l L\ 211 yt' ars. ..1it ..1 .2!i:4. L'il..lm l sial us .-sl .lt .... \\'t'i~ht is aIS() a fat10 r he n '. it.tn..-e r. !I0\ \·.J"""" .5 )'t'ars o ld ..1In l".. " 1 I " M. 70... ".. " 10 5 0 0 ~ ~ • • it> 0 0 ..... I ~ I O. .. 1 l~ Will> I..iIt.')...1.a otlwr f'lC. ..

ant! .l"'t(! ' 0 11 IlI'ig:ht alo!lt·) ~tld l illl·Wa.ld . ~t al nnll ri s h nlt'n t am l va rious t1iWil<.. 1I0It'\\ '0I1hy ln-n. 0.'llI ~t· {M. Ideol body weight lmenl = 50 .tsma (.s takl:"n hy th e IIml llt'f.·S ran Ill.CHAPIH 15 AGE ANO Vv'EIGHI 2. slll...g:.ratt'ly reduo-d with IM I)' \\·t'i~h t ..(1..llla . {·lim inaliull o f dOl!!: frolll Ihe Ilt.9 1 (height in em .· oUlp ut. illill that ha\"(' <l nam l\\' tht'm(>t'litit.t· stun-s lIlay alTt -c·1 n-nal and Ilt'pillic elnulnation.'\ l 'nh .de' an' ~rt>ah'st for d nl ~s . Unfol1l1nal d y. All exception may Ix' in t1 n lg:s \Imlt'fg:Hing: ' g:llI{ runid atioll. Neonate TIlt' lark of maturation o f renal am! he palic funct ton m ccssltates thai tilt' ran. Ihe unbound plalt"lll concentr ation in l tlu' fl"lus is likt'ly to eq ua l that in ti lt' p n 'g:Ia nt mo llll' r in ch rome therapy.t' ill olll.\(..'t'iIllM o f add{'(! ad i po~>(" tissue.(IIlt'('lItmticlIl am ! lx't~AUst· w llal dt'a nlll('(' is pmlx .'ing: Illaillh 'mlll{"t· do~aw' in t·ldt·rly \\UIIlt' 1l and Increasing dosagt' in )'Hung 11\('11 ..' a Ix.in~ rate. lS.dd ini li\l' Iufonuatkm is 1ll'('tlt'(l for b oth nlx ·S(· and emuciated palit·n ts.l!: (':ll).fet us IX'ing: the same as th ai ill till' mot her.lisslleof t1istrihulion . hm\ 't"\'('r. C lt'a dy .k!ing infan l is t'Xllt ISl'(1 to th ost· d m g. estnnat ton of dosa!!:t· n 'fl" in 'Illt'UISis ev t-n mo re compk-x.(IIllIllt'nSl.:t·r body 'n . uf { 'U II{'f ' m art ' . In most of slld l palit'nts.M I~' Ilt'ig:ht.most 1 l:111 as an addilional .'('1Ir'S.. Fo r t' IlMda h'(l pal it'nts.m·tatl' hd lt'r \\i th IJ( /(Iy .'3 and 15-1 1 SII~I'S tS IlJilt a mainlt'llanl'(' R~ n1t'n . llInti ph\lIIil o uuvru mnon.ltt'r app roximat ion u f unbound ch-a runce andmaiun-nancc d( r.lolx'(l. kk-ul htll. thai an ' poorly d ('aft'(l by tilt' infali t.I pialellll.\ .\\'!)fJnl dlild m n Ix' w ry slow indt'('(1. dJan ~.. Ihe fet us ac ts for tlu..(' 1" ("t' (1 " (/ th an IXlIl)"wl·i ~h t. on t1t·li\l' ry .r- .(. 111t'1l Ill. ' n-quin-nu-ut s dqx'nd ou lilt' t'ill\\(' of III(' emaciation..index.ly wdg:ht . 111t' ('vit!{'Il('(' in Fig:s. Mpt'tially l for tilt' wry Yll1l1lg:.l"It>(IIII. pal1il'lIlarly Hpophilil' OUI'S..1Il 1 l:I-SS till' pla(. )(· In passi ug. dimi nati n. dnsag:l' rt 'l l lli n 'Il\( 'IlI ~ an ' uot (.' ('\('11 g:n 'ilIN than llo!t'(1 in Tab lt· I.."t'.'dJ!. insurance actuarial stud it'S) ca n he eslimalt'tl F rom the following: r{ · b tion~hi ps \\i th I Il.9 1 lheighl in em . inlt'n..lIlt'(· of t-n-atiniue can t111'n lit' calculated Irom Eqs .lt'i~' g{'Il('m ll)' l)fll. \\i th half-life in tln.'M and t'lIIild ah "t1 patients must also hI' adjusted to ma int ain 11ll' sanu ' an'raw' IInlll. Dm ag. in kilng:rams (fr om lift.. 111t' ri. W Ht.• re na l clearance) is lIot illl. cwn 0 11 iI hody wt'i~hl lth l"lSis.. m m ld pn )\'{'inad('(paale for childn'll . lr unu-s (Il('ig:l.Il('(· (I rl·b lt·s t1llSill.:s to IM neonates an d yu ung: infants he Tl'(IUl'l. Dos 011-:... m lclllalt'( l hy (.l Thus. ill whidl l'il-. l'ilrtlia<. add(>(! atte ntion lIlig:hl h(' wn'n 10 · n "t!Ilt.lolx '(! dimi naling: · orga ns of lilt' motllt'r. IXJSiI!?:t' R'(llIin ·nlt'llts.· rln-re is an inen·il-.~ IOl llt· m 1a r riltmtioll mil' in d lild n'u and in you n~ ad ults of \\i ddy dilTl'ri ll ~ si7. :\ drastic d . People wi th lar-.o.. Ilt'patic and n 'nal h!{)fxl flow. Dt·pri\l. Ut'sitlt's l'a n ·fully not ing: n'spon~..is the intidt'nlal t'xp'lSun ' of h-tus and slll"kling.'(! of alU'SS to tilt' fully dt. I and 2 for ad ults.1521 Ideal body weight lwomenl = 45 + 0.qnt red dOsagl' rt. Usua lly. 11It. d nJg:di min at ion (t'.1521 T Ilt' 1'\ 1 )(>('11'(1d t·:lr. umn. As sUl·kling: Ol1:lIr'S rl'~lIla rly. if to\(itil)" i ~ to Ix' avoided.t·s haw Ix't'n found 10 t'(.'}-. II1nllil(l rin ~ o f tilt' p lasm a ('(II\('('Utrutiou of dnlg5 with a narrow therapeutic lndex should 1 helpful.' t's tilllitlt>(1from Idnll lJ( /(ly It.t and luuld} prohahly ha\'t' h i~lt'r clearan ces.of udnuui\l raliu ll of d Olf. Bt't'illlst· d t·ard.l!: mi l' 10 plall'a u pJ.'S occur so rapidly ill tlu-se t'arl~' sta1-:t's of lift· Ihal il is imfM iblt· to pn'tlid \\i th l'(mfidelll'(-' clearance and hence tilt' M n . howr-vr-r. T o a first apprm illliitinn (h.. Jdt 'aII M Wt'ig:h t M II. Infant 10 d Olg:\ . thai l'(IT1('('ntmll' ill hn "I-\t milk. Cauti on mus t dt'arly Ix' exerci sed in adm i ll i sh' ri ll~ drugs In this r 1 "'lit'1I1 IXlpublion .!y may tln-n Ill. For Iho'O(' d Olg:s Ihat ( ".(lm't1illg: tilt' ad ull dOSige for Ixxly \\'('i~h l .• wi th nlx·sit)'.lfly t1t·\l...

. ..li" "I" 1 1 (.1hlI. SI"'(1n"" rt .. . '11' -. the dt"lImllt'l' expc. m .... ' [ s' rnxe cm2 01<h.l An !1ll..In-n. oJ "". .}('I" r"" ~llr ~.5 o 2-7 6-11 12-1 51 6-20 o <2 2-7 8-11 12-15 >15 Age Group (years) nil:... I h. ""'It."Ii.• 10".li'''' Dllring 1>' ''' '\''111111'111.1. " ..1t' "' ...1... \I" ". .""...t d ..1.. CI..". 1'1' J I I-.4 3 2.) fI. . " f .tk·lI lal i ll~ maiutenancetlu-ra py 1I S a.uic.. ~:'I1" . " .I I~ 1' 1.·IIi.( lu ly "" "10:1' 1' 041" .. 1"...5 2 1.1 Imm II. 20->t'ar olt! is 1.•......I d lild's maintenance dOS.2 0.. l>i' P''''..5 o 6-12 13-1 5 1&-48 o 2-7 8-1 1 12-15 16-20 Phenobarbital E thosuximide 10 2.J d ".• .... n M ' r l.6 0.'....lr.' )' M lI1". ".5 0...... '·<>r~ ..t ic" .'l1t'(! for a 7()-k ~. the < :hoi<.US 111 2 L\ tilt' surface an-a of an a\/t'm~t" 7()-k~ ad ult....I..W~ .. .. tloual to ~IOI llt'n11ltr fil tration run . Takill ~ II ..~ tilt.'thud o f (~.10: J-" 1dlo w ol'" in . Typical adult maintenance dosoge 4 when...... tI .no! "''' 11<..5--1 1. Al'l:()nlin~ to this concept .8 m2 1 ) . IA... 1."'.....ilo..5 2 5 7..hlit-..' IlH. Carbamazepine Valproic Acid C HAf'T £ ~ IS 0.4 tunes that for till' reference p atient (Ell_2 )..In . 13-11 l.....5 2.I~t' is calculated [mm the fonullla : Child' ~ maintenance dosoge • 14..· Fi~.<>m" d rul( <~ ""~"... II .-' uf sunat'l' an-a owr w(' i ~h l a.Lapl.I A : l"k' .fl" r d. n..Imt'_I" Urut. 5'yl'ar· 5 old as the typkal patient n"(-'l 'i\iIlR till' dm ~.. s.li< ..Iit·. In .\ OliI(' j ustificat ioll..8 0.f ~l "rwlli ...... in ...ld] rec 1. 111l' surfan ' an 'a of a clnhl can ..(St"t.5 1 0...lk.. 11:1'.

tl l l .p n 'tlo millan tly ex("rt. :'1:011 ' tilt' l11111p lt' IIlC'utal'7-' c1t'1:rt':lSt' in tilt' llalf· lift' wtth dC'('rl':Lsin ~ size. 70 kg x 3 mg/kg • 100 mg/ doy :\ol k t· that the.tc"tlllll ("han~t'Cl should I. ( :('rt ainl y. 6.llt' r Tllainlc'Il.."t'n 6 mouths and 12 yc'ars.it-St's.II11 i .tI~· gn-un-r p mpn rtinn nf th e total pnpulati uu .e .~s Ixxly Functions tha t ha\l' dt'(. cml)· . lcl)?..11\ I. A reduction in dOs. the ~t'Il('r. TlIC' n-ason is tha t cleanuux.1I' ual ad ult cln.()Ik of thr. I.ifinn an.s. T his is c'slx"t. 5....·!s oltl'lI no!c"t! in ddN ly pat it'llts.iliJ.cn('(' Ill..' C \\i thnu! clust· .mcl h .' ddc'Tlllitwd [n uu its hClI.an-u pt·r l.cl i "~llinu .)ll ll1lV.. l i ~h IN . I~' \\"( 'i ~ht til tilt' II.usual adult tnaintt-nnmx. tllc' IIlarkt'tl mlc l pn ~rt's si\'l' dc'C.CHAPTH 1.LSt"t1sharply with acl\":Ull'i n ~ vears .. fmlll I )l'ar to 2U)t ':trs of a~c '. Us ill~ this Llst n-lanonslnp.() kg of Ixx!y weiv. of a shnrtN hal f-lif(" till' d rug lIlay also need to hc' p\l'n monfrc"l l' lc'utly..llon ll a1i "~'t 1 dail)' c1c}S(' of tol mull)'d n ill till' child . ft. Eft.I~C' is 1Il"t'tlc'C l pa rtie'u lar ly in tilt' weuk am i in firm c ·lclc 'rl~' !l:ltit·lIl..l(! ~ V. in Il:Irt.5 243 Ill.H).a I:lrv..\lll't' allC l ll~t· is c"pn'ssc"tl in E(l.\ p rt'sst'tl ill Eq.llt.·i ll : tlu.ht. tilt' in('n ':l'it"t! fn"tlut'lIl'y and c1t-gn 't· o f ("t. The c1c}S(' n' luin>tlma)' "'PH It. ' r matnn-nance c11}S(' pc'r kilc'h'T:un I x x l~· wt'i~hl t than an adult... For c'x:lIllplt'.' n-duced ill dclc'rly pa tk -ut s.lIcn'fl. Thus. . 15 )0 7 Child's dcsoqe of lobromycin .uljm lnll'll l pmhahl y t'xp lains.ly \\"(' i ~ll tusi ll~ the OI)S('I"\Ollio ll th at surface urea is p rop o ional rt 10 I M lC. on an 'mv. c1C1S:I~t· sllCllIlcl llI.tn ht..tl c1t"t. I. ti lt' smalh-r an d hr-nce usuall y tlu. may ht· n-wri ttr-u as W eight of Child] 0 7 Child's _ 14 .(· 1I11l1uatitJlls am llllCl lh c' :1\·t' r. As a hm.' alltl a~(' . Such a pali t'II1 oftc'n su!T [nun a -vr-rul dist. 15--3 for chtldn-n hd w'C. n-celves c'rs multiple c1rtl~ lIlt' r..lIls" "t'r 1~. . IM I\\"('r ( wt'i ~h t n.'i 1l dosa v. 1. Tln.is proportionaltu sm fan ' un-a ami sur fuo. c's timalt'tl Irom the mtio of surface areas Ies timale'tl fWIIl IM~ly w"t:i~ll t ) lISill~ E/).nwHs of clrtll:S that an. un a\l'ra~c' .c..lul'C't1 in tilt' t·ldt'rly populalio n. :l\uidt"tl.SS I x"t~ lll st' tilt' elclc'r1y p atient is.' 1iC't'tlt'tl in a 15-kv: d lilcl? :\l1s\\"('r: 1lI0 1Il~ c1aik Th is . adw rst' clm~ t'!T General Equation Tel rd um 10 tile' ('\am plc' of ('n'al illim ' autl similarly hanellc"tl c1mv. The Elder The d elt·r1y ('(ms!illl lC' an i ll (' rt·:~. tllC' rc·la!innship Ix'lwc"t'1l n 'nal dt':U .rt'.-r cupitu tha n do pt. 5 : IM')'tlllcl211 .s.\C' \ clisp m pu rtion ate'l)' with dC'('n'asill~ \\'('iV.nc't'C 1 for a hiv. A dt'p rt's. (:onsidt' r ti lt' example of tilt' anti hiolil' t o h ra l1l~ 'C.c lns:t~t' ft'h'. .i~C' plateau ('()IJ('('lJ!r. is sc't'n in FiV.St'C 1 dc ·ar.4 x ( 70 . no t oul y Illay a l -~'('ar-ol cl ehihl n-quin.()-)t'a r-old pa lit'nt n-quln-s.c·h ilcl. rt'f1t"t1 inv.l1lt')' .l~ a low therapeutic index am llafj?.t'Ilt'r.. n-lutionship t'... mW1v:.'.).·linc' ill Ixxly l um-tion witll a~c' ( F i~.r.rt"lS(' in n -nul funct ion illlplit·s tha i tln.un lxx ly w"t'iv. hut ht "t.~IllSt.wt'i J.dCN' is 3IIlWkv: clail)' P\'(' IJ in th ree d i\iclc'tl clost's. [ ma intenance dosage · (kgl 70 kg • Typical cdclt ma intena nce dosage 5 To illustra!c' till' lI SC' of tilt.IP)'.<:ll-:c' C '\prc'sst'Cl rt'lat i\l' to .\Il('(' d(}S(· pC'r kilc'1--rr.."llplt' af any orlu-r a~{' .JSt) ('(lIiSUIllt' mort ' pn-scription dm). QlIt'stio l1: \\1m! is th e daily tC)hm lll~·'C. is nun-h luglu-r than tltat in tilt' aclult.ht. an .t'r the.' ially so if the dOl!?: h .

a' ..· gi\1'11 in '-.. ~ ~"'\1'Ar-4lk l t..1 1<... pn"tlit1ions a n . naull' I)'.· . .lIIU ' tlo"L~t · Il ll' ..I. \ ·...." . a corn-ct ion ill lilt' ex cept 1.2 1.' combim-d to ¢\l' tilt' ~t' l l('m l t"tl" atiu n: Ma intena nce do""".tl" 1 !J1\I'm . [We ight Ikglf)7 U5l.nj( " ' . I \J ~".. · .pn.I<' .. .' ~ flllll1io.. 1 aml.I) slIrfaet · an-a in childre-n. · in Jilluh (. Tln. 111t'S(. . which art ' I'slimah "tl fnull a \.""" '11 . ' ~"t1i".6 0. Tlu. ...lr-tllti IWJ'S(m (60 k~)_ Similarly.. . 1io.."\"("t·1l dt·ar.oI.·t'l IIM.11." ill II. alltll 1 ~t'" Nal 1l' correlation (Ib~'n.nuunn-uaucc dosin~ run. t..0.110.unk""'K~· ..~"i n~ rdl.. tl.1111' initi al t'~l i ll1 a lt ' uf tilt' dusa~I' n".5.4 12 4 6 8 10 12 14 16 18 0 10 20 30 40 50 60 70 80 90 Age (years) ':g 0 ~ 0 ':g ~ ~ ~ ~ ~ ~ ~ ~ '" -a => ~ ~ i!! ''5 " .1~ I"lt . ."' . U/~'..4 . .~ a UO')l ·.rn.'j.1 . these .· m.."... I. 11' " i ll.t ' ..·)1I1111 1 ).lIlt·u Ilt't"tlt"tl for a lliltit'n l of any a~I ' 1M.. \"~ri.1..rate of adllli llislnllion is n-qui n-d.N. for a .1 1 l.·IK_ IS-1 2.· mai .~ "i"l: 1'.1"M' .o f". :i . .tli' ·lLl lIf all)' .IiIT. lu llIl plah'.'1..1 'IO N II.111 conceutration i.tj..' "'''I:I. ·i~ll t S ..s needed..Increases ulmost lilwarly between I and 12 )1...". (If lilt' tlt 'numinatu r.i " l: ":'1 f> .t~t· nnl M.. .f"•.f. )661:1 in Ell.S..1. :"0 chsn nction in ~(' IlI IN n 'fjllin 'lIlt'lIls is madt.LlIIaill!t"Il....· .11'li of a~t·..'I' au..lillli "hl. .. 1 ~2. . Fur examph-.II1I"t· al)(l l)(M....1" ..Age (yea rs)] .~ n·I<.. ·ar .n .... ~ A B a: 0 ~ '" .11.'. wln-u mainlell.S) an d iti )'..'j.". ' iI K"" ~"" in "..bused on dmll ~I 's in hotly surfao.~"i"l: It .. I . Fi ~m' 15-12 suuunanzes tl....... this rl'1alionslJip is expn's'>t"tl in Eels.·al'li....a)" ..\.I" .ln et· of tilt' Sitll W an 'm!-:t' unlM. . -' uti' liN . (nnll 1 W..... ~ 1 "n.~ I . [140 . ~ "i lll: r.''''ri~· " i ll.r II..n' .. a 4 '~1·ar.. iI 12-yt'ar-ul d d lild (:39 k~ ) rt'illli rt '~ lilt' SaJllI ' daily doS(' us tlnn -fen-nce iO-k~ lliltit'ul. · . IIUt....• in 1 1:..' ·..5. ~n " .~1 a dult 1660 ..0 0.•iIl1 .yt·ar-old: SoS ( l oin . then.(t'. ml: rat.. In ~' · l1I· ral.. tilt' Infant amll ht· neouate-...t lll!' rate tlf drug .· 1. ..".I• • .an-a .dio..ri l~· ". ma intena nce dosage 6 thai !:M. tth a~I' .InN'" IUN'.. II' ri' n. 11U'~· l'fpmtions cau st'I'" 10 fad lita h' and imp r ove. nf ~ ' .Irt· pairs of a~t' values for whit-Ii tilt' satm.of I ·Ul-A ~t· (hlll~t ·s Iilt lt· IM.lIl11d (1)lt('t'lIl mlioll.-r 10·....>Ic1 {nolll 1 "" ...l lh.'" lin ..' or IU.Iut" "! Il·rtir.IIio". 12 ~1'''''' l.I Ih. ' "••n· II"". 1 . ·r..·nnih IIII' nJ1l~h appru\illlalioll of ..t~ lllati(Jll s (..l lil. .·lwt"t·1I I antl2n ) t'."''''''''~· ..dmillisl ntl itJIl a.-.CHAPTE R 15 )l.10 . " 2. 6 is lilt' pmtlud uf lilt' a~t'-rt'lah"tl "..8 0. U ll a\'(·r.Ill 1M.'i Bt'< wN'I!lI' vulur.IIIM' clearalll't' tncn-ases up ttl 20 ) t'i1rs (If a~l' alld tllt' ll dt'(·lil\t·s tln-reafter .I!-:I'...·al'li of agp .o" U (" ••1io N ".:.II'~ l l'ri. I\I"('.· fm".'(·Iim' ill n-nul ck -arance .. a fr.I" I" 10..t!-:t· w. ~ 0 1..11.t· dOSit~I' dtilll~l'S with a~t· hl')lJlld ) )l 'ar n-qutred tu mainlain tilt' Sim I(' a\"(·r'.·. tilt' usual majnn-nam-e <lost· .ultl chik l (16 k~) n'i l' li rl'~ til(' S...f "1:" .

e: ' .~C atd!-ono. Art' lilt' c:litT un..._•• D.. uot 1111' typical patien t wh o may If{' 5. Comment o n wl l('t1lt'r pach o f th e fo llC:J\\i ng statements is true or false.bl. STUDY PROBllMS IAnswers 1 Study Problems ore in Appendix 11. For )(' t'XiUllplt' . ~lnl1ll' OIlar filtmlillll rate = 120 mlJmin.311 P" )"t'ar.agt' rt'Wlllell of g eutan ud n 10 treat a seven. . Hl'~unc:l 20 yt'a rs o f agt'... ._ Dlph••h. an' hSh'll ill T ahl e 15-4 . \'ul lln l(' of c:Iistri lmtio n va ries in di rt"<. e-. 15-4 ). Cakll la!t.agel!.. fu of 70 mllmin 1I1i1) ' 1)(.. IkIta .7 I1min fo r a drug may indicate hiWI Ilt'pal ic extraction in a 70-year-old pancut po pulatio n ill whom the hepatic hloe:xl flow lIIay If{' 0.. u.o bje:"<.111 reg ard 10 change in phrsi{)l~c pa r.! pa ti('lIls lilt.CHAPrE ~ 15 AGE AND 'M:lGH1 2" IISII.> I1min ..~in g age.'i o r 70 )'l'ars of aRt'. Il. o atd~ . Their find inw. renal function dec reases h)' app ro:\i lllatt'l~' 0 . Arc:' t he:' dilTI·rt'n l't's in volume of d istri butioll ac ross th e aRt' ~n lU ps Ihc:lS(' t'xpt'(1t'tl ? h. gs alld 10 rlu.etI..fE ~ 30665-671 .'s ill clearance acros s lilt. In cluldn-n. J co" . Aw. art' 3' t~Vieill fo r ~u" ng Iwahh)" ad ults. 1 5-4._lJ. sl uc:lie:'tl til(' phar macokinet ics of lilt. :\ fina l no ll' is ill onb-r \\. a n Ilt'pal il' bloe:xl clea rance o f 0. \wight 15 kg.IcI.. The:' half-lifl' of a d m g is sho rtes t in ) u ung ad ults. IO -kg dl ild ? ~ .mg(' ' coucent rution in : a . / d.. e.8 L'mtn inslc:'ad (If 1. 111e:' us ua l adult dosa g(.. ~ J . T.. dt'<lf' U1t1.IIIS1'l1by r.. hepatic blood blow.3.~ I·"dOlllmw.'rt"L ' with a~e ( FiR.. OI1-:t' ~ ~'t'a rs .\'l'f compari sons a rt' made in l)l)il~d. .~i llg Ixxly \\"t' ight. Shnous " I al. A cluld.1in· of ma. st.. . and hepati c blood How = 1.5 L'nun.. Phys iolo¢ e parameters such us cardiac Olltp ut ..v. 2.' hoe:ly \lo'l'ig ht dec reases with incrt'a. a mai n!t'uam:t' c:Ios.ining tile:' salli e a\1.infection t'.. odooIy~ ...~ lyeoJJ We<g'" {kgl Cleorooce IVII'1 8Q 32 Q3 6QO W<Nso 1" V olume 01 d '~II 'bJc: lO'l III """'1/_ <rd. regr rm-n of a drug is 20 mg once a day. renal blood How. a. antihistamine dipllt'nhye:lmminc:' in cluldn-u am i holh ~l ll lll~ a lld dde:' rly ad ults after i.inta. udnnulstmtiou. h.~ tl/ ' m gillOsa wi th tln.1ec:. :\ correct ion is also worthwhile m cmeciated and ohe S(' patie nts.II adult dosa~l' is \mrtllwhile wln-n adm inistt'ri ng d r u to the n-ry}UlI lIg. . Simil arly.)" should 1 d une c. 11\(' values mos t \\idely quot ed.Ulll't ers co ncermng s a~l' .~"" Q8 1223 ' 70 32 6Q 71 50 Q66 ~~ood"""'~..e.t1if)' )uur answer whe n )u " tbtnk it appropriate.l? ('n' 3. O ral hio:l\"ililahi lit)· increases \\i lh i nl'n'a.1 990 ~ Pto•• <.~...1 0 I.. wit h normal renal Iuncttou fo r its age._phl• • 1HII ..m 'fully.1". . \\11al darly dose would )l JU n-conum-nd fnr a 3-) l 'a r-n ld . age gro u ps those t'xpt"<. . a renal d e a mnt1... e:'li llitl 10 ' 1 til(' GFH of an t'ldt 'r1y patien t po pulation . Qu. to t he (-luld. \\1 Wllt.r.1 p roportion 10 hod)' wt'i~h l ... a lld ~lo rne: ' OI l a r filtmti(lIl mi t' c:!e:"<.

.2 iU. '1-· ." " .lIlKI'ill dm ~ di slrihutinn with a~e ' is nhSl'fY(...'5 sunuua ri. c ~ 15 E 10 '" Eu 0 ~ '-' .gI.'ars of ilJ. 1 .. \ .·nniI.-..:I'.. Tahh.tml'\(''Okilll"lit' fiIUlillj.ln illoli"iol".trk ..h. ' ..S Tn. He ual .. Tl n.IIhi dl '(l into tlm'(' a" t' . All Hlil'? 6.-. l/-t...I.'}. : \~. . .(... 1 .... Fi~ m' 15-1 3 Sh' IW~ tln....tilt" ~t' l w ral implicanous o f tilt' filll l ill~ for til(" admillhlmlioll o f ceft riuxh ..13.. Fortv-t w n of 1(..... a. 4.J .....(1.. .1.lIlt! hiliary excn-uou an' a bout ('(lua U ilJ\.ol." mps: 20 10 3 H }l·a rs .... I!M 1I1 1n. h .lll('(' ('ll'r ~ l lIan.( and hiM· life an' \( .( ('< ·(trY." rll. All suhjt '('Is n'('('iw"(( I·it hl ·f 5 or 10 1II ~ om lly twi ce.01".suhjl'(1s wen. with nor ma] n-nnl flllldiull 1 for her a~I· .va r iatkm in dl'ar..&'''' ''-iat I .(ollht ft·llld ip illto IlSl"(1 . (l) til 12 hr ).) U r 't:-' ebk-rly f"ul<ile p ath-ut.5 years 16 years 33 years 61years 104 ye ars Age t'I". \\ 11at an.. C"·Mr. 70-k~ palit-nl ) is I mWk~ adm inistl' n '(l i n l ra m "<. " .. ( ". ~ e 5 • • • • • • • • • • • • • • • • • • ••• • • .1 "1m . Ch-a r a~(' <!e!'ll'lIIlelll.(1.~ 'S ..\l JIII· ill ind i\i dll als [rum ) Illy tu 92 }l.. ".~.(' ('xI'll'('I('(1 t n-m] of ha lf-lift' \\ith a~l' .IS.I..1".' S hr. (-.. in ti ll' lIIilllil"l'lIwnl of h)l'll'I1t'n siHII.In 10 5~J )l·ars.' III..'). C ....· I" '. W_ I ~ ... TIU' adult dust· of ~t'll ta lll id n 1lS1Ially 1"(.lu.> ( :o.oltl...(S. OIII U .t<Jimillal ion of Ihi s y ulw dm" in normal ad ults .. 1 :Ii" 1"...al s. Blydwrt l.('lI la fl~' I"\l ·r.(lkilld i('SHf the..' ('('ph. c.(1.·Ilt....Ib ily f OT fi 10 30 days.: ·• ..• 11. "" hio:b i!.\ DIS P... This antihioli (' is allllllSl ('o ll1 p le! l'Iy renally (·x(·n· h'l.. 1...do:.c~ IIr I .~ tll !:t ~" . ...IIlIl t'han. in a ""IIIP of 14f) slIbjt '(·ts .iw II Ihal IIH dl...SlIj'll'rimpnS(' on IIIl' ri ~urt' 11.7n -M . :\ p rl 'mah ln' infant of ("Il11('t 'p t icJllal "~I' 3fi wl't. thr p""" ' r . • • 'i -0 • • •••• • ••• • o 9 days 5 months 2 years 6..'" r. e ..246 AGE f#) W'EIGHT O W TE 91 5 20 • • • • • • • E .1'11\ also n '('('i\"("(1 tilt' d nl~ inl nl\l 'Unllsly (eitln-r 1I.. c.J ' lSpo n u alllihintk' ('t·ft ria.. .lO .tm ' tr.-h..('"d l d ll lll illlla j. la J U mit 1....( UZ....'I al. ru. ~· .· uu-te-r (u lf ) Il f I MII I~' sUffa('(' an-a of 1111.1wilh 1 .. S uI<' tlo..''('(1 frulll I tl. .. nne] fiO 10 Ml }l'ars. Wt'i ~h l 6. ...1St..~ tll l • .. il~(' S'j yt'ars. .11 (rulll " ~ t' " '. 1. Dist11SS bri('lI~' Iht' dlilll ~I'S Obst'f\'(.' ..". dt" ardlll.'(l in tlu....ut~-S i ll n ·ftri."i(·s in ACe .('11 .p·ar.-h .1\0.:).5. till' d(' lJIl~mp"i l' tliia am i p!l. t:.. stud it'(l til(" phan llill...(ll1llllt'fl(lt'l:! (fur a I)pi(..n-l<.r ~'.

\ \ 111'11 atllll in ish'rill.e.e..Q28 0 041 0 052 .. Ih rt"'l' t1m~s IIRs 1)(1'n fou nd lx-tweeu olll'S(' a nd normal \\'('ight slIhjt"'l'ts.e. CUlIlIIIl'I1t 1111 wlw lht'r till' d istrihutiull of fd ollupim' vum-s wil l.n ~01 '*'"' to. Table 15--ii lists mforrnanon o n till' \~111I 1Il(' of di stri llllt iull u f t hn-e..t.rt'lnw('f in IIII' nl'M'S(' illlli\itl ua k In contrast.. Eslim<lh' till' l'Ilrrt 'SI'M lmliu!!: oral hilJ. "<G'" . comment Oil tilt' 1lt'1'11 10 adjusl rlu.llit'lIts.e.I\1l.... admiuistrutkm a mi that till' t1 m ..t1m~s ill <~ m l ml and nl)('S!..e...v. . 1 ).IMrt'lll lim!!:. 'OIl .l. 70 30 40 "" "~.t... a nonpola r dm).. _IHI •••M. un tla.""" 2~ 3Q 4~5Q """.iJ.a""..v..e. for t1ifT('f{'llt1'S in .t'.".>.. parann-n-r.. 1' . De • . M_.IS ol)(. ">'!MGt 1I:"" 0 0l' WEIGH! TOOfAl.'tt'1l values wt. if his or her \\'('i. cwn afh-r <1Im't. an iudi\idllal was d. \\1 Iid .- "" .. .e. a!!:l'? f. \\1lal ll1t·t. a ('1111(1'm ('xisls whet he r u r nol duS(' t-' sho uld hc' \\"t· i . .'tin..._. tln. Illta ill lilt' Ilm 't' su l~n m ps ap ply In all lhoS(' in r-ach of lilt' n -spcctlve ill!:t' WOUp".. I . ID-<j "'''' . tilt' wc'i~h t -{'llm't.... h. :\" CI Si ~ l i fi l'<1l1 1 di fT('ft' nt'(' in plll'illla btndtng of tlwSt.. W mu d l ~n '...UIl.. 0 68 0 82 0 64 0 45 ~ 24 2Q " 0.lIl.IllSWN to p art ~l'~? 7..-_.-.AGE AN[) 'NElGHT 2. \\'illl ad hity rt'sid ill!!: in rlu. ~ -.l'.\C't tin suc h fimli n.lhil ilit"S fm ('ad . t1 m ~s 10 ol'M'S p atu-nt s... Q ..47 143 153 165 16 2 164 91 98 95 <I.'" " ' " OO>NG .iIIswI ' ri n ~ IIIl" IIUI'shullS below. For Cl.e.. \\1mt t"plains till' t1i fTt'n ' nn ' in IIlt't'fTt"'l't of ol)("Sity on 1111' volunn.1 S-. " .. (O to 121tr) with iucrt'llsin . d ..cleunmcc values t"Stimaft'1! from till' t.. IIII' \lIl11111t' o f dist ribution of t1ill7.. comment OU tlll' 1ikt'1y n-ason fur 111I' oml hi ll. Wlt at illljl.. .l'il' ill AL'C.'tI'11.ht -{~ lm't.." Ill'S(' .c:h t I'xpl. <b'vo<oI <loM III ..' hq )illi(' metabolism.S(.of di st ributioll lilT ('(It'll Ilf tlu.'p..'''''".7 .e..e. rt'hrinll'IIS uf these t1 mh >"S'~ .e.ruup.l.. a. 76 88 77 "" .lS bl Kly wl'i!!:ht.lin ~"lIr ..\~l i lahili t \' values .e._ "'... Individuals..rtlllp.pl•• _ .. llCO'f WE01lI'\l 29 981 2Q2 27 937 91 032 107 281 0. ~ ~ a J CJ..e.clm._pkl.1...s 1m\'(' 1111 lhl' dl).. :\"t'illlt'r t111'1lpI1o yllilll' nnr t1i!-:o\ill.lssifi(''ll .ht fur llt'i ~liI wa s in t'U1"SS of 150% of idt'all'MM: ~· wt'i!?:lIt. II1nst likd~' exp lain s lltl' ill(:rt'.'s t-'xh'n sh'l. Ci\'I'1I thut Iitt ll' fl']odop illt' is found ill urin e after i.s? h .O]Ullll' of dis trt lmtjcm 1)('I\\·c"'l '1I 110nlMI und ol)(. .'h anislllllli.CM 10-12101" 26 52 17 12 13 A~ 60-80 "A!.ten _IHI M __. a.. D.(. e...C "'~"""'''''''''8Iv<_ t Jl 1~]4 lQ\ll . n ·laliwly p olar dmgs.e. "hlJ\\"l"'l1 it t1ifTt'n'II<1' in till' \.doS(' o f fl·lollipilll· for a. DOS! .II('f ill tln.S!.

Eslobli!>h. pn>Sl-'lIl't' of concurrent diseases othe r than till' O lll' fur wlnch a drug is IIst·. 7 . of SOIl1(' t1n1~S has la -en s llm\ ' 1 10 1)(· illlhll'lIn't1 hy tht. 8 . using phormocokineliC principles.an' oc casions when Ihe plnmnacokus-ncs of a tlm ~ is altt' n 'tl ill 11ll" di Sl'll<. a. cardiovascular. tilt" an -a uf prillt'iral Focus in this 0 chapter. 3. on when oltefOlion of drug odrmntsncnoe should be cOMidered 101 patients with becotc Of renal d'secses ..t rt:'sp.l'S known 10 arret_'t dnl~ killt'til'S anti l'Olld \l{lt'S " i ll.l' listed.. DISEASE STATES The pharmacokinetics. .riahilily in dmj. 4 .1ISsiull o f t IiSl'iL<. from phormocokinehC principles. In lh l'S(· Il<lti. An example is illllllUlI1>v. t'rt(' nsi\'(' rh-tatls 0 11 atljll ~till ~ t1n1 ~ :l( llTIini ~tr". .of \~d. the pcneors age. " It' chapter hegi nli with a ~t'Ilt' rdl di M.'i tln.·nt.· S.t· is a major source. ami n -nul d iSl·il.~ 16 DISEASE OB JlCTlVIS The leader win beable 10: I list a! leasr Sill deecses in which the phom'oOCokine41O 01 drug~ is knQlNTl to be cbe-ed 2.. .l' for which it is IISl't1.S thi s \1lriahility "a. Then. mM·.1. usr and brieRy discuss the phorrnoc:okineric pOfOmetefs rhol ore chen cseed inpotlefllS With hepatic and renal disea!l8S.l('Od~.. For lIlan y (LM "t. ' is tim ' primarily 1 d ilTt'n'III'C's ill pharmacokineti cs . 6 .<.. 11-"''''11 in IM marrow trunspl ant p auents lIlt' for Ihl' prevention o f cyt omcgalcvtrus ccmphcanons. gender.mlll i('S .1 Examples o f co ncu rrent diseases that illl' n ·ll.Il i()n in patients wnh renal in sllffidell l ')'.• vart. Sketch /he OrTlQUfll in ee body with lime loIlowing the do$oge 'egimen fecommended in objeo"".tion eltcreted unchanged is deoecsed in 0 PJ1ient With known renal functton.loblllin. whi l(' in normal subj ects it is 22 clays . list the O$$UmplIOflS thor undEKlie the application 01 renol h. Esrimote how much the clearance of a drug of known froc. a dosoge regimen !Of the pot. mlllwly !Jt·Il<ltic .hility ill dnl~ rt'spoll Sl' are ltsted ill T ahlt.l'IL<. 6 .. 16.~ we ll as th l • pharnl.. weight. and 5. Judge.ha lf-lif(· is :lIM Ill! 6 .nchon rests in d<»oge regimen odjU$lmenI for patients with renal insufficiency l>iSl· a. 111t' subsequent dtscussjon centers on Iht' first tlmO(' ~n )lIps o f t1i<.2 days. Estimate !he creatinine clearance of a patient hom serum creonntre.ent in objecrive S.

.oed.......laO' o . • ---.«>" ......... .""'""" C>".--........". N' roeo-l sensilivlly ~educet dose 10d..._ .o:edo::-> .::l......... ...atIOl1 • Cleoto<>ce ...labMv'no. Br nch. eIoMJle. Gd... .~ Th_ " "'""'"'" FoMJOC cod C.. "* ." "".. .~ !.. 0Cfr>0e onIv In ~'" ..-oc. . GenIOmO<:ln G<o~ . 'ed.· oc.." Cor d >OOC!l "" d. • . wi'" c....".::~ ..0 ~·co..... • N' !Mpa"ed fhelOboI'vn ~. ...-. ceec-ce ~o.. ~ • Pe<:ko do>e 10<MlKl e><CeW>'e !Joop....~ DI.. .d doe to d . ""' .ne Doc lo........"~l '"""""'.m...CHAPTI P 16 1)5£"" .... .go. dearance oeoeosed..... t"'d<X' . • • . ...... • NS .pl...uen .lh«I~ ".. 'edo::" ~~.. 01 ... d..l. C<.-e ..d lI .."" (). rot Ca<d'(M}"'"lar d..l.. V ~tCNN ......••••pe...d..... . doI.due" do>oge 10 ~IO><'C'''Y W"rb.. ""'-' .. kT>"'Ola''d1 "9"" . ' PecL:e dcoage 10 leo.rbuban "'""nlol>ecl....~ ' ''>pm""" d ""~""l "'"'~ T oll:o.........."" d.""01hemorrhage """ ... .. dnt>boo/lC hc>t!o>ed 1Ol<iC'ly ""...ml"'''' --~ . • .....r1Om"... """"""'" ..lIlty I.oLrn.--:l 10 'ed.... .. Taltl•• 6--...ooboI~.."" 01 ""P'fO'OtY ""boo< Reduced(J//..n ~..~.lI\OI IC:l'< ..ogt Penal cleo<anr....ng lime Booo-o...."" cllO><iC"Y Pe"'<J: 'h '''''''' ~~.educ" n..-.t... Coogo>"~ =d~ -" h I....-IaI irl pkw........o 000 I\c.._ S..t. Dr.ed.ne . "' M:xe <opod IaI in CCII\OIO-=-oOtl .......~ c... Qv.....Noej ""'"".. Auecl.b< OS>l _ -<--"... [)....-.... rna.. .. """"""'" .nl -IW>rph...i...... COiOti"""""ak.........1or loI<JIM NS ~... <i '""'<c ---d_ • • • •..n _ " lob ......" Hwogfve""''' "9"" .........00 1 "9"'" "'x'" ..... 01 d..m j"..o....o:e dosogt 10 Io.... usual dr:...~""" na d '""'''''' C..dgt 10 ~ .1IOlolld ond/(J// dl!l(JIIO"ICe NS "'bor.. Ovg eIe.. '"-" AA!>O'¥m" """"'" • CQMWN'S Sb. ~cJ -... n.....~... "".. ... .. .....>eO"" "-"".. dc»e 10 \e$wll~ rJ 10><0<:''''' AdjU$l do»oge <XC<JI/d'''9 10Ihyfood OC!''''''' ....~ ./- C""'onc" o... .....1y --..'" oIlO>. ..~ """1::0::..n .~ todoc".< . eeoc C>SS Q65EVoi"'tCN "''0 """""'0 """"".o<:... IneNaNtl Va....... ...""~"..._.e doml"...."9...""..d~~n -~ .

'\'ilh few l'Xl'('Il- lion s. h.l'>S 1I1(>1.ltic s UIIlIlIt' o f distnbution is found tliSt·'L<.>t·'L o n d m~ ahso rp tion is I)()(lrly understood.l. d('{· n:·a. (hitli.clearance o f d n lJ!.. for a duninisln-d ln-panc 1I1l1 )(Jlmd dt'anUll't· tlf IImny dnl ~ .and volume o f tlb t rilllllio lJ. t1iSt'ussiun.l'i('tl plastnu h imli ng:.l'it"l.)(:i alt 't l i!l('n'. T ht· ot llN is Ihat lIIan y drrhotil' patit'lll s dt'wlop 1)(lrtal hyp .lSS ht'pal k Ins s d llt.lIIl.{'t l. 11lt' rt· art' tv. Half-lift' is (:onl". iIlNt ·.l\ sul1alt'tl increase ill volunn..url~' (. Tlu.S('t1 s}ll tllt'sis of alb um in allt l Ill an~' protetus. Anotlu-r p otenttal pitfall is to t'fIliait' prul(Jl1~ati(Jn of Imlf·Jife..1:t't l th an tlltlSt· t'!im illillt't l hy ("l.· thl' [iver is the. 1)("( d t·aroUll't· thai t. disonlt'rs of tilt' her-r.o nk-rs lL' II sillJ'lt' entitv.l\'al sln mls l'all g("('a ll}' illt'n· il'>t· oml biuavllilahility: an illl'n'll<..lmtt' t1iSI)( lSitinn From al}<.\ful. Fig:.(' lIa."mN'.dt'pn:'l.t st:1 of ('tJfadur n 'q uin 'mt'nts al u! t'adl alTl't1:t'(! to a di lT t'ut c!t'g:n't' in N . Atlt'mpts to t's tahl ish SlIl'II n '!atio n\ sh ips. and th uS(' for whkh 110 eha ng:t' is den-en.(lIIw ntmtion \\intlow.t·. CHAP1£R 16 Hepalk Disorders Ik(~Ul Sf. th at tilt' orul h ioavailahility o f tim"' lJi ~hly rs t'.<. ind udi ng: variuu s t' n0 1lWs and dollin~ fa(1:ul"'i .lth\\"lI~ "S of t1 m g 1llt'lal)( IIi ~ Ill . Iht'n:' appt'ars to b a f..\o: this impn-ssjon.lIt't l hy I)(JII.\(· nu l 1)("('11 It)(J SIl(1. am! Iht'tm 'lit"'llly a t"tl rrt'!al itJl\ should t'\ isl !)('hn't'11dlall ~t·s ill tht· phannal"l.dtioll to a diffcn-nt ('x·!t·nl.ttit"dt·ar· a1 ll. whi lt' ~t'lw nllly SlIpportill.. lola l ck-arano. first -l).l~ .t1N ' it is l h i..d dm~s appt:ar 10 he ilio n ' afTt't.ma (.explanatkm lit's in gs rlu. tht ' f"(> an' llllllWn JilS 1). III contrast.of distrtlmtkru .s is. II ).. I I an ti 12). 1)( F m rn th t· furt' goinv.major sill' for d nJ~ lIll'tilho!iSIlI.l'>S. Ont· is a d imini. Ohjl'1. u nlike d Ol~ t' x('n'lio ll.lr. To a.llit' lIls v.. TI ll' n-sultant fall in alhu m in concentrat ion is n-sponsible fnr a dt'f:rt'.tril'(·S.'lt'all apprn'Il-l. a l'(lIld itio li ill whit'h a sig: lirit'allt fr. tln. h ili. 11 1t. all imp res sion p n '\ " ltils thai special care slulIIlti ht' tal('11 ill atllllinistt'fin~ drugs to !).d E.l'>St·s pa rt'l lt'h~llIal lissllt' in till' livt'r o r l t'Illt'1"'i t1in't:tly into tilt· Supt'rio r \"('na ('.1 llislII...1:t'tl 10 1)(' mort' t'\h'lISi\"(' for t1mS(' tim"' d im ina h 'tl pn:'tllllnillanily hy : .(·s. II tJ\\ '('\ 'N .lIll'(·nlmtitJII OIl pl.I~t' may Jlt't't llo 1)(' ("('1111('('11 ill palit'nls \\i lh ht' I).ltie fum1:ioll in1lMimwIlt il~ a rt'Slllt of 1 )(ltlJ d t't' rt'. ('adl \\i th a dHTN t·. TIll'St· I)(Jrtal .>uhstalliially dt ·p ("('l. o f Iwpa ti(' ory!.-en tlhision h('lwet'lI Iho~' d m~ for e whid l dearallt't· is rk-cn-ased..t1 iu lI at p).o f a t1istrillll tion.l~(· .l<.II)' ht'l).L hl't'n rt'I)(lrtt'tl s for Slllllt' t1m~s \\ith t·\!t'nsht.. is li ll~ data S U~('st tha t dmg: cliuuuanou is tlim iu isht't l in ohstm(1:i\"(' ja ulltlil't·. All adjll stllll'1l1 ill t1tlSOlgt' is pa rt il'l.1t 11U1I~h t'lIl'()ur..u n '<l-'itlllS for Ihi.Ilarly warranlt'tl w il('li Ihe usu al n 'WI1WIl n:'slllts ill lh t' lI11htll llltl t1 m g l'UlIl'(·utr.~ .dm ~ sho uld ht: ~ivt'll illt m\·t·mlUsly 10 t'IISUn:' co mph-te bio. An lucn-ase in V pa rt k llbrly wi th d r u bouud to alhumtn in p attents wit h d rr hus is.( '(1 o n unl )( llInti dnl~ is . O il a\"l·t. 16.i n~ or t'X ' l't't '(!illg th t' IIPI)('r lim it of tilt' Illl' m l)('lIlil' l. an .\\ith t1i miuntion o f ht'!).(lIltmls Iht' 1l1l1)( lllIIti dm ~ l"l.tr:\("It't1 hy ti lt' lin 'r is iJwl"t'. tCI tlt'p n 'sSt'(! lwpato('('lIula r s a(1hit}'.{lrp lioll when allalp·jll~ p l. . 111l' pmhlt'lJl ' '>t' is 1"l.u)" excrettou.{'t1 in d rr t. thnll ~h .L Un ' tlf 11t'I).25.IIIl't' for a t1 nl g o f lo extraction.~'t l in ci rrhosis. or hal f· lift. T Ilt' illlllle m "{' of lu-patl c-d i. A fall in hepauc t' 1l0 'l1t·s is w n-sponsibh-. p mltll l~t'tl . i ll l l lt·~ · p atu-nts .('.. vailahility. t'SI)("(1. in at'uft ' virul ln-patttts.. nlt't ahol i zi ll~ act ivity.N·.Iva \ia l'Stlphagt'a l \.Ill appnlpriatt· 1Ilt'..~ wllc'l1 Iht' d t'ar..1 dt'amnl'(' ant! im '("('il<.llt'all (Sl't' ( . ht'tl firsf -l). lilt' vnlunn-s of d ist ribu tion of some d m g: remain unal n-n-d in 1lt'1). It is likt'I)·.lIlj ll~i1ti (JlI .1in· data. This l'(llltiitinll mist. .l'>t' in d l'ar..11 or d ifTlIS(' . .llic tlm~. hut Ihu~ ' of ot ht·1"'i are incn-ased.osis .{'(1 oral h iua milahility.(l!I('('ntm tioll-linw d ata . an' Ol"l'a.sionally ill t'Clll flid ..haps...t~ng:. the. 111is failurt· prtlhahly ariSl-'s ' 1)(' (.~st'SS clearance and volunu.ani7..s . il is appa n:'nl tl mt t1m g dUS.('(mllk-! arist·s Irnm an attl'mpt to d 'l. II t'IMtie t1ys fllllt1:ion is a g:rm lt'(l pht'110llWIIUlI .{' of gn 'atN than :21111~ h.I.bepatic. It ll. (}IIt· n-usou fur rlu. alltl .U1It'h'rs o f dOlg:S.i lh di M \(' stat es lI K )(li f)i n ~ Iw'iL 1'I<ltk (111111ioll .. an' caused bv manv di st ' il'i(' S.tlie fU lldioll.J1llp lim lt'tl h~' li lt' IIt'('(! In <.. each diS('"~W afTed s various ]('\"t.{'I).s i~\' lwpatic-di .<.l(1:inTl o f tilt' I)(Jrtal hlt)()( 1 b~l ).1. and an . t·tTt't 1 is t'XI)('t. h\11 lud ep-ndcnt pa rall lt't t'rs (C hap . in la rgt' pa rt . \\llt'n "'J stlltlit'tl. t· .lkindil' I).

..tl1iw Ilt'lliltitis..I." .. Alteredmetabolism in chrome persisteut ill'llillili\..> t·l ·····f c ······1 100 40 300 200 100 50 ······1 ~H " 'l" '" 1. ..J...l'.. 16....Im.1l·li.h"n (t.~ n.. TIll' ccutrtlmhon u( ( 'ile" lliltll\\'a' · to tota l dnJ~ elhninatkm illSiI \1ln ('s with th e d rug. dccn-ascd.=.1.. "''' n 'lti' '' 3: -4 .j !inoe) "". au clec a n -d c1()lti n~ u mc (p mth m lllh in umc ~n. 1.OWTEII16 251 ls-pa ric drsonlc rs.lrt'll t that w hil(' tll(· uct ivitu-s o ( the otla-r th ree l'IlZpnl's arc Oil an·ragt· \C... In drrhosis.).T1l('ll~lIn'll in )j\'t' r samples ohlaillt'l! h.m's n-.. In <im .ti"" .. inK 1'1~ " "'n i ll 1l•• JOna! .M.d l'll. till' phannaco ktre-tics of ti lt' ))(·!lIJJtlilUA.... Ill" H<1"'. ·.l .11h d rrl .1 .. . 100 ~ c 0 <.Ii I" .''' ' .:.1 i."'u1l..\ u....in n( pn.~ o...1. r"I i "K." ~·. · I . I'ft"'• . ·.. · ." I.. ln•••". .01. 1 .. K-'M'lrall< 'm .11n1llidalillll..'T'\.idly incn ·...1.J."hjrt.(·1\ . I. h" II')'· I"·rm i-.Ii ""1 ...indi..( .. I.l . ..· Tl-' a. (""'IU' :!: SE )... . wh ich is r-ltnnnan-d al mnst t'lllin·ly hy glm...i l\" and others in whom \ 1.\ Il I<. '' "fl"r .il·s.. t.. t ".. dlnlllic . ".. a nd ti lt' aet jvitv 7 n'lIlilining In tjn. 700 ~ Control 700 400 Cirrhosis Q.> g~ c c _ ~ ·QE ~ 400 200 c 0 co _ _ c ·~$E 1 200 ~ 5~ 8.'it't....• " f dm "" .........ls n (tt'n lx-en rep orted... albumin (less than 3 Wd l .·hiop \.lnlK .". 1l alll i drrho~is ts llw n '(()n ' a funct ion of tjn.Ii 1".. 111t" ( ' II/lUll" activitie-s wen..n W..t .OIllhillatioll of a I(.. .1. tl m~ metabolrsm is ofh-u t!t'l. ..a..lvt·N' reactions. . G lm1Jnlllyltmns(t'r"'\f" app('ars to ))(' unaffecn-d b n-panc yl di M'il'it' . G H.. the re an.· is ilppun'nl (""1l tilt' act ivities of (nuT ht"Jll...'..( .1.1_ an. H.. f"\idnon.. Thls \1lriahilit.idllal palit·n t.I " no!.hiht:o' of ['n" nu. 11..1[' n.L It is also app.\1nt· in\'nl \"('ll.""nth..!upat l. siWlifit'll by tjn.·.. lrnin. In M.1 ....Ih 1""'1 . is 1IIlafT r'l1t'll ill Ilt'jla t k d ise.·al l· r than 130 11 u ( 1I0nlla1).i" lit In -. 50 o 2 4 Hours 6 B o 2 4 Hours 6 l~ B n " " f'o'. i_. '>r. 1>10. · ..--l!i "cl .1 ".lfl uf .(. 1". \11 jR. (.L\('l1.. "'h..I'''''' '' ol.lio:"lu( til<" 1o:1. "".· pilll' U\alJ'pam.. f".tic ('Il7). and till' prt·sl'lIl" of l·Ill't·p ll..\ " 11..• Wilkin "."·h· n ni" ...I .. I...· U llnh . spn nsibll' fo r l."Kth."d.. fn.\·t·rt' cirrhosis..(.' sonn.. CIi'I... Ir. Sup port ing this observatio n.mj ll~lli io n n-acnous ( Fi ~.(· clost' and 1lI()lIiturin~ lilt' pa!it'nl fur !d. ·nl h .· InA " ...J hin lIit.•I.. IIII' slIhs lmlt·.iml h idmtls with normal .. 'I-_ 7.i metabohsm fn 'fillt'n lly requires n'lllll"ill~ 11. '" 1 .. Im l/.. Th e <It'l..' " .. . litth1 1h i l) n-nuuus.\J-J. ...4) ". a com-Iation 1)('I\\1'(' n tilt' sew n tv of tilt' condition and till ' Iikt'l illOtJtI o ( d-p n -sv -d metabolism by uxida lhl' und su nil' ('~lljugatlf)n reucrious h.. " 18r. • • ..\. <Iu". g a.. 1hL. · I''' u l t. "r...I7 !""'Iit' nl ' . 1).p.( II. tl.ni" .. n.. (I "'WI. s h.9 ..."n·...ft."U. 16-2)." t1K.. . 1 T 40 300 200 100 ~ c 0 0 Q. I) .

... '~ ll r...". r ' Ii.. Ilowt·n ·r.1t.l llm.... L EX('t'p tiolls an ' tilt' hraiu sud tilt' lIl~ucilnl i lllll ...".an illl'n·'N .· ...1 am i .. "r'·r.lIt.roL. n sulr<t"" '" "toll": 2... J."'ic .I<'~~l r "r..~. l h~ II'" n..lnu... is truly 1It'('(lt'(l or if lUI altemutiw (n 'nally excreted) dm~ is a\<lilahlt'...md lu nJ't'slin ' ('a n liat· failu re.. ..1 d rt'ulaltll)' stall's. ·r. 1 irnl'lie"l ic"" (ur .id l illd udt· shock ...• for II:lub'II'i"'''' Iran.·..1 (A. i t is 1101 sll rprisi ll~ thai tilt" pJlanll.. r "71'... Ith""In "..l(tlkindks of dm~s llIay 1M. A d iminis llt..•" ...r.01)' "'llt....I ( ..) Io""'an I. "'ir"'I. " ....."11 ... w ith all . ~.JT '''1. dm..4.· m nj"lI:alilll: ""~11""S.hod y. ·rs. T"Inillilli.1 1.. Hr..·r..""'" 1"'P"l iti•...t'(l \·<&-"t:lll"r pt'rfusillll til n nt' Ill' ilion' parts . • • 3 "" n K.eli ".." p. • • • • 6 4 c..\.."j"It"'ic"' l"'dl.oh.1 " Ir 'r. ..1 rolf . ""'1 . .5... 1S-2..... eartliat' Olltp UI . k.•"till" .... f. alltl t·iln lioa(1i\·t' il~t·lIls ...." . l..........· d".1 kl " lrUl1l1:lo..• . in li.u (.~ ~ (2.u lalury tli'>l lr' ders . in ' " " ''' I"'Iic'" h ..·.·.." lIlmll)' ilt1illJ!. .. "1'1.' Oreulatory Disorders Circulatory t1isonl..pl . f. C . S'". fo'r.• alld ...ly...tlIs dim inisht. tilt" rate Ilf atllllinistmiioll of a IX llus dust· 10 patients with dn:lllatol) ' d l'pn'ssiull mu st 1)(' 1t'1Il!)(·n.luced. pat ihs.. tI. . • '1: e & • • 0.. • • .. partkHlady ill th(' ('arlit'r monu-nr s.' ".." ....1(1....I... I~ .... . ''''~llll'' ..1 by d illlinist.....l.... M. 1. 19'1lJ. . ~'K. and dilllinillioll .~'Ilr.nil: ..252 ~"' AS! CHAPTU! 16 Blucumnyl- transferase Sulfotransferase A cetyltransferase Glutathione transferase 0. .101 i. ' ' " \...L M ..I>. .0"..· IlIdpt . · ".1m"..... I)o·... Soc" k ri" i.v.ul...r-. A ......j(1 and muscle. • ...n"...... I" n "...."..2 • 8 8 0 E 15 ~ :!l ·e ~ c 0 10 E §.tr...8 0..r.l.· hlootillow limy illllm'lIn' d m~ ahMI'lltioll .f tI" .5) 20 I • ~ • • 1......l if till' rtsk o f loxidl)' is to Ill" n .1 fraction of an i. "~.o t :\ . .drug inlm\t'llll11sly if a )(· pllllllpt n'SIXlllst· ts t1t'sin'(l..\1' h.... .. \ " If"lr..M .·~· ." ..... ma liJ'lIall! h~lx·rtt' llSi()lI . 110 d.~· ... • • 6 4 2 0 A 0 0 t l.1('..1 ...~llr.u.L. ..0:1 0 dnt.~"an' " . ...... 1 "f ....f tiM IM....u...1. Fur (' .. .-l"l. ~ .1fn.': .. an' "t'lwmlly d lar'1l1t·rii"t... ."i. . ·. lp:oTt'... ill tln-se t'Ollditilins Iht.1fn" ll P.. S .. . disiri hutillll. t' ... holli S dose-...'I..' nln-n. of tln. 5 : ( -e: 't' ... 1ill d rt. . wJ.. 1 pt'rfusioll of absorption sitt's .\f.ive."'I" · " " "Ll" "".f.. .....1i. ".. 'rmtlt' dm~ absorption...II~· ". Ad i itM-S ur tl..-ds to conshk-r if all t'Xtl'lls iH'!\" ll1t'tllIM .... in "" n " a1 (hl..lS'>I )( :i"I<'(1 pmtr... "-. Gi"lw'i. kiuetu-s of d istrihllt iull is also arTt"t.n"Io ar.·I.i(' 1"" "". . If..>11. P1 wn""onL 3f..\ f.. ole.r" r 1 h'uf"i 1 wmpIM fnlln p. ..·.: C. 1M" ... Slm1.nal'lIt"..!.lA 2'.M 'j"~ic. mn...l ~"I.h"" n n. n-nds to Ill' se-e-n ill pa lit'llls with dt·p n·sSl..<J'I" 'lll' 1 1.luch t1l11St"(llIt'ntly n .l l1lnlin\".' r~.liZt'(1d mJ!.'. In tlWst' t1t·pn·sSl.1 hy tlM· t.·IlI.lslmint t'stillal lr..-: p-atlli..f. .. it lllay 1 nt'l't·sSiU')" to ¢ n ' tln.4 ..l'i(·ular stall's.":IoK'ln" '~ 1tfll"....... 11..ri ll"'ril~. "" ' -.N ·.. • I • ~ • • A i ~ 2 0 • . " lV.... with perfusion In lllallY n~.

.· ~n. TIll' IIf reduct ion in n 'lml d imillat ioll depends on till' n -duct ion in n' lIi11 fuuetion.. i\ co 20 :5 S u ~ ~ ~ • • • • • •• • o 0 •• 15 10 .· ~ ..· al1hit)' ). 11t·1 1t1 'l. IISt"t1 as a d~llall1il' te st of ) Ilt'palit..' is llllist p n illailly al. 1 depn'sSl'l1wlll"lIlli·rfusicm is Sl"\·.pin..')'auim' ~n>t 'n ...1 dn l~s is (·xl')(... .Iimillisht>tl: thi s \'o'tlllld furt he r dt·pn·ss till' (·II'anlll('C·s of both lidl)(" .. n 'JTt"Loli..1Il lll"t"lis information on whit'h tIm h i\('('ulil ulat. R.. ilion ' impo rtantly.Ilien t \'o it!.-vr-n."Io:.."."S(' RENAL DYSFUNCTION In pat it'lIls with l'C lmp ro1l1io.' . n "j.llso w n-duc..nlia· {..:\.n -llr. .. 1fi-.l lu-patlc blood Ho Sohc't' in r'i ~.l.1 (. sllll'\ll In en . E\ id"'nl"l' 1 s ll ppo rt i n~ thi s lu nn 'pt is il1 ustrah. 197'1:..-cr-n lrigherIlow rates. (.LS sllU\\ll in Fi ~.-pri"I.fj~lIn' u1 n 'm imls us Ihat tilt" .' in d" "tnuu... ..M-..'i -2)..i'M' ki lM-til:s pn.....I I~' .is p. Tlu.rinwll of amikadn is ad millislt'f('{1to a pati e nt with n-uul fun ction that is only J7ll.· of hi~lJ ly ...... As Iidnc:ailw 11..ara. It"n'''' Zil" .• than llsual. Imw to adjllst d Ol/!. H .. and that the time n-quin-dto appnl.". TIll' hel ). I~ I( IJ imlc)(:."i "" W".~ ::J ~ ~ ~ ~ ~ • 0 0 5 1 0 15 20 lndocyanine Green Clearance (mUminlkg) alltl thr-refon....J "I" M..h It'ssN extent ..illl" K "' '' i" p..fon' dmg {'C m{'t'nln l!ion nc>t'(! 101M ' Il1aintail1l" l.. lI a\i u ~ a mul'l l louJ........1 by a st nm~ positive ..stroltioll tn al'h i...•. <ltlmiui.~..illl· am i iudoc:yilllim'l!:n"t'n in patients hot t. usllally ahou t I~ llll JlI1i n/l. a filurt h-l-:t'lll'mtion l't'plullosporin illltihiotit'.amno-s should rlu-n-fon.h "'i ll""'1 (...n. .' 'an itlt' h"Tt"t·Il..od .'t 11111ulatiu ll delli' lllls on bllih Ire..-. is unlikely In fall to a vahn..c.IlISl· ..1.·xtra(1.[unc tion..i"" or 11..ltic .UM! 1«'....Im·lalio n b e-tween tilt' d t'ar 'llll't·s of Iidol" .:t·r ha lf-Iif.l....ltit' tlow.t a d iminish. (.... t.tilll· and indol_ ').. I6-fold variutiou ill dc·anll1et· of hoth lidomi lw and illllo(.CHAPTER 10 tl K 16-3. dOSiI~t· sllould Ix' reduced ill patients wi tl l l'C m~t'st iw ('anlial' failun' if 1111" risk of tmi dty is to 1)(· k"'pt low .·n·ly . a dl'{·n·..:..l-sic primipl. T lwy an' d' '\ 'I'!opI'(1 \\ilh till' \it'\\' that d m~ t·lTl'l1 alltl tlwn.to...1 (I'WlIl'Y of administratiull allll lJalf-li(e.{ hd"nu 'll" and i.("f' ..lII..Ill op th. illl· an' lJil-:h h"'!). s 16-S ..lilt' unly (C hap. dUSiI~t· lIlust 1)(· n'( llll't'{1 ill tht" l).. 16-...l.. ' •.. a. allil lido.. urin al) ' "'\{'n1ioll of t1 m~ is dumuislu-d.-xtraction mtio d rugs whoSl' d . till' d OlI-: accumulates eu't·ssi\'t"ly.IMI....ltil"nl than in a p<d it'nt \'o itll nOTmal n 'nal flllll1ion .'t· B o( Fi~. to a mlll.til" re-.. till dl~""r"'ll't· ..1 J.anoxia Is "'\I')('{1t>tlln result at . 'S Th e din i{'i.. h~' prrm i.lal t1wrapt·utk rl·spoll... ~ h. This nll1~t' is almost n:rtainly ~n·a l r-r than till' nUl ~"· of lu-patk. 7)..4 for l'l·fl. \\'ln-n tht. Ohs iously.. T hu s.ca rdiac· Iaihm-. n -nal blood Ho an ' ..ll'h plateau is a function of half....lUin. ·.."S that I')('nnit this mklllatinn follll'\'..R : l .·Il11lar ell7." Mi..· n . .1il1.• "'xt't'ssi\"d\" in rt'uallh -sfundioll alll i.. l..hlood flows in pat it·ub. n 'lIal dysfunl1ion. Tilt· h.In'''R1'''''1.. dq~f(".. till' tilll!" to n'aeh sli·ady st" Ii' is mud..? • 0 00 1"1\00.. usual i.10:1 ••..alio"T... wuhout and with \-a l)in~ t11 ·~n...)ll1..s 2 m l /ll1i n/l.1 ""'MI "'ill> " l"llh mikl (o) ..... P..) ~ • zs 5 .".-xtent of 'll.iclo:. 10 a\uid I'\l't'ssis"{' al'('um ulaliun.29'j :l lfil~ 1111.."\'t· ..1.1. l " "' K'OS!iW ...Ii.. 16-3 the almmt · w.of normal.Itc'Il<ltil' hlood IInw and ."t'S of l'CJIl!-:"'slin..c.1 ill Fi~." .. Icml-:t'r in II.1-'0 a narrow therapeutic s\i mlow (S1'l' Tab l.......ll-~ lo\\' a...." cl.I. ."Il n-ual function..

. fi' varies in n-nal dist'a..lI is 10 t1(.-s.r...J (11 "<1i. 70 -kV.~· "ith Ih' M' f"IIoM'inR" r..n "f a I I " I-".~ . . in Clearance 111t' r-k-ments of the problem of renal dysf""l1ioll an.UK ( ..-r 3(). G.....1 i".U. 1991). F"'Xl"'.'it·.11 ......ft " f ...lI(t ) 55-yt' ar -old .. I1 M ll . ".f ratioM ' i•• i "lllLot. 10 .. TIlt' j:!.."S.~1. Knup p .....· in tI.Ullll('\' dPI)('uds o n Ill(' renal [unct ion (('mai n ill ~ a lld 11ll' fmd inn t'!I(t'rt'!( '(1 unchan ged.. !'\uh' thai souw elearauce re-mai ns (y... -.0"'.· 1 .'<Uls(· till' d nl~ is nor ho und 10 plasma proteins.. 1f)..1 +--~-~-~.. " 1 ' .'... /i " ".0.l<'O Jf'< 1i1l1l: .....· I 1. o 12 24 36 48 60 72 Hours Deaeas..l".H. In what follows .1 m. <: 1I~ ..[unction.... {'>l''a {'t' n lr"ti"'H i lll" rn. .... an.. lIlan ~ . I ("'diu" .) 0.!'" .pl . C I"u H(d J." is nllfT"... in("\i.... •0lI.r in ....t' lI m~lI i l ll tle of d lall~t' in unbound dt'.'"" antil... measured I~' c n -athunc ch-arance....fIi mt· i n suh....l.oft"..." . ." .Iiff" r- 0. TIM' ..: 1 n ". TIlt' finl step is to relate llllhollmi renal clearance in tilt' pat ient with renul dysflllK 1ion(d ) impairment .v.(·{(.0" \..·.nh.. ... inte rt'l·pt) even wln-u then.1 dy.... C ..._ n M' \" " jo" 1< "'. 11111.....n '.R.. I.K1-' 1 )/. ST. <.. ._ Ii:n"'I"'t1 ...." .-\.. T I..· .."l.."..·'K':\·..~ o 6 12 Hours 16 24 rill 1'111:.h. i. patu-ut... '" .n. 111is rt' p rt'St'llts clea rance by nOJl(t·nall><tlhways .. 16-5. ('(.. Ct·rt. is Inw and ill(.I'. n' II... Inl•• " "M 1 "1< M. Creatmine 100 1 " -" C learance (mUmin) <10 11.. because the all-im po rtant unbound roncent rut km is n-lated 1 unbound ck-arance bill 0 also b cauw . l.'54 CHAP ER 10 T n .. ~ l af7."'. ". ..' m...tlinint' d. mini. I"" M ' -nl n '. 1 fn>'" Har hhllip . . mak inp."tlK..is 110 n-nal funct ion... F. 1 " . I..30 I. 1 ill 1""'it-uh "" lh "ill). is tow wln-n rena l [unction.11(1 clea rance here hr. em phasis is placed Oil unbound rather t han total ch-amnc... ..'(-h "... e li" . SLti •.I.l 11 " an' in a fUliI·"t ...-n " f . for man y d n lj:!.. ~. '......kilwt i"!i u f (.. (A....IM "'II: '''\T'~ ' I i I.1M' . " n .. n~ llo:1-n't"S t <of n -" ..•.1t-r\.. .Ui.\.<.r.17jdilllt· clearance . . ' ..-iI:!'1 . ).se a rt'latiun ship that allows es umation of the maintenance reg imen ill a p atient with rt·IW.l\l 's lillt'arly wilh renal function.. CI A1II(I) .i ll. '111:' 16-4.l..... l1" ' lIun " lti h f·!if...M to I. n·.... D . . .~ .. "'1.. a .od.. interpretation !><l'it'(! 011 e total plasma concentmtkm uncertain . • . ~ lO r . t · rt'l' llJ f"'''1M'' ' i-~ I ':'~ uf 1M. l~ oIun~1 (~ ".• ."'1 o f arni!<. ...-p..1.-. 1'1.f...Jc.r.on' II....-pI. S .5... . '" • 31-60 61-90 >90 n "'r" Pl:2&l-2'fi.' S1l0\\1 1 ill Fip.. 2: lor.lil... ( /ru i...".. .. 0 CluM) • RF · Clu. 1 un!Ju u"d (('!1<1I c learan ce in Ihe typk.. •" ~ .I'M Piu"...ol.. " . " If.. This is not onl)....~ . n.

IWi..1 ..i.. till' nubouud n-nal ck-arunce y CI"' (I/ . J e lin. l u tln....(I) . H' In tilt' 0 \ I~Vit'al palit 'lIt .flv.. §.... Cl"' .: D'_ J:r ... 1 1'OIn".. E.. A..)'''..fe(t)... c'stimalt'(l '. its value ill tilt' lndlvi dual pat it'nl I M'('( IIllI ' S 5 6 150 ~ ~ 2 • H it..·n.1l1ion..K. t D r_ Tl I"nlll1 tI... 16-6.1 ""11t· d.io. CI". R."K~· ill OIlo:"'''P IIf 11l1'"'''''1'h ". hy ill tilt" p ath-nt can bc' n-lated to T Ilt' 1lt'\1 Sh' p is 1 ('(Illsidc'r tlu. it is O n Iht. :11.J....' f1. Roan.lilll...l<.Ic·· lo:rt. ("c.. Cl"'n(t ) is a fr.... 11.. Using lilt' app m\illlation m i t'(' (1 -10 - A ge ) ' Id (r/) o ..• \ ·n .. .rit" hno'OIrh ' with n ...It~>I . · ill p. 1fi60 for tilt' fa ctor II)' which nonn-nal cleur- t1t'\..1.1" IIIt'I'l:1.typic p atient.""'M~· lJl·h'!t' rt'l:1>lj"'h.5!l..'".....lh '~.. .J fundi-"...1 Tt'T1". 01110.....·1l' l~ 111) rt'lW I""' K~ l hnn ... nl T it .I" nf. its value ca n ht. IS)... filr.... ass u mption tlnu CI" ' .Itt· f. "·"lai." I is 1101 dlangl'1l in renal d iM t '.uicnt (C hap.M. for lilt.. 2 U t'l: lI l1 hi l1i n~ Eels..1c"'1'1)' ri o .. of unbound (n-nal + nonn-nal) al ch-arance-.1"....atin'h with im(lOli .id im.unbounc] clcanmce II)' nOlln'n . pal it'llt by laldu g into account his or her agc' and u 't'i)!hl. .nlo: .6 PTE ~ 16 m T Ilt' nihil of tilt' Iwo is IIII' n-ual function Off') in tln pa tie'nt rdalin ' to Ihat in the Iypiml pat ient. 11M h~OII ("1c·..d rou tes . 100 i • • jU'>!I1I.ah's [mill Ihat ill tilt' t~l)it'al p.L. I end 2. 1' " . l in ill ." 1>. 01" n. :"ott· 1...-rual fUlK1io".· d" "r. ".l J E 50 ~ • •• 50 100 Creatinine Clearance lm Um in) o +--------~ o 150 .CH.

.. illllsl.. "~"'1' tI.· tn . 0 . C l. l1li_~ rt' laliomhip is shmm ill Fi ~. I fi--S:\.lnll( "ilh anjt1t l ..1 .~lllW ("Slimalt't l From crr-at iuine clearance ill tilt' dpfull(.. til.. 16--.n -Iations hip ht'twt't'n l~d ami n -nul fw lt'liou for vahn-s of j d O in .". is tlu-u /.·arlllll....~1 n-L.(d )/C I .1 alKl in· .. lIul.·.' -yt·ar-tlld . ln. 11 '40 Tln.nt. lilt' 1111110 1111<1 dt'ura u{'(' ratjo.1 ... ~.u(d ). n n ·maio ..- o ¥---~---~--~ pN·" -ti tu d ..." R(tl ) is (·... ('tllll(l<lrt't i tu Ihal in a pa lit'lIl wit h fully fUllt1innillJ... thl' 1111110 1111(1 ch-arano. ional palit'llt rt'l alin ' to tllal o f tilt' 1 t)'p it'al patit·1l1.. Thus. 1 ). jot" am i " .... T ill' half-lift· in a patient wi th n-ua1 t1ySfllJld.b onnd d . 1.1('(1IEq... "1 of rr nal f" "t1i" " .~ ..U\ 'II(t!) is c qx-ctcd to 1)(· constant .. jO. « 'n..(t ).i ll ~ usefu l rd atinm hip is t1t'riwd for R... "..It when.oti\~· I" tl.i'"'' i5 th. CI.. the rollO\.0.1..t~'P i('al(l<lti (.. a .. .] r-o-«.I.'rt'a.oa\ rlJl"iwm . C l./I .R(t ) and CI . I" a ~"'P of 55-~"'df""'1... On sll hs lit ll t i n ~ Ells.. 1 d ." f Ii ~pi<. am i ' nlal ""1• • .lIlti ll!it (I"t. . o 0.. 11"0..." ... "f o .vahu. of course.: kk lru-ys ..<1 h.. 1 )( '<.. t.l<' ) in I'ar..1. does not 7 HI" is Incorporate il~(' und wl·iJ.· n·na!fur.)n · rt'(l lI lId mll~t..n'...pil.....fr.lt:tiull of au int ra·....oal d... . whill' CI .1 p"'p". ·n S. rt-. EXIX'rill1l'utaIlY '(t) is tln..u(t ).f.'(p('<... in de!t'nllilliJlI?: tln.. .ultol " i llo n-nal do·anuK fn' ''' II \>11 "f 0.J "r ..·.· 1.... 71 l-k!it palw ." 1 0 00 ... It is appan'lIt that [(. 1 " dc·..·.... U" tHlll . I\('('all that t 'IJ = 0.I d lilll~t· S the most wit h n-nul fllll(1iol\ > wl u-u fi ·(t ) = I am i is unchanged wllt' li F (t) = O.ws lillt·arly wit h Hf'.. 1 ill uri ne in a lyp iea l ll<ltit·lll.· t"l al "nl• • " . Th t· ex ten t of till' Increase depends on f j..01.1io"..'56 ( HAilEI1 10 Fur a ~\'t' ll <l~l' amI w(·i~hl. liy dt·fillilio ll...J(o(O.2.... . The. ( ~.o f j e( t) is.\ '..\) ". for a t1m ~ \\il h an fi·(t ) of ll. ii.md n·na1 d....5 . . tn '"".:llt t1in'( :t1y. . u pali' '1II. 111' Fig. n ..1 of Ih. n. l 'u n trih u l illll (If tilt' n-nal I'Ullk In all mull's IIf • d imi nution in til(' l~]l i<. In . independent of n-uul function.~.".fi H ' Il0W.." 'n....·ar· ....... . t " I(d )...1dt·... i" . ' IR' 16-7.. itl" \tr.5 1 Renal F unction (RF) 1.r.1<' of 1. (R F) fu..iulI.lin . hi" ..5 i'" ·.a tes tlu.CI . . t."a..693 \ '/lIC I.. I to 5 into Ell' 6.. llIlK witl...</ li" ..fi rst tN IJI .i ll thl' patient.ti lt' n-ual and total ck-umnces Hf tilt' 9 ..ll palit·nl.1 da"h."'.. ·... illl.1by . play a m it.. lw..(I ) an..k~ pa tit·lIl.\1.... A~t' and \\l'i~ht .15... in .. I" (u . Agel ' wIId)O') 1660 RF ... ." .t wm 10 n -nal f" " (1i"lI...s. pn .1(111 (<:1"". . TI.. -I ) to (:Imll~l' in direct pr oportiou to n-uul function (RP)..1I1 for whom t!ll' usual rt'W ll w lI is Inte-nded. 0 ..· t:.1 ('1o''''''''''~'. 15 ). 8 d nt~ ill tln..) tloS(' rt'(.. n"I\ « ·n. "f (~"..

. II')' ill t1i n "t1 prop ortion tn 1.I .-.. allll l)t' rl. (t'.. 11.l~t" .IIYI' n .'t..T\<I c. ~ ~ 2 1 0. '~l'W"l l'"li' ·"I ..0 ~ 0 025 0.... If n 'lIil] Iuncnon tlu-u "u .. 13--.• ".. II. cn-atmiue clearance. .J.... tI.· . "" .... .I1<'" 1 ..I.. 1 11.laI "'~ I..hl.. o ruther than [rum 1ll.'t· is lI~\l a! [y t'~l i lllalt"t ) Irom !>t'nl llI . "S F i.1 IIW. 1.~ .um" I'" ".-..L"lt i ' K'Tl~"'''' in l"o.CHAP R 10 TE DOS' AS! 2" B A fell) 1... IJ'" I""..U1''t' occur in )l lllllv...:.... mad" wit h fI-sp' '('1 tn data ''''<Illin ''tl ill till' di!Tl'fI 'nt im li\idllals in Fi j!1In' I fl-il... 0 0 ~ - 0.\' .f "..1 n·.' r <I1ll1 smalle-r pat ie-nts..5 0. 1>••1.· I.".1tl"f'" wh"" "I.1'1..1" " ni.25 0 Renal Function 0 ~= ~ ~ ~ ~ ~ ~ ~ ~ 5 4 felt) 1.n1.1 ""I. (Ill.' d' ·ar... t..".(1.I. ..\11 From tilt' t'\l m analysi ~ .>I.75 3 0.· .· ·. ~( p"h" ..25 0 0.1 poi nt I u-t"tl.. 111 r-axis ......·r"l.". . ..'i~l l t .. cn-af imr n.0 1. II. shollid I... ill"" 1 "".1Mo1' IIfhio""'. <1m\( 'I.ojl.1i" "n. • • -r0.... AI"" .-....·."t1 tln.· in II."" I'i"... hh-allv.. ....".a ps n -nul t1iw 'lS" ... l.l...·...patu-nt wit h n 'na ] di !>t'a~.-\). h..·.·" "•• .· .lIlt't' may alsn II<' n 'la lt"t! to a~t' und \\'I'igllt. weight ...'( ~ "f II..V. This pos itin ' corn -latiou tlf 1I01lTt'lm] dl'a rlillct' wuh c rea tinin e clr-uranee Illay dis tort t h" r.ht..1...0 0.0 0.u. 11. a nd lilt' uonrt-nal d . wt'iV. ~ I. 11 ' " "I M I \~ >Il1 n ll' (If disln ]II.. o n 1.""."..11.1..25 0 « ..· f"".1.""'. l fi.II ~ Il s('fu l m '~~ IiI'S in its d.'I ..75 05 0... .5 0.1i"" flor whk'.ji1n .' ..I.l li...er lind larger pat i t'IlI~. n 'llal eh-ur..nl " ... '" a ~-pkal patio·lIl..1 1: ~llK'IIn:...'t·.' I.."" ..• palic 'n l f.. (.5 0 25 0 g « o~ ~ ..: " ".·. lS ll n'~ nf n ' na l fun ct ion a n' h.. Estimation of Renal funrtion COllluum[y I'rnp loyt..lSlln'IIl. I..· M IIIIM · i... ~'1>t " ". is a function o f .1 f"' .. 0 1..'n'atinim' a1 nt....1.·1 '.~ ar e ('xp<"t1t'() in o]d.. and s maller mlllt....tl..'a r..1. ('lIm'laft"tl \\i th creatinine ck -ar auce...'... ..1.· . "1 till .lUI han' lti~llt'r t'fI'a tinill.. ' am i ill 111I' t~V i('''] pa til' llt. ~. I. allt l n-nal d isl'. 11. n-e-al] that \ 'u 1t..·".".... O il a~t'... I l i ~] l(' r "alm' s of nonn-nal d ..· ..1 I.'a r. ptlsma '11111 urine.f...·n.(•.ic"·.... An addi tioll.~ D~ ~ ~ ~ 0 ::::I .u l('t·~. 'a r.'a r.'~n's~ io fl ~tl t ha t tlu.·".m. .·1." 11(11 ) a nd ' '1I(t) an' tilt' dnl"~ not afT.'lIls in 1" .1 1:.s In lit..y-illh'Tt't'pt is lowe r a nd till' ~Iop(' is ~rt'ah'r th all l'xl)t"t1("t1.75 1.....·" lil."·"I.nn.·ann". n'~p('('l i\l' ly.lIlt't' IIf mallY t1n1/-. half-life dl .1i•.\ .·".ly \\l.mpa hl.· (·ak. 1 . "..·. . 1.S1"t1 011 cn-arirum..""." " i" ro. .. "f tI.lltt't' \ '<l l')i fl ~ ill dire-ct pm po rtioll to tilt' n-nal d t'a r... 1 · 1 ".oll< " "ffi -il ) ..75 05 0.l h n-nul funt1inn am ] Iractlou t' \(Tt"t('t l lll l(' l l a n~ . III l'Iillit·al l' rad i.If·l.1 "f ". :\ p.· .1.· ..~ .l'it" O llt' miglll "\1)1'('1 th at nonn-nal d ..·ll('s zem. .· "'K~""'I:< .I..IItIs tn ' ...ltl~t'S tilt' 1ll0~t wln-n n-ual [uuct ion app m".'ar...11).' ('\alllint'(l !>t'pa ratt'ly for its d t'lw ml t'II..·11 1.75 ~ ~ ~ ~ -'" <. ""t.d ..H('t' ~I lt lllid 1. 10 F i~ll rt' I(~n Illust run-s III<' t1"I)I'lId" I1('" of half-lift..Ie.. lI11bu!llld \lll ll Il W~ (If t1i ~ l ri hll t i un ill wln-n. :\'otict' t ha t fo r a dn l ~ e xt'rt"tt'(l t'ntirt'ly Iln dmn ~t.· 1 ub IIM fur a .f .....0 2 " Renal Function H I(..

_ r " 1 4~1 ~.. For 110 ull ll'r r-o udittou. ~to.v.I\I' for illllh-idual....Agel x Se-um «ecnoee W~ghl 12 X Se<lIm "~ '.:0 ..C~'JOO'J j."":J" J 'J .o- l~_ '~h"""" . '9 ' 1 r..... .. CI• • ra nc.".ltlill~ doses in pa tu-nts \\ i lh n-nal fllndioll imp. it . .lim ll'lIl app ly.(' ftogilll"11 lilt a p... or oht'S(' ad ult p atients . serum creatiuuu.J .'OIIISol' its daily production :n M is ma tdu't l hy its elimination under nonnal drt11Illstan('('s.(·II·a(.\\( .· Ad -" :20...is W\l'1I by M R ..."1 \\i lh at:t'..ty (If l"l )lI('t. ..lf<uwt' meas un-ment lIlay 1 ' mo n .."... It should hI.' i\i ll~ lilt' adjusl llit'lit of a lII<1in tell. ' 1fi. 'alillillt · dt'.' .-"9 .1 1funct ion ill lilt " illtli\i tlll.mass [sou rce of l·ft'al illim') for tlw ir a~t'.a ppnlM p ria lt ' than all (" limait' of ih \-atm' [nun serum cre-atinine.. 16-2. incomplet e urine nJ llt'<.-J .. POOT r-stimutes art' " h lailll'l i.j-.r udju-tuu-nt of maintenance am l lo.'• ..:l"' ""~ 11 .' e mph'L. \\i lll all a\ c 'ra~.bl.1ioll is a major p robh-m n -su l t i n ~ ill lilt' underr-stimation of crcannlm.11 h-m"thn II. Sol'n un ('n'a tilliIW is rdah"tl lu (·n'a!illint· ck-aran ce hy Rote of creatinine production Creatin ine clecreece Serum creatinine - 11 Tahl.e 104 x 11 40 . :Y. 10 all dist'.n.. .l!{t ' unbound (~ . n-ual illS ll ffil'it' lI('~" is 10 mai nt ain tilt.tI .U1(1·s in this palil'lI l am I in IIu· pal u-nt .I!in iTw aloll!' can 1 " used h' "i.." . .CHAPTER 16 involved. ..l wln-n. b ... \\l'i ~ht.urd Ilt'i ~ht ..' n·.. · pal it'll h a u..l) Se<ut"l cecnrwe 70 " .. • • ...._-<1' ". I i ....O''''' • ""'dcJrord -g-ob ."" $e<um Cf@(]l.L'it' cnmlitinns in whieh d mK r-liminuriou is all...(t! l . ... adj 1lSllIwnt n-qum-d iL n 'mlily p n-dicted ' and <I \..... hm\l'\l "r... lrtJuld 1M" 1I111t-1I IIMI ra In tl f IW producriou and d l'. t.. "'''''''8 j'>3" ... A.ghr .: .1 . o n tliL. h h:h l~ IIlm(·ular. n-ud to dt 'l 'lillt' llh in paraH. '1'1 11' simpl('sl \\~.11 prilldplt·.... _r . and gender. t ' ""''''-.lh...o>_n'<ld..-A.n. IJtlm..sin~...!.. . Senun < '. .." 20 yt'ar~ tJlIwa rcl for p atients with normal n -ual funcuon for th eir a~e . r9 7 8 S . Ik ll. For "lIl ilc'ialt'c!. Chll.... .. 0 AS X He 'g~' )( ( \\'e 'JI-... \ \I i1inl t' llilll ('(' Hah'.lIl('t' fro m \I' n UIl r-n-at inim-.".C l .. (AlIISol'l"llIl'ully. '"'_ P>. Filially.'t1 thai tlley a rt' mos t al'('II(. is t!l(.ne 11 40 ..l.n-uuuns n ·latin·ly constant (about I IlIW tlL) front a~.2 '1l1111llari/"'" sonu.- c~ .ch-urancc. <Jd""'b b<>1>-""O:X. ?~ .oir. Adjustment of Dosage Regimens T Ill' .. ..o f tilt' n-huionslnps ('urn'nt l~' found to appm-ximah' enutuum... ~ . lYO>l'-. """_ "'dapotd """' ..un-nt wil l. · muscle. wd~h t.~ ~ $e<um creol..C0dl/C0~ F 12 t ~llie.ll(1' lI l raIi01l al ~ lt 'atl~ vlatt-.(f ..tlon of Cr• • tl nln. '" ._. l1]('S( n-larionships Include com-cticn s o f en-at' [niur...Arl x 'Ne'g". .Ul(. l. ...\".. CIlII" 'q ll" lllly.ll )lalit'lIl n-mams h i 1 ' ('ak lllah 'd ."... s< UI1 P an"r...ow'''' . """"""""'\I'_boo . ]7 CJ'. For Iii" ..".." lt ) an' tIlt' creattnnu.iZl.. " " _ . Th is vultu..""...Agel x We. _. ~"'''' f...1 85 x Se-tum C'M"O.ne .. n " Ill 'l·th 1·I.Ar1 " V\ e y h' 1 23 x p AD ...."" 42 5 x Heighr x (We>9h1)" 70 boo too ~ .p rodrn-tiou lilr a~" . ?o "'" "'" <J ~ cJ.dc'ar. ell.m lll(1' (If t:n 'atinillt. ".uloue.lml C I .

.til(' bilJ.g: illjt't'h '(l intramuscularly t'n 'l)' 12 h r to a 2.6 ..n-!t' d(lS(-"s and ". \\llt'li hioil\'.rat e ad nnntstnmon.trt'lll tllat tilt' mainteuamx. 16-9 for constan t.to al'hit. I i .. dt'{"rt'a.05 TIIwKg: X 6Ii k ~) 1 '('1)' i2 h r. i O k~ p ' atient is ii ml/min (C hap. compan-d to the us ual ratt' (If ad ministration to till' t~11kal patiellt.05 5" e 0 ~ E 0. tlu. admiuistrut ion is hy (Iis(. &i-kg: patient with all I'stimatetl l'n' alillint' dea r.2 0..ibhility tlOI 'S not d llUlJ::t'.t featun.l'>t'tl hy a faetc r o f 6.FIlI i am i F(t) art. it is app. Thi s tl. or a o uubiuatiou of b oth. (lJ. (2) Ti lt' maintenance tloS(' ma)' U '\ RF 1.4 C E 0.of administratioll ill a patu-nt with n-nal d~sfll lld i oll is 15 Till' n 't!lldillll in dosi llJ:: r ute.Ijus tlilt'lit of a maintenance reginu-u llIay II(' ITl<ldt' b~' dt'{·r't-. tlu.1 ~ u ~ ~ ~ U5 0.CHAPT 16 H 13 Halt' o f udmiuistratiou ill n-uul insu llid t-I\l:'.I-s illg: till' fn"lllll'nl""of ad millh tratioTl. the value of Hi" ill tilt' 23-~'I'ar-()td patiellt is U. U sill~ Eq. Ti lt' outcomes of tht'S(..5 0.tlt' llf amikacm sulfa te should he dt '{"rt'.0 . rt '~i nlt' n : .is Illustra ted in F i~.SI't'U to dl' pt'ml only 011 the mt io o f unbound d t'aralll'I's H. is then ID"'/'lidl IDMl<II~ = CLvI~ .l.'l-)l'a r-oltl.ing: tilt' mainIt'IHIII( '( ' tloS('.the dysfulJ(. 15 .ahilitit~ of t1nJg in tilt" path-ut wit h r enal im lillid l'nl''Y t ~]lil.required ran.lIlainh-nlUll'.8 0.I' Asso(-iah-t1 with tht. T o ap prt 1.\tlt)(d) .'i II 1I1~ (7. rt'spt'{·tiwly. As tht· t" I)('{'h 'll cn-annnn.do sing: r.seven.5 1IIWJ.rt-hrimt'lI Ill i~ht he OIl('of the fol1u"i n~: ( I) dush l~ interval increased si\fnld .lItS that till' tinu.IIlI'(' of 13 m lJmin.2 0 0 5 W W Time/(Typical Half-life) m ~ . 0 ~ " 0.\'l' 11ll' dcstnd plateau is I Ol1~l"r the mon.5 ).15S-YIar-old.dear'alll'(' ill a l)pie. TI lliS. n-ductkm ill n-nal fnlld ion is a p ml f)ll~at ion in half-lift" Wllid l IIIt'.ialt' till' difTl'n' nt'('s nlllsidN tilt' udjus tnu-nt of thl' usual n1'i nlt"ll o f amikaci u · sulfah ' i . C"MI 14 and in tilt' when.tilln (Ell' lu}. 1. III prad iet'.0.l palit 'lIl. (I)u!t )(t ).t\'ai l. appmal'!lt's an' diffe ren t.is rln-refon..

IIlt'1IS con sidered.'. a p p n'liahlt. 24 I... Ilid l may inl·f{·<l. a case Illay lit' made' for a Io.... d Tedin' It'\ t'1s a rt' n 'adl(1: 1 a ftt'!' I hl' Hrst dn..-. lmi" ht r"t i<"lb .' .." alll! lo\idty of till' d m g.r . Clearly.. . Fi~. '''''1111'''' "l ""...I" i.. silt"'" lin " n 1. " "'1: 1< . . .. . .' " .llding Do se. « 100 " ..lj.. .s '" 0 400 ~ 300 .lII.~ of ()lll.m. CHAPTER 16 he. injt '(1iull s.III w.10. admi uistration of tht.{<. " If" l...l li. B " .. with mallY hours al ho th h i ~h an d lllw ll"'t'!s.. 1 1>. lUI: t'w l)' 12 hr. ".2 hr 10 a patient \\i lh n-nal d~'Sfllnl1 iI)1I . Pa rt k1.(' ('\ '('T)' 12 or 24 hr ill patients with 0 '11011 dysflllll'tioll ..!IIMing thl' nol dow of tbl' Ihn"(' n'~ llIt ' ns just constden-d ( F ig..II' IH) . ill. .. e 200 E 0 ~ " ... l fi. O uly a Iwn fole! n-ducttou in tlnm ai n!t' llilll('t' (LIS(' \\nuld hi' n -qui re (C hap . . .2. n-w ult'u: S. dlan¢ ll ~ tilt" interval to th ree <lap «h sllt'd (·urYt·) results in Ihe ~ rt'a tt'st Hnctuatton.\(' .tl e a ll (F ig.s 0 ~ 00 400 '" . .fold .. 11 500 . ~ . « 1 00 ..lt·1l1 \ ill 1111·111111).. " 1.1:. . i\ill ~ a usu al do<. A 500 ". \\'ilh lilt' n. (3) Hoth . . 16-IOA is a . kd d l of t i ll ' amount in tluhC I)' \\. .\(' lllt' d mu l't· (If :U1 "d". Finally.) ..\'. ..'t·s. A('('()nl ill~ly.. USll i11 I ll lSil~t' re~ lilt 'II to IIIl' llilt i('111 with n-nal dysfll lll1ion rt'Sults in a f\\1lfold illl·rt"L\l· in till' max iumm umouut in II. dlan ~lI ~ bot l. ' ' ...ri\l·u eH'T)' 12 h r In a t}Viml lliltil'llt .e· l!osin~ int e rval is much !ongt'r than Ihe llitlf·lift'. .mt'lI 1 of 500 1Il ~ j. ' ~~ .1.' . . l ~.for atl tlm-e n. 1111' initial dose' is IIU much Il'ss t ha n th e a\'t'm~(' umouut in tilt' hody at plan-au. 0 24 48 H ours 72 96 I'le.. .p il1 un' is \"(' 1)' t1i lTt'rl'n l fll r 1'<1(:11 0I1t'.. 0 96 -- .. In ("0111I'lL\1.I.m an d avplate-au an' the sauu. ma ill!t·JIiUll't· dn~' a m i dosill~ tnterval h lnUet! t ' I I'\"t' ) n-duo -s hott. ( )-." 200 e ~ 300 .la rly lafJ'1' difh-n -uces in 11 ll' .. .. Hucmat ion am! tncouv enleuce tn Iht· patielll alii! ." .(' lIlilinlt'lI aun> rP).vr. lfi. then.11 . . '. ~..5( J) "'I: (.' Jlwfl'm't! fur this d m g illl d fur many urln-rs.. N\ .. Under li lt'S\' l'in:·lllll \tallt. . . Sill''' lIIay IN. 111 linK' fo r the tllR.~' 72 lor. It is illlporta nI..is Iitt lt. I"ol"rt. 110W(. so fur tln.i b •. ".I"i . accumulation (N.'»).d osdy n-lan-d to (' ffil'lll'. ."''' 1 " III · n 'na! r'"I11.t.. I f~B ) . to ('ullsitll' r wllt'tl. 12 J..n 'tlul'('t! hy a fact or nf 6 .111111'1 ttl I ".. (. ' ) if tht· fo run-r wt-rt. 111 >11..\(lill~ dust.. TIl(' typical half-life of amikacin is 2: hr.(' of soo Ill!!: can It-iul 10 h i~1. 10). 16-1 0.". S 'Il" ...~q." body and a sixfold lucrease in tln. ~\"t'll Ilml 'lhso rp tion from K A lth ()lI~h hnlh t i ll lt' to n -ach plalt·.t('(·lltllllb tion Ill'(·allst· Il. . .(' of Irequeut i.pa l it'll l under l't lllsitlt' ra tio ll the-half- life is prulnn~('(1 shfnld to 12 lrr (Eq. 11>7 "'I: .. Sh 1d ..111\011\11 of amikacin in 11 bIK !~' 1I' extst f. . A sllla llt'r l l liid i ll ~ diN ' Ill i ~h t Ill' p n lllt'lIl. "...r. ltlSi ll~ mn-rval alill 1 main te nan ce.. iIllUL. nf tI. ." .-WIII('n of 500 rng ~\'('n t".'.-Illa ).. i.t' Illay he:' adjusted to n '(llIl't·tlll· a\ 'I · ra~t· dusill ~ rate sh. .I. era~(' amo unt i ll hody ..' t1n<. ."" ·'I. In tilt' ('l1 til(' t.·W"wm.. tlu.5l .• 167 1Il~ ("'"('1)' 2-t hr.an' rage amonut a l pl. ... .... .. . ..lIlt'lI: ('. silt· is ('t)lIlpldt' . . n .. . .·..'(·Urs wi t II Iltt· rt 'lati \('!y frt'(jllI'llt wW llI(' n. ·f'S!· (·!T ... ... us wi th 1 1I' n ..· "~lIh-'''''l(~ 1't')(i1l" '1I.Uld Instantan eous. level s ill till' hellly for all ('x!t'm l(1:l lx' riod :Ifk r i ll i lial i n~ Illempy ( Fi ~.If 1111' 1~1>it. '.t rue. an'mgt' a lllount is mon. h nM' ill " 1>.. . d LO.. . mit (...... In this example \\i lll amikacin. .' om'. .. ..'('ry. 0 0 --24 48 Hours 72 . C hallj. (· ··)-.t' r Iht' maximum amount (o r l111l{'t'nlmlion l o r Iht... .i ll ~ IIII' r mai ntenance dnst" (colored curve ) reduces 1Il1l1ua!io n h ut SII!Tl'O [rom t he int111ln 'nit 'ul.. '.

A .dual. Simi larl)". For a \"aril'l~· of reasons . rt~artllt'Ss of tilt' ('()fltrilmfion IIf ti lt' n-nal mull '. pnx.! t'u 'n'lion 1'\llihits t'llllt'l' 1I1mtioll-tlq)("IIlIt'llt "i nd ies . Eq .l(linj. Unfo rtllnatd y..(' is aSSIIlIlt'tl lll dt't'n'aw in d in 'l1 p m1d po rt ion to l'r!'ali llillt' dt'a riUl('t'. !o lx' ' -alid .(t'S in n-nal d~"SfIl1l(1 ioll. t·.11IIl't ·rtaillty in prt 'l lit1 i ll ~ t hl'i. 1111' M 't'(md pro blem is ll'>.J.L I'am-amilloh ipp uric add . is O. J I OW( ' \ N .chronic reqnt n-nn-nt s for a d r u with only a small d l.patients.\('ft. am i t"IlIM prtlhlt' lIIs. . II j.tIIj. rt'~art ll(' ss nf IIU' funct ion.importance o f nonn-nal dl'am nn ' increav-s. mdhot! faltt. n 'fl" in 'lIlt'llt s. atlj nsllllt' nt lu-n.tbilily . til(' n "'jl" llst' 10 a ~\'t' n plil. uSllal h . As n-nal Funcnon a ppnMdll's r:.11ll1lt '{'t'!>~II")'.lIll'l' is not di n '{ 1ly p mporti oual to tilt' IIlt"lsun ' o f n 'nal rlllldillll. "{'n Ht' ual fund ioll is tlllly lint' lIf M'\'I'r. dt'a mn('t'.1 appmxi lllalion is in t'!ln lllit. Il<l\l 'l1 0 11 a d l'llIj.lSa 6r.lJll.1 fun ct ion uln-rs lilt' ah ility to nwt aholi 7.' rit'I1("t'.lh M'\"('n' n-ual <liM at 'll'.x. lilt' manufacturer recomuu-nds III It changiuj. n1::ard lt'ss uf wllt'tlll' r tilt.11 MlUrt't'S o f \1tri.O.·wi thin tilt' po pulation .tinltmidt " ('..( lilt.'illWIl is l'u llt'(l for.l\ t i ('"I1~ · n 'llllt'('(1.(I' ill rlu. lilliu <ll't ' all t'''lmpll's of a(1 i\"t'I~· M '!t'tl (. relal ionship hd '\"('l'n Intal d e.I.'.U1t'l's di rt't1ly pm 't'n po rtinll«11l1 t'IltII)~~t 'nlU l s l'rl' atinillt. lIo lln 'nal d t'ar.(s.!t'(1 t1 lll'hall~t'( l in t'Vil'al l'li.p robh-m s ere)(' au. tolal clearance is small.a-r c.J""i if hi o'l\"ailahi l it~· l·h . is pmbahl~' un wa rran hx ] for iudi\. General Guide&nes and Umitatiolls Eu"t'p t for d m gs \\.( us lilt' fraction t. A prtlb] l'lII also ('xists if n 'na l fUIl(1ion \11rit'S \\. 111t' flllld iull lIIay 1 illlpnl\. making pn 'tlil1io ll of till' optimal dn'i. or IIwt aholism o r n'n.stahilitv o f renal funct ion with tillll' . d nJ~ is t'\('n 'It"{1 by ~Iu­ Illt'nl lar fi1tralioll ur a('lin' st'{'rt'liuII.n 'nal t1ist'.)' tioll . ha M'(1Oil ('Xpt...iIl("(' lIslIall" vari es w.M al'('u lllllb lt. tln. \ \ l lt' n ji'(t) a pprt l<l('!lI'S(JIll' and 111-' approacln-s . Viml \1II1It'.CMAJ'l£ 11 10 26' pa rticular ( ".~ i s It"l·llIIifllll' to n 'lIllJ\'t' unwanted ("1Il11~t'llou.t] d t'a r. A Fu rther t'l'lIIplit·. 111t' (> S rt't'(lllllllt'lldatillus an ' sUlllumri/. 111 li ml' or n 'n al d t"lf. itlld lM'ni\I'. intt'IJlalit'lit di !Tt n 'n('t's in ahM).l~t' d ilTit111t for all individual wnh margtual renal funct ion.. l1 m"C' J"l<lrtil11Jitrly di ffil11h probh-ms an' r-ncounn-redlu-n-.lh accu racvof measureIIlt'lIt (If rt'na l funct ion.20 to D.t't1 ill Fi ~ll n' If). ilS tht.( n-comnu-mk-d adj llstllll'lIls an' h<ls('li 011 a num be-r o f assum ptions ..(I' i" olil'u s. dialysis Sflllll'tiTllt'!l al'ill lueteus ' ' t'li minal ioll of t1 m j. ft'll. 111 'LssUl uplion appear. 110 d JaIl~l' ill II ft1. :\ dj nsl lllt'nl o f t1 n l~ «d m in· i\ tmtioll I"L lJll n 'lla] fllllt1ion alllllt' lIlustlM put into IM st'tl ' 'J""ipt'l1l\'('.. ill fl'lIal fllllt. . All thn-e.d Jidl is n-lutivd y uncommon: t'lllllp mmiM n ·n. TI lt' thin l relates to IIn.'. lI.1 flualifk alioll.... divtribunon.t' <lnlg. OUI' is M a rdaliH' ly Iargl' d lilllj.lII j.3fl or less and ti lt' ll11'tahlllilt 's an' illat'l iH'. th n 'n. ). A llIpl i ~\. 111t. 111 \'1'1").(t' ill n-nal fun ct ion alolil' .ttioll ill p k-uts w.t~t.( nil till' h . t1istlilllltillll.ma ('lllil'l'nlm!io ll..lrIM'nit-illin . alltl IIlt·tahlllislll . if n-nal flllll'lio ll is (1.lia l.lS 1 01lj.su d at('ll w. ConM'lllll' ntly.UI~t' g ill n-nal function.70 o f tilt" I.j. fi nally.s lin k stlbst' l!Il't'S.f in till' d osing rail -. une] cxtran-nal d iUlinalillll is Ilsnally 011 least of this llIa~ui l llt lt" an d till' the-r"lwllli(' r.-an'lbility ill absorpnou. TI lt' forl'gninj.( lIlt'um'lIl tliM 'ils(' slalt'!> ha\"(' lint !M l'llilsidt' f('ll.( dllst.. and tilt" t1osi ll ~ rate must 1 ' d r.ji'(t ).tpy in these.(. which would ' othl 'I'\\. a reduction of les s than 3f)l.mUlt'(' and n 'na l flllwtioll Illt'lI IM '{'llllw S ext rell w!y ('llln plt. alld t. I . which (1l'l1IfS wlw n tilt' 'l1 1 kidnl ~· is all ofl.s ill Iht. Inw Ilu'ralx'ulil' Indkes. a topic l'own'tl in C hapter 2-1 ( D ialysis). a dlallKt' faun 0.( d uri ng convalescence or dt 'k riomtin j. . <!d.llil' llts.1 ioll reduces tilt' rt'lillirl 'ti ralt' ofadm inistratillll fourfo ld ..l\l '(1 0 11 n-nal fUlll'lio n.tan of IIldaho lislII as w"('11 as t'x('n 'tioll . n j.(. t"omplit1tling t1mg tllt'r. Ull dJan~t' is 1\('('(lt'(l (St'( .. usual pal il'nt populatiou.1St ' IIf am ikalin.!lid l' lllly IaIW' til lI1akt.1 t"lr.t' is lilt' concurrent and rt"~II ]ar UM of a .t·rtl.(IIll[XlIlII<ls \\. ..

.Ulj:!.. 12-10).lT:IIII"t ° of d m g.L"l" Paueuts \\i lh renal d i ~'a. Vlw/l. Part o f t his ('ha ll~l' is dllt· 10 11 e11''t..<-1t"'ll for n-ual flllll1:iull impai rnu-ut ulonc-Tlu. 2 1. Di~()llill binds lIIuI-II less to lis.. I nste. + 0 02 ~ JB + 52 Cl".('n oll s l"tJrnpOIlIllI(s) Ilial .'UIIlU· lates ill n-ual impai rment h...ll.1 decn-asc uu-ta-' d 11 d boltc clearance and \\. " . tilt. is also adin-" Pn '(Iic.. th t'n' an' W. 111 a daily maintenance dU<..It~ 1..' h.' «~ -4lJ'Q 1971 vv f_. a..'t·lllt·nt hy <Il l ('mloj:!. B.lIIislII al't.s a n ' pl mTl n.of dlstributtou iUld it shorter...j ~l<nod>okl~ e .262 C HAFT 16 H Furtfter Considerations Heual d is..\1l in Fi~.. • ' ~. Allot hl'r uurom mon hilt potentiulcomphcat iou to adj usting IImg ad minislmtil l1l in n-nal di st'llS(' is metabolism in tilt' kidlU~·. 3 B + 52 CI".·. shll\. ~ .L'i n-nallv t'.o .I Ca DI.\'11 t ha i 1I11lln'lIal llIt'lotho lislll IIlIlSI tllX'\lT ll\ \\"{... 111(' changes in hoth total a nd n-nul d ('a'Tlllll't'S an... <Ipp madlt's han · IJl'(·1I pTt-S<'nlt'tl fn Tp n't li{1:i ll~ l'h..(lllllll{llll ' invalid a.n 'nl 11..ld .'n' t1 l11gt'St in' _ ca rdlac failuft·... 111(" t"IJl'l1:aliun.(llo¢ {'a1ly inadi n-..tl x ll i l e Kind il's . ami 110 dm ll~l' ill dosage nW"lt'n is a ntid pa lt'l l in n-ual fu nl1:ioll impairment . Here.• sta!t·s.II.4 8< OQ': CI". dm~ ill patien ts with n-nu l di ~'a..half· lift· than that p n '(l il"ft '(l F rom loss of n-uul function.'ollilting for IIII' rest of till" (:hallJ'e is uncertniu ..·lltially uuclnmgt'( l.. Rules for l. ~ I t'l..and renal clearance increase ill p arallel when non n-nal ch-nrance n-mulus constan t. In th is c hapiN .. the unbound vulues llflxlt h clearuucc allli v olume of distri bu tion u f tlw~' pri ncipallymetabolized d mgs rem ain eSSf.18 ~_ Ct t> + 0 Q.jP"o-x"'_~'I. V. is 'Lss.o a!t't! \\. :\"ulIl'l ht. an antihiotic that llndt' rgtJl's h)ll ml ysi s dll ri ll~ ('. .doooota . is th ai lo lal plas ma cleanuux. ."3.Ift I_ f.\ ¢n' u in C bap.. ho\\ ·l.t· nflt'li alTt't.'ts ilion' t han jml n-ual ch-arancc. m(l. {1 J1l{'U ITI' n l di st'lL'it'S may alte-r d()sa~t· requin -nwnts.. 111t· 1II1't..ITlQN M id 5eve<e cWocaldalo J ·~"""':S.. 1I ("tJmIJllllt'lIt uf till' SU-{M... 16-1 flIT adult patients \\.. an' summarized ill Tnhh..<'a.I~C n-qum-uu-nt rt'tllll't'{1 he:. in \~rioIlS diSt·a. 16--.. Even so...111 \"..t'S in ti lt' d l . it is ap lla.en 'lion byu renal bmsll bonlt'T dt'h~-d mpt'Jllid. P11t' 1I~1 0i n a nd 1ll . This d mllgt' lIlusllM' can-fullyconskh-n-d wlll' ll interp n 'ti ug plasma ccucentra nons uf du·st.tt· tln. 111l' total plasma clearance.slul\.l. This dec reascd nssue hilldiu!?: reduces ."tll l ~ ­ ) ca ll)' a nd to\ i{.011 Ihe d ilTeTt'lI{"( hd wt"('11 them Ix-conn-s s malle T in ' patien ts with 1 ' r renal fllul'tiull.. kid lll')' ("'"{'n thou~h it iIl\1Ikt.j~"""""""".<.. WIth MlitII • • tII h • • _ c....16-.1 ioll of IIII' lo lal at1:hit)' o f thl' d m~ lind of ti ll' dnsa~l' adj ust mt'nl Jl("('(lt'(l in n'mll failu re (~n hl:' lllueh mUTt' {"tllnplt·lI:.. th t· pn'st 'ul"t' of St'\l..'er._ "Cl.lll('(' dose I lowt.1:s cn-ascd omrcutrattou o f plasma allnuniu.·s llIt'l aho lis lTl .slIl's ill un-mia. a l'tltlt lititm fur which the dmg is IISt I!.l'i IInll'tl ill Fi ~. .·lm\"{· a decn-ascd ahilitv to Ilw lal xlli7...ll'ss.~ md tim! t'llpt. .l'i ht 't'n s ll~eslt'tl.dJ<tll~t·s iu d iJ'oll:in dt'a nu ll" a nd voluuut' uf d ist ribut ion \\i th "m al function a nd l"tlllgl'Sti\l' cardiac Iailure. o htai llt't l fnllll pllJlula tion phanuaco k tm-nc studies..h(' hllliu!?: doS(' n-qum-d hut 11as little o r 110 dT('t:! Oil tilt' mai lllen."sti lll at i ll~ n 'nal d eaTlllll't' of a dm~ fmlll s i o ..dmg. An example is that of Inupeuem. rcsll it i ll~ in a smaller volunn. tilt' lIIt'tal xlli!t· of 1II00vhiue " lIloTphilll' -6KllIl'IITOnide.1Il~' ot her acidic d rugs an' two 10 th n-etnm-s It' ss well-bound to plaxma proteins in un-mtc t ha n in normal sllbit..)'1I u f t n'ali n~ suc h sit ualio ns .II t DI••• I. Furtllt'nllllTe..'ima concentration. • 1 'C)U".v r.u')i n~ dt~n't"'" o f n-nul function..g . CI"_RC I . Ihe in h 'f{'t'pl valul" p n . .... .to rhn-efold. P{'T lmps.'i Of (llSTW$.-.(F ig.t· a\ well . Increases two.\Slllllplioll is tha i mt"talxJIiIt. For ('Xilmple.\t·f{.:l..-.~t (.slIlIIahly wht'n' no kid nt'Y funl1:inll is p n·~'l\t ...!t't.IlI'(! nu lIn'lIal dt'amllt'(' 11\\"( IllX 'UfS ill t ht. . . ~\i llg riseto a ('o m 's pomling d m p in Ihl' sleady-slatt' pla. Furthermore. alt l ll m~h d hplm..

'ly. Given th ai all tll.·'pl..ar m....u'oki .·n...KiM!) ' ..1 m m.. o.. i" dil. -il(. inl.·lIn..lar Filt ralinn rate .".73 m .: add ( '''Kll~ i7..1 till' ' n·na! o.. TIll' .al c" ·ar.1l!!:..-k ) d .......'l"n·lL..S( dru have com.A.zo~..wt i. "a ~ ~~ . G. Hank tlu.1 Li ~t ami hri plly disr-m~ ~ i 1( .•• diam l"'1rl ruo.('ol . .( "n. m In("l~·a ..p..f 'ast·~ in .. J .'I." . A. a..•..·r llo 'h~dn'P''f>lic4... \'........1Ii('h th t' pIJann.. t . "'rKl n. STUDY PROBlEMS {Answers 10 Study Problems ore in Appendix 1 1. a1"~rn ....jX'utic windo w ..'-pt iola.. "f tl... 19'>-l.M TI. :o..........1 hm<h hnn .73 m2) 1.i lb n-nal fail" .· . .a )...10.' "'ith d. ti UIit that tlo.. regimen of th e cephalosp rins listed ill adu lt 1).· n·.· n"" .. a'l('M "f tI....1 l ( Slot" H I:... 16-4 for whidl you would re om mend th at consldc eratiou 1)(' ~\"l 'n to a change in the usual dosa rcgtmen. gs parable therapeutic indkx-s...U:. "~ Po Enl\Ooi "k'...l. I" d . mna! subjt..· l\Oo~1 dl'anll"~" d" n"t I" lTl·.raIk.. ..I"r ) " aud Il"na! i hla<.'rhi.1 n-na l function .. .....· in l'". tlo. m 'lLl illl/: n ·na! f" 'lcticll1_ Th' i""' r' . ge T..l creatinine clearance or wrutn creatinine havt' b en giV li.·fun nllmichtM) al.Cr. Hr ..!i... " . II. Snrp risinj.t ..{ im lp" "" m (lhic ·nanwri...iu . 11i3-193 ..• anlibinlk imi1"·.. ~· ' .. Tntal pla.. fmm most impo rtant tn least important..~.pl ...I i <.. 100 . ltl. "'i l l..Jium in ". rl. K_II .. • • 50 - • • ...I..· thai monitori ng of plasma conceutratmn. :'\al111' th t' situat ion s in Tahlt. 16-11....n"..rtic·" ts . 51Cr-EDTA Clearance (mUmin per 1....." 10"" I.ll o:-· n·"...'nts \\i lh \1tl) i ng dt~n't's o f n-ual function.J • • • •' • 1 00 150 .1S ar K! p.• "'ilh ~ E ::J 200 c • • 1 • • Renal S u ~ c ~ ~ ~ \ tI.I"'l1 .......ihilo r d \a.'JId"'.. ..tatin ".situatiu ns in Table 16-4 ...' ph. 1 6-4.. IS.me . for ('(msitll'ring a dmllgl' in a do sagt.• anticipated change in clearance as tilt' hasis uf you r ra nking... hl·I.. ti l t' topic of Chap ..~' ~" rf...." • 13 • Ihal tho· tlmll: i.. "c~' '' rri nll: (Adap'" '' Irom \''''1''''Il..ar .'f'1 i..no" r('I.. '. l- Clfn . h . F't J!CE NT o 00Sl' t</i!-MlJV ElC tfT£O ~O ...T' . fh mt .1c ti.< .h" li. hul til t' \1Iriah ilit)' n-mainiug is often su ffid t'ntly la~. I•.. lfi-71..I lhal Ihi.."'i of dn lgs is known to ht' alte red... A CeIt... 2..In ll: must il.. a nmrk"r uf ~1l1"'".." .. This kind of infonnalion is use-ful e t' fnr initi alin g d m~ thempy in an indhit hml patjent.." .... lIIay lx' prudent fur a t1m~ "ith a ua rrow th" rJ..l ".nati nn I..a.I .. QB Q6 2B 10 B C o E Cefon"od Celo"'Ondole Celoranide Cef!az'd me B4 B O 5 40 20 '" ... .CHAf'T 10 H ~"ASE 400 " ~ E M ~ • ••• 300 • Total • .• J!j . 0 0 •• .1.jn ..mli....f ·' ...t't1 l t Il 1....

Allp rU\ imOltl'ly tj...'" """""'J e. kJ{.l 1. P n 'pilll ' sk('l l'Iws o f l ilt" an tidpalt"tl amou nt o f S"llIlt't II1l). E\. ....I ..lo} IQl'. .:.\ indicated hy a serum l'n 'ati n im' of 2..0. IIsualllloUnlt-na lK'I:' d o.... 7U.. -I 111 T alllt· 16-6. IXIIt.. b .' 6 II t ~.lyb Blood c'ec-coce.v.11111 . e. IXIIIIS tillS(' ( 't.v.palit' lll In til(" va lu l' {':\lx"(1c'(l in II t~ llk·..."1e 16-5 .k~ 1).. r.. eonce-ut ration s ll'iSCIl..2.l" modt'fald y hupai n-d n ·nal fUliC.r>e Img/dU 18' 10 " eo 25 82 3 15 06 I 6 Estimah' tilt' l'n'a lini lit' d c-arall(. timeha d tl. K I " .".l'i a r. .-4."". """' • • 06 ..'t" in (·'K.dic ci rrhosis..· bt"t'll ad jll s!t"tl for: I.fj hr a nd 0.. wllil'h is n ·frad0l")"to ot ln-r antibioncs . Express n-nal function . n . a~t· a nd .oool. TIlt' l'Ili ltl's a!{t-.. -t-year-old... -ithin t ht' limi ts ) UU dt' r1w"t1 in "a" al xnl ' 10 m inimi 7j ' the Iikt'lihol xl of tl u. :2.. 't·i~h l ullly ( 110 atljllstllwlIl fur n'lIill d i~ ·aS(· ). _OC<tlOoClO'O 1""".' ill tln.im 1 i{~ in Iwp.h of lI WSt· illdi\. h J\it· m.- Oro! BoolNo.1. .il.J 5. h ...11 tltt' oral hif)a\'ai Llhil i ~' of pen tazoci ne."ull! 'A_ _ d_'-""loaIIA ~_ t e-~ nQo>.n. ill a I)Vk aI 5S -)"t'a r-ol ti 'I pa til 'nl ..-1 I J1~.lldut· iUKI ITIl'pt'ridint> an' (·liminalt-c.lII ift '~ lalioll s of ('.We 16-6..'i-) (·a r.u h . \'am 'ulIl) "('in j<.. . CHAPIH 16 3 . C " I('lllah' 1111' n-ual fu ndiun i ll each of tilt'S(' pa tien ts... • __ 0 18 1 15 0 08 0 08 <I"d~ 0_ ' 0 00 " __ 0 87 0 57 t~d""""".)Cl llf a df)~' o f vancomycin is normally {'x(:rt"ll"~J IlIl(:h all~c '( l . Til l' cluld h.. ()I'h' rlllillt' ....llIl1ll1otri/l.-_<1 _ _ . Its IlIllf-lift" and voluun.. X Ullt ' of tllt' lII ts U1l(k'rgoill~ a dialys is proc ed ure... IUIS-(:Ill lall IMI)' \\ilh \ Iapllylul'ul'{'al p lll'ulIlOl lia.. dU )'\('1I for IIII' t he rapy o f a 17. nhout Iwpatic d r rho<.1 prilllari l~' Il)' I K 'ratK: melothol i\ lIl. w('i!{ht...ah 'C l t th IIlt'm py in a I) Vieal 5.. <I.. ~"B:It <low a ... l il' lI1l 5 ... Tahh. "lI~("!it a 1llC"(-hanism to t'xp lain till' a1tt'n'tl \.') ... Hili...p l..\!'t'Ssist'ly h i~h tU lIt't'u l:r...d iu m of \"llllt' llll)..unouut (o r C1 l1u'('nl m tilln ) .."i li~ tlMI . :\"(1 luatl ill~ ( "N ' is ~\l' n in t<il!J('r sit uation . ilion' tha n Iha l Y l)f 1lIl'Ill'rilfillt-.'i -yt'a r-old palit'lll who n-ce-ives a )()( )O.Jill .(. Est im a lt' till' maximum and uununum stt·il(ly-slalt.. {lifT Tt'n l Clp in id alla l~t" • i . '" M 25 " F I t<) •• F " M 15 08 160 30 Age 1 )«1" ) (em] C'eot. aud n' nal runt1iull. .d lild d("" t·lopi n~ utol:o\ idly a m i a Iurt her de-crr-ase..uiNl :::J.."'_ ... .cluak h .!') . ill pa t it'll h .hl rig1 I """"'" 5efum .• IIIWdL. lll' lk uhst' rYatioll s tlf I"... 12 h r.IJl ~ i. 06 .of t1 ist rilmlioll an. TIlt' l'Il iltl. n ill t1w ho(~' .1 dnsil~t ' " 'WIIlI'1I fu r the 4-) l 'ar -oltl to a tt ai n a nd uraintain tI.g"..ill n 'na l Iu ncnou. .)t>llt.10-.·" phamMI"lI\.1 ill ll .is. n> )('(:ti\'t'ly. '-aricm" dat a UII fl M p a lr tients wi th \-af)in~ tkWt"'-"'S uf n-nal fUlIl :tiull an" li'Ott'tl.i tl.is afT('(1('lllll ud.tli u of ('n 'a l inillt' d c-amll('l..

f !Io'o<b<I"..I.· SU5.. \\11 ~ \"t ' li or. a typic..il'll clearance of lor ' .. and elimination parameters of this d nl~.. .>lrOpleg >c (n .... I .'tl lw palo(1..uA'Il.. E lilll ina lilll\ h . a possih lt. ~ Thoo 47 J S4 · J ~8 .v.B Gorv-!O """"""' R . ami o ral (s ustained. 1M ""'<lV.. < "" /" .".. .. I..t.. AhsOIv t ilJll 2.....release l-.ltl. 1)('tTI '.: fylU. H_hhy hltiMb ... wi'" 1p1_1 CenI 1_lury . ..."l'1\ Iwalt hy suhj('('ts and (:irrlloliL' IMlit. an a llXio!yt i<-'....I<->""' ''''''' -' ''''''--' '''''<l . and . I.()9).lIular Illt' laholic ad h ity .uts wi th n 's(M"l1 10 III<" foll{)\\i n~..... AU~" P.. I QQO u. . T Ilt' plm rm. U 1 lt' lIIorrl.. in ti lt' tet raph-gic an d abk-bodu-d spinal injury) patients.\ UC follo\\i ll~ t.l\'aibhilily o f lorazepam is gUll .'il ·d hepatic hlood Ho w...3 0 4 1 :!: 0 . CI". is affected by cirrhosis.q..bil o.:: "~it1.kg am i F "" 0..~ l«o:... Ti lt' d Ol~ (2. la hlt't ) admlui stranons.5 15 :!: 05 Doc~..kl.c h_. and sCtLa ti\'l ' hypTlot k . ..tlc d htl...-dooo<o<aol~ "" "I 31 :!: 13 25 :!: 9 20:!: 12 . 16-7.. aud . antiemetic. Ph.".. THYSlIltKTS ce-orc PATIENTS dose (l 00 mgl 0'01 dose (400 mgl (w~i nech eloo!le Iobletl ~AWI<xtod~ ~O"I8> '" Inlrovenou~ 0 8 ~ 0 . of Ilu. ! '-tIaooftop. .. Loraz epam is pri marily l'I iminalecl by ln-pat ic g.. par aplegics .'pillt' \\i lll tlelllo nstrattod t'llk ac. f)c't'n 'aSl.\('okinC't K'S of loraz epatu . mean pe ak aud tmuf:h concentrattous t'xpt"{1t'tl O il oral ly ad llli n istl' rill~ 2 1llJ. 11M' Ullly nu-un val ues.p~""""" 01 ~.. For till' d jl ll 'l)t IS!.L~ a sing:lt' I.1 ill patir-nts with spinal co rd inju ry.'"'f . 7..K 1S 1 ".. aut kxmvulsant .o.0 8 0 52 + 21 :!: 1.hall~t'll in til(' uri ne.hj('('Is... Le ss t ha n 1% is l'xl' rel l" 1 1Il(-....\l1~t 'S in half-lift... ''''''''''''' ~ 0.H·Uh . Discu ss each of tln' follll\\illg mechuntsms a. 16-K 1111' dOl ~ is bo und 1 albu min A 0 O. ""'<l.lpo M On P>o. :2. I_ .·y . 1) c Tt.!~il' u!{ p n -scn b -d fo r Ihc' trea tnu-ut o f l'nl p -riplu-ral arterial disl':L and i utennit te nt claudicat lou.'S in Ix' nhnifyllilll' kim-t ie par aun-ter valm-s ht'h\1.9 for all sl. 6 . T Ill' kiudit's (If IX'lJloxifyllim'. T ahlt· "l' If s!lows tln....l. was studled in patients -'' with spinal cord injury .L~ . di sl ribution .c.....st udy ill I t't mplt~l'S . tll) .In 2-min Lv.. UShlf: tilt' ktm-uc d al a ill c'lI Tab lc' 16--.abso rp tion. D istril uuion 3. tln.J -MI<I:.91 Pcropeqc (n ....0) Conl'ob (n _ 91 20 ~ 0 37 ~ 11 4 2 + 19 1. .'I""'<JI<<nl ..ltl.tllf:c ~ ('al('lIlah'l l for tlu. 1)s( ' Infusion.)"" .CHAPT E ~ 16 . U M' an average weig ht of 7U ..' of t h is probk-m. Brit'lly d is('lIsS how Ilt'p al il' cirrhosis is likd y to produce ti lt' dl.....L \slITlling instantan eous abso rption....... I. C ~ G a<dJaolc>-. expla nation for tilt" dt"{'n 'll.. IJ.... ~.mg: t1 ' ) \ \01. M.~ J I6 ~ I -M¢ l QQI a . TIlt' res ult.d l .. Dl'I N lIlillt' d ifft' rt'lIt1.·llti ly (t"\l-' ry 12 t reauucut of anxiety. C.2 14 :!: 0 5 1 330:!: 170 017 P o-<..t'()I (.. . and controls art' S U IIl ma riT 'l1 ill Tahl t.." ¢ \"l n . 1Il J..11I(lIn midation. (1I l 1 lrr). Lor.1 rq~i nl('11 for . calculate lilt.6:!: 0 4 10:!: 0 . a !x'II:fodi.. Soogn JI ~ S ' Ell:>«>.u.••ptI.

1088 ~ .. Entt'mlll'pafie l')..~ .. .266 "w'" CHAPTH 16 3..95 . 1..-..1. oI "''''''' 0. 57. TIl(> c!t..v. 10.') min. \ ......" ~ \1.107 Com>d GJ 1. "_Ithy Celttrel 1. ~F "'. ..I••IHIII..9 4. 4 6.I.. pTl'St'IIt1· of Do tllt·St. ~.It•• 16-9. infusion over I.95.h With Clecrcoce ImVmm/lgl Holf..l.llic c irrhosis and six Ill"altlJ~' SUhjl't1S . ohservations support tlw notion tha t variah iliry· in ch-arunoi is ~n'ah 'r in till' hepatic ci rrhosis than in its ahst'n('('? B ril · ll~· stat!' the 1Ja..I_.37. _ I .. 4 2....1. o!lM'rY ' ('(1 in six patit'nls wi th !It'I)...5 liMtII· at> H.IW:llthy sulljed >..14_1 V.16.92. .\is fO I" ) U IlI" con- du_illus..":li nidt" an untldvsrhvtlnuic a~l· ll t . oI ~ "..u s«>-sn ........ vre-. r.7 Q 18. The dmg (2 mglkg) "~d.<. Q 5.a rnllll..28..0 0Adopood . Tln. CI_NM_ II. 8 2. 11. ~ Ckrog.lf-lif.. ..alf·life "allies for IIl '(.:lill g of tlmg l hmll ~h its g h ll'Urllnid t· .s." and h. _ ~ . S. ... ll·rt·listl"l:! in T nhle 16-9. 96... n..illll('·" Ims of drug or meta bolite in f('(:~.·n 11)' i.. P. Inc reased biudi ng to plaMI'" pmtl'ins._.. 8 3. 43....gad. 0 11 an'l'dgt' ... matched in u-nns fir agl' and wl'i~l l t \\i lh tilt' cirrhotic group.-.lole [1111 ~ 6 2. 4.78. H~c CI"..

11. 3. Furthermore.ltiiUIt is Illust rated hy )lal it'liis ". Illan~' undesimbhint eract ions <In' therefon.atioll.ta ke place wtthout alT t'(iillV.ilall(lin~ of. interact ion is lilt' c.('S ur (1)11t' ui d iliollS..(\l1I1 is tha i 1 ). 2.lrt' many _ Our. Ihey an' ~mdt1 1. o r phannacodynauucs uf e rie t1m~ is .. im portant .. th e mcKie' of action and til(' pharmacokineti cs of each t1m~... lnfectious.. \ Iultipl(' dnl~ Ih('rap)' t'an ~h't' riSt· 10 a tim/!.U llnll~ d OlV.poll'lIliall. .S \\11"111 tilt' IXM. That a ~\"('Il tim /!.(' of Ullt' or mort' dnlJCi. ec ca sfonal ly..\Iso . tilt' outconu. 111l" reusons for Illultiplt' ( I m~ Ilwrapy .of c. o r a faitlln ' s 10 recall.\'01 "t1:. hod. of in!enlt1ioll t!t'pt'll(ls o n tilt' 1'1 11I('('11n 'SIJlJIlM'S of tilt' IM trutton of lI.niltltlt' to he chnicra II. Furthermore..It1in/!. a\ui tbhle ..'(·sSl-s and pathways of tim/!.lltt'n11 b)' another.1Im·1I1 d Ol~ ' ad minislratioll is d iminisl ll't1 tll('rap(:ulk t'ffic. like' t'sSt'llt iilU" all xl)". i'llt'mc1itJII. Implid l in lilt. defin ilion u f d m /!. · Anotl u'r n '. and I'<lt:h clinician ilia)' ht' unawa n . D Ol ~ jnn-racttons an ' of ('UII(.U1t illft'T. ( ''UTll III O ll ly rt 'l"t'iw ' two or ilio n " dm~s concurrently.lJ. iscbeed by uocther drug.("t. inpatients Oil an' r.I's and hence on dose and lim e.. The IMlssihilHit-s fo r illlt' rat'tilJlIs ..ie-d pmc.t' illtl·r.I. A t1wrtll1f'utic tim /!.Im~ interucnon Ilt'(1lrs when c'illlt' r pllanmllll"i nt'lit.INTERACTI NG DRUGS OBJECTIVES The reader will be able to: 1 Discu!>S the graded nature ofdrug inlet'ochoO$.(11111 medinu lethal dose. .'(·llt 111Ol1.ltil'n ls fn '(1Ilt'n ll)' sulT r from seve ral concurrent diSt'il<. i\ .mc. man" alT 1t' t'(. The tlt"grt't. l'\)Ill't 'nlraliun or till' t1lt'rapt"lIlic alii\1!)' of 11ll' (ImJCi ill\u l\'('(I. a nd cance r. Interactions an' o f a !)1)(' or of a suffil'it'1l1 mav.l'>t11Ioxidty o f Ollt· or 1II0rt' o f tilt' admtntsn-n-d dm ~s ..lli iu llS 11t'IW t'('1I t1m~s wtthm Iht.q re lilt' 11<..1J1lc.:1 in till' treat ment of SOlllt' ('ond itiolls.vno dfl.ug i$ cberedby concurrent drug odminiWOtiOn. · an' almllst huurlcs s. (If ('I1I11'('nl. AnhCijXlle the likely chonge~ in plasma and unbound coocenb'olions with time when Ihe phormacc*inelicS of 0 d.!>t. lilt' dnsa~c' of lIIa" y d nl~s nc'('(lt11I u demonstrate a d ill i (~dlly si~n inCl.k of IIll(lt·r. tlmJCi an' p rt'M 'riht11 h)' tlilT n' nl clinicians. j\(' 'toUl" "7 . illlt'r. combtnation tlOl'S 1101 t'nSIITt' 111I'occurn-nce o f a clinically SiW lifil~.-llt.of tl lC ot hers' thor t' ' apeuticuuuu-uve-rs.IIISt .(·s. Yl"I ft'\\"of Iht.ln l d n l!?: int e ract ion cau t" (. r-luninanon art' " XI minor ttl ht. giveo unbound pIo. imlt"t'11.Tlu. ami p<lt'h ma)' n...'9 concentrolioMime dolo.n'..:t> fin · d m !-:s d u rin!: a huspitali. or illcn . -"1)('(. kcettaj" whethet phorrnoc mencs 01 phormocodynomics of0 drug.IIndl'sirabl" t'l Ill~'I I IJ( 'I1('1 'S of a d Ol ~ inll'ra{'tinn lIlay ari e Irorn a 1.. i'ltl'mrlum has then oceurn-d. i lld lltli ll~ a \1Ult' ly uf cardtovascnlar t1 i!\tlt<. ettlu-r tilt' II1llXlIIIld dOl/!. or bo!h.l'iOIl is IlIa! dOl I?: com bfnanons han ' 1)1"1'11 found to 1)1' 1)I·m·Rei. 4 Showgraphically thecceseqceoce of 0 phormocobnetic drug inletOClion when the mechanism and the circumsceces 01 itsoccurrence ore given.

ud~lla lll il' and p ha rlll .... slld l . lxltl l a rt' dlilll ~t"li. 111t· rt'.• states ..· hn:).K1i n~ t l m~ had 1" '1'11 adminish 'n'tl 10 lilt' patieut aln'atly slahili7. tilt' It'nn illtt 'mdl.NlIlS fo r tht'st..to ~t'lJ('t il. CLASSIFICATION Om' s~~ lt'JTl nf d 'l.. M'1·II. slId l . who wert. Pre.ill ahsUllllio n silt·.. Tl w ill!t·r....two is madt' hf rt'lalill~ rt. . this d 'lssifl. tilt' lin1UlIslallt"l"S . tX"lolsillllally. pllt'lluha rb ital ap llt' ars tu rt't hll'l' tilt' " bsurp tio n of th e tliun ·Iil'. a nd I~·fon· pnx"t"t"tl in ~.".C......inlt·r....16 tln..L':ulaul (·lTed s of warfa rin.si f).(l t Ullt rihlllt·..nterOCloon ld. . a nd ill paueut · l'l lmpl imll'l·.K't·S hUI is alStI tlisp l'U:"l't1 by t11(' utlll'r.tilt" l·.. wln-n tilt' Ililtit'lIt is stilbili1.. it is unlikdy t hai a dm~ rs.. Ct..i l~· s pt'aki n ~.. inlt'md inn 1)(. \ '..a mple."l1on tilt' ori ginal d rug. "od alt'1l \Sith a d inimlly si~nifk-~nt intcructiuu in a n inclivalual shollitl always ht' l~Irl'fllll~' s dooum-nted.n\ll first. dmg:is ad minislt'n'1110 a palient sla hili7..f)' p!la rm 'lld d nt'tit· paramt'tt'rs . Ct ·rtainly.t' r.l(lIy 10 iutl il'lllt' ' an y .lkillt'tit"S or phann'll't... a S("tlatin' hypnotk .17-1.".."ocolfy umIObie CIt mv/l.. I'l m nlliu.I.u1 inll ht·twt't ·1I " m t1n1 ~s . An ('Xo'lmple is tilt' t'lIIllPI.. a di Sl-1lSsioli of wlllli is IIlt'alll hy Ih t' uun l i ll t. Dist illti in ul.~ ih l illi()11 ill wh idl Ullt· dnl ~ alT('<.' al . A a nti H.sl lld it'(l pms pt'(1in ·ly and who n't't·j\'t'· chloral h)llmh' d llrill~ warfarin Ilwrap)'... In t his book . For cxamph-.('Iwmlly... m il l ht.wh ilt·. ue h 1 .rI ••YreeIellI .1 hlontl flu\. . lhtlly ef 237 W. ami 10 m.d-ug_"""' '''K(l~. 'l.. bIe10 e-. CIII_I Ny••••- 237 6Q 28 2] 19 ~d · ""-xtod """' o:." till' St"l'lJllda. · d t'h"l1t'1l ouly when tilt' illtt'ral'till~ dnl~ is initia!t'1I 11r wit hdra wn.Jmh·. n~ t1 "'~ iut emetions is 10 1I0lt' wheth e-r dmg rt'S[M IIIS(' is inl"n'. T Illis. Cilluml hy. . lIu.o lTl'JI( li n~ t1 m ~ is \\ithtl r. wh id l l<1Il a riModiller t1mlll~h a phrsk~l l illtl'r. unly if tln. . III this loLs('.ilrll1al'lll llWl~dlly atii\'(' SI)("l:it·s.'11 on tilt' dm~ combination..pIed..tlk rt. Xu dl 'lIl ~t· ill 1111' unI XlIlIltl l'lIIW 'n lmlioll t rt·slltlllst· t'll'\·t· illlplit·s it ph.-s to d m .l<1i oll .. Uflt Ilt'lp tn tlt·Jim' lilt" nu-chauism of tln.'lil ion IX'''''''('1I two )(· t1 n l~s for a l'lIIllTllflll hilldill ~ silt· 011 albu min: {)I\e tl nI~ dispI.mondaTt'n'nt ill tlwt pane-ut than would orlu-rwtselx. was pote-ntiation d o f warfa rin's (·fTt'(1 1II1all1hi~ IOIlS I)' demonstrated. A fillill ~t' l\t' ral connncnt no-ds 10 1 lIIadt· n:'~anlin ~ tilt' 'it'fillt' nt't ' u f dm ~ aduunlstra)(' l inn Ix·fon· l'llllsidt'rin~ sl)("li Jie mechamsms u f t l m~ inft 'rati io ns .-.-eII•• htw 17-' ..K'llkint'lil' d ilTt' n'lIt"l's ehn. 111l' iuteracrion would alStI han' IX"l'1I ck-n-cn-d if t ht' i nlt ' r.-\ d m~ inlt'ral'tillll is likt'l y ttl I. tilt' t hlS:I~t' rt""lt'n of ti lt" a ITt'f:it"ll drug woukllx." a l<.t "ll o n tilt' d m g l~ltIsi ll ~ tilt" tnn-racnou..tml'K'llkilwtic t1m~ iuft'fiI li io n.dllal differences ill II\(' dU!."'e .. Fur t·:>.nle<oc hon J ~~ CHAPTE 11 l/ ... F. fu rtl'>t·mid.l" l'OIllI)('lilinll for prolein hi lltlin~ siltos.. to eonl'lIm '1I1 di St·. C I.L ssifil'1l on tilt' basls o f wllt't1lt'r pha n nill't... All po!1eIll$ who receoed chbol hydto!e dvllng worfu"l1 Therapy Those ~I!> who recewed c"b al ~'0IEt Ioi olleo~ 3 coeseccnee ~ Impou.fm is \m rt J.xh-w .\('f!llI·llt"l o f drug adminis trat ion. S t rit.alinn tltM. is l llllll~ht til poh'lIliah ' tran sic'IIt1)' ti lt' ilulkua.dat a ill Tahk.t All '. int eractions an' d .. ill patit'llh' n ·j.III\' utl lt'r fati o ". II .t III"t""l tffi'f1. half·lift..-twecu rlu..l....#{. Yt'l in olily 2:2 of 2.. \\l lilc' [•. Ihis \\l m l implit·s . TIlt' n ·sult is a dlan ~t' ill OIl(' s l" o r 1Il0n ' of till' primary pharm 'K'llkilwtil' p... d iffe n olll'(" in n 'sl'Il lll_ an' "'<Ill)'...-. kil .... hil t th e n 'nlll d eOlrdllt't· llf pln'lIllhn rhilal Ji'..sm a t'lllll'l'U' tmholl o f tilt' pl. 141 )9-1 .Jluole . .·SptlllS(· 10 till' IInlxlIIlIll pla. ill!t'mtiion \SHuld Ix· dt'tt'f:1t'f:l if tilt. .L'it"l1 or decreased..lltlll . I~llalllil._ DetectI• • W.Kiioll .-'''''_ C. ..Ultltll('r.l.-m1.. Illd lldt'(l art' im li\. ~H'II th t' uSlIal largt· dt~n:"l' u f \'ariahilit~..l."'9 chor..I~t' n'¢IlU'1l uud duration 'il' of ad mi nistrati o n of l'al'h t l n l~.17 pa lit'lIls.ge~l P()6e<lllohon 01 hypoprOlhrombonemiC ocree 01 worfa" n No deomonlhoble ." is inh 'q l n ·!t'1ll1lon. llIi ~ll l thllS 1 i1t'noted by A H B.. in tilt' . hut ti lt' rtoslilt i n~ n~i lllt 'lI llIay still Ix' wi ljuu ti lt' lIo rlllal mll~t· . whid l ill tllm alt t'". l Q1) .rI.. is aln-n-d.. (.mllllt'!t·rs.rha ps d inimlly lISt·fll l.. or t1 lrtlll~h a!te rt"ll physinll)"~Y.".1 _~ ..

ti\'t·ly \\i tlt D mg A.t'l. This Intcract lon is f/lli tl in'c1iOfwl am l mnv ll(· dt' lluh 'tl bv A -+ B. which reduce-s tilt' hi(). tI1 ~('S in a\·t'm~(· ptL~ lItli concentranon \\i tll tiutl': an alte n-d rate of ubsorpnou l'ha ll~es only the t1t·~n. mu st always lx' kepi in mimI. .' situations in wh ich hio.1:\ t1t'pit'fs tln. till' dosing rat{· of D n l ~ A i. till' {'()It{'('ntration (If Dmp.(lIltml is satisfal'tOt')". t!Jt' Tapt'n tk {.CHAPTER 17 INTE I!ACT ING DPUGS '69 is i1 K' rt'. T lwll.rt'tl dt'aran l.thd m \ \ 1 1. olls plateau \'alue in 3 . op tima l t1lt' TaP~' \\i th D nLJ!: :\ in Ihl' e prt'S('lll.cousfde n -d \\i tlum t also dt·fjnin!!: tilt' It·\"(·1 of tilt' ot her..'(mlinllt·s 10 II(' S adm inist(·n.": A. h ut till' chengc in rl'sp(lIls(' of ' tilt' uffecn-d () m~ H. II n\\"'\"('r.L~( 't1 hy tilt' d iu rt'sis pr odue-d hy fuwS('midt·. ~. howt.mtil ah ility is alte-red. in 3. illtd Ihat. . in alllilil><ltion of ti lt' ' ' prohlt'ltl h ilt dt'si ri ll ~ tn ~\'(.situation in which a patient sta bilil. a1lt'rt'tl distrihutton. Howe ver.\ lie aftt'r a siJ l~l t' dust' nor Ace within a dtlSitl~ interval at plan-au afu-r chrome do stng dla ll~t'S unless tht' hin.1 o nly if tilt' usual d()si Jl~ mt{· of J)rtIV.mort' rap id the absorption p n x. Ah emat i\l. A is appmprialdy in{'Tt·.~s i ll~ many . tlwop hyllille.1\\i lhollt also constdNill ~ tlu. t·l1ll~ll'in. ill tht' case of mutual and e h idirt't'ficmal tnn-racttous. T Ilt' t·\"(· uls an .'tI..~ i n(' n':L~'t1 appmpriatdyal tilt" liull' thai D m~ n is inloMlu{'('t1. thd ra\\11.att'tl t·fft'<.\. tht· ti mt· I M'i n~ dctern um-d by t!lt' ehmlnatton half-life of thi s d rug. tilt' measured resptlllSl-' of O lll' d ru~ caunot lx. it shoul d ht· borne in mind tllat S(. ('.n'CHO/wl illtam1ioll alld lllay b denoted by A ~ B. :\ f(·adlt·s a Ili~l lt' r p lat eau wht'f(' toxki t)" is Iikdy. As 101l ~ . ~ to 12 form s tilt' basts fur <li S<.('l.\"(.{1m{'l. Suppost.2. .(lIl('t'lllration o f [) rtI~ A ri si n~ t('It) hi ~l . \\1lt'1l ~\"t' n in sulTk it'nl q llanlities. Esamplcs of 'f d m~ inh-ract iouv are listecl in Tab le li.' l d m ~s almost ah\"d~".'("til.t'l.111 1M n :nsidert'tl indt'Jll·mlt'n tly. at duS('s nonll al l~' gin'n . It is apparent Ihal if no sle ps art· taken to change till' t1osi n ~ raft' of D mg A. tv.(' o f J)f(l ~ B is adli('\"t'l. 1i ...l'>(".'3 d imination half. and altt . tilt' antihiotil' wl· euocu-in inh ih its tln. chronic dnt~ tln-rapy. o d(I('s 1101 alTt'd tilt' rt' SptlllSt' OT tilt' pba nnaco ktncucs u f enoxacin. ItOW rece-ives g () m~ B. Cousidcn-d 1I0W an..('ntl pba r macoki m-tic panul1t'tt'rs rnn ht' alh'rt'tl sil!tultallt'tlUsly.dist.l~is Oil l-!J.I.1on Dr u A. hO 'v r-r. Ol\ llt'foT .111110t II(' adt't luatt'!y dt'fillt.I. wit h eJll r h. on anol ltt'T(Il"lllsion .teh other.('.un alT <.'rd~e value.'I~·.. '111t' material in Chaps. 111 t'()ft{'t'ntratioll of Dm~ A t' mJll ld t!lt'n f(·tuO\ ttl Ihe pn. tilt' effect of one dm~ 0 11 anotlu-r is r-cunmed under the S(· I><tTiltt· lJt'ad in~ of altert'tl absorpti on .3 e liminatioll half-Ih "ts.\ anti i that tln. i .thti Tau lt . li\l's. this may not lit· lilt' case. the two d m ~ t<~t·t1lt' r. if tilt' . affect t-. A pm hlcm ariS('S. TIlt'S( situations art' common in . hul tlw dosin~ mtt· of D m~ A is not {um'SI'ltmtlingly rt't lll{. Ii-I.·llsS('t1in Chap.L Do tg H t. hilt t1lt' phyllitlt'. 'ss the h i~l lt' r and r-arln-r is Iht' p eak plustua ceun x-ntration am i th at nei ther total . 1'. its concentration falls 10 a lowt'r plateuu.1. In a IInidirt't. ahility of tilt' dru is altered . hil\i ll ~ rt'l.'lltmtiou· rt·spmlSt· {'UT\"(' uf tilt' t'fT('{ of D m g :\ Oil Dm ~ B.~.fiOlIllI interact ion . regarded a-s a hic!. (".· that it is tlu-u Ilot it'(·t! thai tht' pat ien t is Ill) l un~er 1 'It 'i ll~ tTt'. Fi~u Tt' 17. Clearly.l~I)t'{ts of phurma('ukinl'l i{' d m~ mtr-racttons.1 tIlt' pmhl" m. l l1is llIi ~IJI lit.iII ust mlt 'tl in Fig.'ft't1 ' t' DOl!. Anotllt'Tpossihlt· situation is O llt' in whkh D m~ A is adtlt'tl ln tlw n ogllttt'n of a patit'lll stahilil t'tl U ll D f(l~ U (F ig. l1ll'rdl)t'u ti{' · {'(mtm! m lllld a~a i ll 1M Tt·sloTt'l.1\1Iilahilit)" of D m g A. if [)m~ B is sllh"t't!IIt'ntly \\. at roucentratious achieved ill the rapy. Therupeutk-{'Ons("'!llt'nl1'S of a dmJl~e in t'itllt'r rate or extent g of d m~ absorption wen. in this cha p ter. AlTERED ABSORPTION It was stated in C haps . Ht' rt'.nll' taholislll of th('tlphyllim'.'tl.wail.\.'t' of f1ul1 uatioll around the a\l. tilt' dall~t'r o f tit(-' t. For example. . tln. tilt' nlT" Il( lill~ d m~ is u. ratt' of D nL ~ A is not f('a djus!t"(1wllt'll D nl~ B is \\. FOT cnuvenience .·r.I B). t!osinp. (' .

e. """"" r " . r r r r "'''''' CIITlelidne . then-by ({'(luling the affinity of the first dnlg for tilt' protem.. w '\fU. r El)'Ihromyc:. ('meI!d.~ d'gox. WtJrtonn Ouintd">e d .n .bors Iheophy4Ilne rneIoboli$ffi C.. Itony\cyplom"'-.:"'lI'... AlTERED DISTRIBUTION TIlt" most common explanation for aln-n-d dt stnbunon ill a dmg Interact ion is displace me nt..t!l lI!lroc ne :yd VolprOIC cod d.Jlo. In this COloO. Occasionally.. gwric emptying Epineph"ne decreoses blood Ibw 10 . til(" di.. .. Somettmes. hi nding 011 anot her si tc-. ' . Di splal '\'ll1l' nl is lilt' n-ductkm in the binding of a dmg to a macromolecule...'" By Inh'b11flg mono"'ine o.<. Eocb Io-w<s the effec. '.ng \.. for l'OllllllOIl bind ing site(s )..s "id l \'( '1) ' long ha lf-Ii. Insidious. I1SPONSl .es !l6CrellQfl ~ 01 hlhium 0 . '~ ""'n. Thus.lies micrmomal en'Y""" Ery tllfornycin inn..270 INTEiACTING NUGS CHAPiH 17 .f elo<y meaning 01 -eecl cec-cece delouh ceoc-ce.placer..... NoeloproIoI j ..nrecl... all allost e ric ('ifNi causes an enhanced affin ity ht.. j ust constden-d t· lI1 p lJa..:tod d>\O) ~o~ . usu ally a pron-tu..<... . which was e ithe r iniliiltN I o r stopped sOllwlimt' pn"\ifl usl)'.ne or pc»lgOngloonoe: OO<etlE'fgoc neuron.. . ' .'*PO» efled Calcium . ..' .penem . me """ p.twt'('11 dmg and p rotein... such as ("(' ' 12 ' p llt"llllharhitill (' 1 (If -4 d'l~'!i ) . Volprooc odd Ouiotdine . TIle second d rug.pr~ as d.. TheopI¥lone CilosIOl" -0 Im.miniY-..wta.llQI'l d phenylpropanolomlne Mutual -*:Il~ eIIecr.h..1o~hn ~Ilampll'l indocM . ' f>/elocbpromode "'a."...n IMompofl ..n Irom It_ blnd.on s...~i7'(· th t • d t'p('nd e ll('(' o f tune scale o f events Oil the half-lift.j_>o'\(JI . ChlorpromClZl1le rh '~ uplake of guot'lelhid...:tlver>e$$ 01 .. . change s ill n 'sp0I1S<' MI...~e5 pherrvtom hom album. me by Chlororhiaz. ".. himlillg is dnuinished Ihn ltlgh an allosh'ri c effect .hed l.bor.... Dtgo>o. 0'1CM _ to....lto n.e potenhOIeS!he sympothom"nellc oc. . IlOl l!lt(...' .odo~.de d..... Tetnx)d1/'l8 ~ Calcium Iorms 0" mldoubko complex .._ TIl(' ~ i hJ:lt if)m. organ clearance is ollected..m. and til(" C li ll i d il ll lll a~' !lot a\sociah ' lilt' interact ion wi th the causative dmg. TI I(' result is a n w ill the fract ion of tlm g un b ound in p lasma o r tissue . dmg bind ing is then Increased. "\s... or bOlh.... uf the a fT h'1l dmg...... (Hotll s('l i hy compeuuon of another d rug ..nir....l'<)f\.u. Indu ces a confc rmanoual dlOlnge in the protein .ne mllibon meIOp(oIoI meIOboli~ . fo r afT("('kti dmg.le oS lidocaine . rhe 'enoleeecb- oIiWl of imipene<n .

i.1...\ is "<>' n "I' K~.. i' ll l"II. (". lit.....-). Second. r tI..· l Drug B I O~eA rI ...oo..( Drult" i> " " I'K'O " I I".. pl..---.. . ·i!l:.O ""d>et_ Worlorin -'" ..bencIomode lbupr<::krl l~...r{ DidoxociMIII G1.n Jllps of dOl~s thai biud 10 ullnuulu.. 'mini_I.owm.M""jU" I'· l"" "".. lin. ....lt R i.I. Illt'roll". Oplimal ThelaP)' .CHAPTER 17 INTERACTIJ'"G DRuGS 271 Conditions Favoring Displac:ement Two u md ilions must l)t· met l)t'fnrt· sub sta ntial di splace ment ()C(111'li...t ....".. tI.·nlw l..110 I.Imllli~."I < r-ol\(' II.oo Nopro~eof 8enzodoOzepo ~ ac..majuritr (lf thr. tI. This S('('! III t! ('Ilnd ilinll is likl'lr to 1 IIl<'t wht' ll thl' displace-r ( ){"t1 1pi t· s )(· most (If the h i lldin~ sites. AI. ~ " . lt u"h . l'al it'1l1 >1.1 ah"''1lti .<]r "ri". in Ilre.> Do .l lllli'V1~ \ . H is (""K'\t rn'fll~' .f U m ( ..o..8 • 0 i5£:1 2 D..1 to ils p". hl..... .....• ol .'nlrati" l1 r.. in~ r" I.·.. nl. ".------_ .-}~: :1 .n Salqk: acid Svliod'melho ~'ne Napro-@Il Oxocillin Peobeoecd T olbutomde -0"... O 3 -----------.ti<II1 "f D nl lt 1 f. a. )(' Oh \ioll sly.. !\ n . -2 L U 6 • . m ii llliLor 'n · I" 1 1~'1 n m.... .. T.'.urr.. III ~ I) and in tilt' int t' rstitial fluids (2 10 ~ ) ..." 'tK' (111K.I" O'VGS n-v. 1 .~ :' :.. th ai is..T sec ro »o CoYI£ll ~ oe o rwc SITES.. ~wn al a (".abM·Ill't· of a d ispla(·N. 111''''"'' '11 L5 aJ .l (111 K.'n I) n 'l: R l. ··ll. \ ..· hi"...\(' I). USII.I.d>iliJ>. II.. i ll~ r. its III mu st 1 Illw.. (". II ...-..o.u g.A i. l ralw". ' ~ ..Iml!.1"" Dm l/: K. ""~"'fl D m l!..\ p""''' '1lI p:lt''''Ii"I~' if ..<] d ... Ilw d OlI-: mu st l)t· hound IIlllstl~· to 11 p rotein..."...l>. ."istlllierol . >t." A_ " " 'l{..I...·-half Fur 'i'''ph<ity.-olr.".. ..-----2 4 " 4 • " ------_ .M lrnilli.. it cannot 1 displaced.)... if a dOl ~ is 1101 hllund.. Unlit . a pro tein thai ('-usb ahu llllantly ill ph sllla ( 1-10 W3 L: OJ. n . D o ' l-: .·...ll1n\l " tI. II. ' II . l .."."''-9' b«l to _ .. . the dtsplacer mus t IIC )(· (:IIPY tlu. l R.'''· b .....·".. Fil'li!.r ).. .ctMI D..· ...hi ndin ~ sin-s.. ~1 lis t s " . ..'t...·" ......-aiW>il ily . I'atit·" t .1i....1 .. un. x ot all d nl ~5 h ind 4 C o A eO ...5 n... 17-1 ..I..sla nt rate. .dl. Tal ll(· I.n --.·" .I.I.d Ol ~ . Ah...ulltl' t "r U nl lt .. n '''. tllt'R 'by suhs ta ntially l{Jw{'rill ~ the' number of sin -s ami lilhlt' to hind Iln .lllr.-. I~' \ (r. Potential ToxiCity H 0_ 3 2 -------.." I I. n....1 (Ol-.1 ill ... F".I j..1.t"hillA" I . f D m lt..ocillil'l lodomeohac.....Ie.ati"" .-.I..•• 1 7-3. OESIGNolTEO I ~ I "'" ''''''" "" ClliorOlhiozlOe ToIbvlOmrde' volpoc ocid '.. 0 2 46 8 1 012 Ineffective 10 12 Dosing TimelHalf-ll1eof DrugA Dosing Druo 8 Drug A 0 ~:e ~ 1--=='=-=-=-=-=-=-=-=-=-=-=-=-=... " 1M Dnll!: H il will.

. wllkli a\idly' hinds ITlmlY baslc t1nlJ. s!I<:1i us sa li<: Iil' add."{'a u"t' tilt' is ptlsmil eence-n tratiou ad lit'H'd dll ri ll ~ t1 lt' mp~' IIIm t app mad l or ('M'('t "(! 0.3 1ll~ 1 ) appn li.( !). )'t'C t" is may 1M o f littlt' t llt'mlM'll tk L"tIllS("{ llIt' nec' .is said to di splan ' warfarin fmm ulhuuuu..1(1iolls ill p l. h UI il sh llu M '''' 1)(' a ppan. molar (1111(1'n t ra lilll l of . mwL. Plu-uylbutaz mu. tllt'll ' 11lt' t!isp la("t'r.lIX'lItk r.6 Ill ~ l ) .it.11 d isplal't'lIIt' nl is frt 'l IIlt'lIlly dt'lI\ollS lr.'jO.6 III ~ I. F o r a su!lsla m "!' \\. Fraction 1 t.t'l.'t· .'s ilppnlill:bill~ ' I ~ a nd 1)("('.e.. In IM silll ltll .. DoM. ' t lisptw(. dm~s IIiM ' similar alIilli!iI's for tilt" SiIIUt' silt' 011 alluuuin. l Ilt' t jllt'st io ll uf al lt-ri n~ till" usu al tl uS(' {If d n l~ ari.( l\ l·r. 1l. p . is only 1lI1rlWL h ili I)("(. t ht ' plateau comvntratton ult illl at t'ly adlit'\ '('ll is hi~" when till.'llSt"{1 si~lI ified nl l)"? S ud .l. alltl dl<lll~t'S in its h indi n ~ a rt' IIIt'. ht "(.(tit'lIl .ahilit)' o f (lilt ' ad die .Dt'IX'lI(lt'lll1('s ).t all ad d k function is lint a su ffide lll (-m erton (or pn'(li<:t ill~ tln.. i. ~ ("(III1"t'lIlmtion ill('rt'. wllt' rt·.vari ous hind ill~ pr oteins in p l'L SIll<l (C hap .On.'IlIIt' 1I1 d isposit io n kinctn-s (C ha p . TI ll' o tllt' r iu\"olws lilt' . tim1inll h'l' IIt'l'1I lHad(' IM 't'l'1I displacers a lit! d b plal't'll dm~.1 iu llS can occur a l plasma TS. II t1t"('n.'n.fon.. I)('ari ll ~ in m imi t ht' \-\idt' l)" t1 ifT('ri ll ~ molar l1J1l('t' ulmtitJIIS of rln.llIlia lly IMmll(1 in t ilt" lu ly illUl ll lt' di splil("{'r (.. For examph-.LslIlil ha n ' ht'l"n st ll(lil"tl p rima rily 1/1 dt m .haw a hi!-:h affinity for allumun.u n. ~ I ()rt. ~ l lleh <It'I)('lI(ls on wllt't llt'f Ih t' ('n'll h <lrl' <ll 11(" Of ' 1 11( "{ 'ur a t plalt'a u durin~ dmm k Illt'rapy.\'t'l l with lilt' usual d OM'. Alhunuu ami sOllie o l llt"r prote-ins han ' "i('\t'ml h illt li ll~ sites.tm l if tilt. till' llIo lar ("f lll('(' ul ral io ll o f p!. FlIr ('.(Ihumin (0.' UlM' tln..'St'm't' n f tilt' t lisp la(. is I nn~ (3 d ays ). t1i.1 .. Su hst. Acu le En'n b . tilt.I("' r. Sloth'll tlifTt 'rt 'T1t ly'. in t ht· p n. l11 list is lilllift'(IIM. \"a lp m i(' add.1 t hoS(~ d m!-:s that t ll lll pt 'll' fur 11 the.\ 110 111('1". TIlt' p on-uual tlispb' ''t'r is <tdtlt"tllo a sample.L slIrt"tl.)("'i not . l1111('t'n t l'llt i(lIIS wt-rt. is lilt' unhmllld \lllulllt' of <list rihutiou (" II) d('(. is low ( ~Z. SU f ar.ullt· Iht' ptL'IlHI conceut runon ael.rt. Dill' in\uh"t's tilt' mlmin istmtio ll o f a Ini(d i ll~ tI(IS(' of d m~ to ..Illl'llt in tN ' l<.n-vr-rsed. ill li lt' a IN'Il('t' o f Ih t' t1ispb n : r.am plt" lI lt' IIllhll ll lltl t1 l11n ' u tmlio ll riS('s if d isplan'lIIt'lI t 1l("l Irs fn llll . .lIlM' tlu 'y I)(ISWSS n:lath't'ly s mall 'Ulll lllt'S of distribution.'" from a lhumiu (fiI l1l JJ ~ I t1"'('t' li l ra t io ll )..IIIU· silt . 22.n' n l m t illllS 1I111t'l. warfarin \\ Ullld IM l .272 INT(iACTlNG OIIUGS ( HAPTH 17 In and 1ll'lln ' ("fllll l)(·!t· !i:lr lilt' suuu. tl w ir fil vahu-s d mn~(' wit h pl:L SlTlll concentration...pri m" r)' hi ml ill ~ si te 011 albumin."tlud usinll s dl'll\\ ll Imru li lt' iu h-ractions Ix'lw('l' n acidic d m J. ('<1(:11 ('xh ihili ll~ SO Ill I' dl"~n"t:' u f Spt·(:ifid t)': pos Sl'ssill j.lt('llln firm . . I>ispl a('t·rs sha n ' a ll t'Xpt'l'!t't l l"tllllTllIIIl pmpt'rty..l~t"tl.N 'S .St'S ouly if Ih(' Im lMIIII1I1 ( I n ..' and Tum. 1"t". T Ilt' (. Tln-n-fon -. \ \ 'i1h 1110 .of pl .1 a lh u m in .p l'L SlIlil (1)IJ('t' Utr'dIi01l o f pllt' uyl hu tiVm lt' ( HilI mwL: n. loWN than t ll(IS(' n-qut n-d fu r d isplan 'lIIt'lI t of acidic dn lJ.u. uud \"a lp m il' ad d tlu-rapy.d io lls .'nt thai thi s d :L Ssifil'al ioll is urbitrary. HilI III~ ( \ ' = 10 I . III a d"lll ~t· ill IIII' concent rat ion nf di sptl<.' r.mlla {1 1l1tai n i ll ~ l ilt' dm~.' usual mniutcuance n '¢ lIlt'n of 1lI0 ttl 3(11 1 1Il ~ daily is atlmill ish'rt'l l. " 'jlh pllt 'u ylh lll.lSlIl. 10. tilt' mola r ennc-entrution of u l-.'ad )· sla bili:l ("tl 011 a di sp!.1 JJ ~ I) . Ihis 01"< ' l~lI ll't'lltmli(lII l~lm'sp(lmls 10 ISO II\WI~ T h is ccncentranuu is appruaehl'll durill~ salicyla te dnl ~s an. a n lllm i In Ij'j'o k~. or 2. 1 sift' s t)(" u p i('l l hy tilt' cbsplacer.·aM' il\ \ '1/ t l("('lIrs only if.' l~ llllllltlllly J.lhlt· 10 a ll dmg-protetn mteraetious. D isplaeenu-ut inl('r.IIt'l'llll)' applit'.'t'r.j?:" .~ i l ('s 1 ti ll a p!oL<. hUI n llly J. t hat of wa r' fa ri n (I til . 110 lUll 1lI ~ 1) d. 143 ).111M'S si ~ l i fi l'an l d ispla("('1Tlt'nl of t1m~ fmlll Ih t' major h int! · i ll~ sift's .lII~t ' . Iht ' r. T\-\u s it uat io llS (<tn h(' (' n\i S. Bot l.' is low a nd ha lf-li ft. m st' its d t'antnl.. o u l)' a fl 'w art' !-t('lwrallr lislt't! as t lisp lal't·rs .).dlt's th..\'l' n in doM.('11siti \"t. and alhumin a rt' TS ~t .UlM' t ll(' M' Therapevtk ImprKatlon. III 10 15 I. ami t ilt. ti lt' dnl~ is subsl.ma pmtdn fur a dnl ~ \\ilh a s lllall \11111111(' of t1islrihlll itln. ('\l'1I t !lO Il!-t1J alnlC)!..' 1II()('t'lI pi ('l1 is <.." m ·t' tht. admin islration o f a d oS(' of di splan ' r 10 a patit'llt a ln 'm ly st ahili n 'll o n a d m~.111 a 111 :111<11' \\1.lIIt i.. t1m14 10 dispLu. dtsplacers IIlllsl s hllw l1 J11n 'lIl ra tion-dt'llt.td d ~1)"{"t lp mlt' i Jl . and p llt' II)'lhulazollt·.

if tl1l' displao -r were Injected mp id ly t. W. ) dIM'S !lOt. as d is('us'wcl ill C ha p.UlIlIIlI lIld d m g: concoutnuton in pLl\ lIlil wo uld rise appn"<.s ma.\ '.foTt· in dosing mit' is lIntidpah'( ! al slt'ady slah ·. 1'It '('all\t· di spla{'('tl d m g: wOlIl<l lllO rapidly dow1l tilt' nl'w ly I'TNlt'tl unbonndconc W' eurranon ~rrad it 'll l iuto tilt' liI~t.) illfusillll. Conskk. l'ltllh IInl'ltlll lll! d m g: d l'aT.. nt't llmill ~ 1o th t· Iw o t·.'!(.'t1.ex-mcut IltX'UTh fr om tisSllI" btndmg su es fo r a t1 nl~ wi th a large volume o f di strilmtiun. D istriliutiou. Cl ' C.\t I~·-s t ..h.l\('t1.· filtt'n '(! d m ~. 111t' mainl ellmll.1m! sleady slalt· is adlit·\'I'(1." ('r t rn ct if"..Ult l'llIlSidl' ring: a n-dncnon iu tilt' lomling: dost' o f d ig:oxin in tlnp ft'St'nt'(· of quintduu-..~" Ihat of a ~mlll ·m la rl. as most drugs.!ltlllg:h . Ewn if compk-tely t1isplae.('tpm.rinally inl'n'ltst' th t· unbound Iltltly !'It'ltl and IWlll'(' unbound lUUreutratimrs in phsma ami tissut·. tilt' sh·. ind llt lill~ displaccrs.' lIISl· tilt' dinim ll't"SpoIlM (p rut llm lllhill ti uu-] is ' stl t1t'!ay('t! end iuwnsitive 10 acute l'hall~I'S in warfarin I'(JllI't'IlIr. ' st'S 110 d l.am plt·s al'ltl\'t': \ \ 'ith di ~uxi n .displacement of warfarin from alhumi n h i nd in~ sitt'S by llapm"I'II. II ) . IlI'ltJll t'h runil' oml t!osing. then ollly 3% (l IX) X (I fill ' (p t lSlI1a \Ullllllt· )!\" of Illal ill tln. F rom p tlsllla hilJ(lill). qUinid illt· causes a suffk it"lltly Ia ~l' t1('('rt·. if ti lt· volunu.. 11Ilhllllm ! d('aTillll'l' ((. alt llou!?:11 t!i. '(' t"!. Also recalltln.. alll! tllt' n 'fon ' n'sl'ltJIISt:· 10 11lC' d m g: IIlIlSI he iUl' ft·. l1la is hOlilld (f ll s n. Au exampk.'t d 111I'I. tilt' s. 2 11fl\\.': sill'S. ) d ept'lIds 0 11 ext rac tion rati o am i route o f adnumst ranon of ti lt' aITt"!. Sillt'(· u nhlllllill t'!('a nUIl'l'. II n" t'\'('r. o \ lon ' rmumon is displace-uu-nt . E\ t'lib 11.tlioll (Fi~..-". Tltl' iulhu-nce o f di splal'('lIll'lIt on tilt· unbound couccntranou 111 : steady stalt' ( C II . ti ll' small .htMly res ides bound in pla.. 12). thts last situation is unlikely to arist. .' situa tions arc rl'1atiwly unc mmon. 11 11"11...spJal't'(1.. ~ ei tllC'r is any d lang:l' llillid palt'ti in (.'''. It"." t on events at plateau. 5-7. 5 ).'iahly. of a dmg: wi th a lergc \u lull1l' of t1islri lllltinll. coun-mplated in tilt' event of 0 I at'uh' t1ispb t'l·lIlt·nl. In IIII' pn 'St:'nl'(" o f Iltl' d isp la('1 'r. IM l"I. Conceivably. \ 11 e-cunph.CHAP H 11 T INl tRACTING DRUGS ur if displ.'!('(! by di spla('1 'IIlI'nl. <ITt· ~ \l'n chr ouk-allv.1 1)llI. howewr. lIu. TIlli S.1 c1mg. Hecall tllat d t'llT.water spal.Fonner situation is rlu. TIleS(. Ro '" CLu ' Cu.of tlu.unoun t aITel"t('t1 \\tlllid ft'tlist rihu'" Ihmug:llolit tilt' res t of tilt' IM It!y l am! stJ \\ll uld only Itlal}. .('.lst· in \ '" tn W<ITr.1I1l(' is Iml' of till' \-011111' of Cu. . ('n 'tlid ioll of till' OUtl'(IIllI' whell a t1mg \\itl l a high t'xtml'! ioll mtio is gi\" tm illy alltl t'lI wl lt'u elim ina tioTl 1)('1'Urs p n 't lom inant ly ill till' li\l'r is dill k nlt.lilil's (Etl... tissru. 11I"l tu st. . C hap.o f d istrihntion is 100 L am! ~1... III'('a llst· of adwrw n-act ions ofteu expe rienced WIW ll dm~s art· injecte d too ntp idly...t·\·('f . C hap . h ut 11.}q: of tln.'!t"(l foIJO\\ing:a ('onst anld isp la('('IIl(·nt.ol) ..t\ hi lldi n~ is dim inished.Cl . Clu ' Cu . In pract ice. m t lo.important consi deration for 1111111 uf tlll'st· <Im!-S and most " utllt'TS is lilt· I'ITt"l'! (If d ispJaI't'lIlt. 11 adjllStllll' lIt ill dosag:l' o f this oral antit'f).t'if' (M Cha p .of the latn-r sit uation is tlu. tlu.. "C<\IIS(' dearalll't' is unaITt"!.displucenu-nt of d i~tlXill Iromttsxtn.' 1.\1t' hlolltl 1'tllll'('lItTiition is also uliaIT . so Iittlt' d m~ resides ill plasma o nly a millimal ehang:1' ill tilt' ' unbound t1 mg: l. .. I'It"<.(lIll't'nlralio ll Ilt"l1ITli even when all lilt" d m g: CJIl tilt' p r oteins is t1i.Ult't' dl'pl·m ls un fll . :\ mon.i1U tilt' tnlal ptl\m <l I'tllll't' lIlmlioll 10 fall).r a d nl ~ \\'1 a lou' j'rtmc1ill/l m tio . ZS. Cu. (' . but only mOlllt·lIta rily.'!t'(l hy :'\o\\" ('1ll1sidt'r a d m g \\i tll a lii!!. \\'il h warfa rin .hillt li ll~ siks h~ ' quiniduu-.. Wllanl wu uld ht..lII!!:" in n 'sl'ltIIlSl' <llId IlwTt.d m g: ill pla. C \\'1It'1I t1m ~ is infuSt'l1 OIl a constan t mit'.U1('t' and oml hiullVai lahilit)"dt"<. = Rate of elimination . .splal't·lIlt'lll hy i lll' Tt·'l\ i u ~fil inl'n·llst·\ ( 1 1'<lTiIlI('1' (and IWIl('(' I. is IIl1aITI"<.'(· dosing mt t· of tht' tlmg 1Il<l~' 1It"l'(l lu Ill' Tt'tIIl('1't I.IT of Ilisp!aI't'IIII'r11u n tht· UlihOIlU Ilm g l'lllll'l'nt miioll at p lalt'au is IIll'ft ·foTt· likt'1y ..It· iIlITiI\'('IlOlIS 0 . Fur exampk-.rt'.

\\l l1ioa"'''' IIl....1 hi.. tI · likt·I...·n' . lmini .. to 1)(· discussed an.."..) "mil:....:1 d'I'I"'io:.i("(1 Oil tln-se' obscrvunou s...o1 d lillll(" ill tI... tilt' unbouud coucen t rarion al plateau is IUW(' f t han that <!t·h it"\"l"(! f()lI()wi ll~ an ('qlli\ 'alt'nl i.r .... ' . .1 I.. t'lI)1oill in patien ts n'<...• in lh."<1 on " n.. I.l/y. I I "". .. ht An'H ' f ..... I Y'. II.• 3 21). Bo'<-. hnilli-tr"" IIl.... Slim'l l in Fi ~. ti..1 pI"'n~1'Ji '... . U"IMMU"1..'(. ""l r. " ....'i\~...h " " " -t ·r II rr...L...Tt· "S u..lhfln .......ll. ' '''pn>it· ""...... 17-2.o~.. 11. r.i~.. rlK-ti"" of ' pI"'''~1' Ji'' I.. which di.' .• '"'W''''' " f p1"'"~1' Jin "i.25 T otal 16 0 ...Io... Kinetic Features..oll in · till' ' 1o·.... linl( If..''''''1liL... .(·lI~st'( l .. of . ('f'Tltr.mtiepilt·plk < Img.1 1 1"...'Tl [rnsn I...'n lrilli..0 " "Sult.25.". io r...-:\l r.m' th.1'''' p1"' fl}1uin."n>!. ". 'l J....d . flf .......ll1)·.li 'p l""' ''II''' ''1 i" l.0''1:'' in tI. P.. th e n ' is Ill) need to uln-r the dosillp........ ..dJilin .-it.Ir..'nlr...:1..oJ~·. c!'·aI"41Il..ili7... h" i"i olr. S'" '' .1 UlIIM Mll...Ill natio . io'" r.' d... <1. J. i" tl. ba.1<.4'(' p l. i.. n " I..'~..lli d.m.I"'I("I.1i". o f low alJ( l lJ i~h rs extraction an' S h(..in i".... UpOIl displaeenwut . lo'(..· ..It"m _"'p"~lh' 1"" 1' .. tIl"". n .o"1 f.• Ioi.... ''''.111 " ha nl(" d "p"". constder tilt' expected changes in di spositio ll kinetics of a d m p...· of .. .linl( .4.· . r ate of pl.0.. An".. .o"ti... th 11'1(1"" '''0 (I mWl· J ~1 .... AltI"". Itt · · llluillinp.. iJ •• -...... 17. 110 \l.IIIit""'-aiWJi!ityor ... f ) . ".d..lio•. ml( . 1 "'. IT.I .. n l(. .. I.....~"'>w<-." ...1".. For .* 1in rpiJ.ly...ool...J 1o.....d ..o plll'll~1 "l n ...In >! ) .4l1" " f II.. ("olt.. I m 'spl 't1in ' of all~' d TI't1 of displaconwnt.·nl natio . tu a ~ "'P of i"" " tif'nh ~lilt... .1"..in'n d m mil'..4I.'hi llp.. II. "lrllti n" ."""i" ....ot..OI .' tota l and Illlholilid plah'. \'alpruk' .·ltl ... Boll. J'"":k>l"i""I'"I low Extraction High Extraction Intravenous Oral C 0 C o C o "" 1(.:1 -Ill ".. whil(' the tola l plasma couceutration is ( It·Ut'alit 'l l.A... ~ ~ 10 2 Unbound - 00 ~ 0 Unbound N -' .. I. infus ion....liu"..h ho th d rug and dtspiacer art' p.'" ....pt. 17-3. a..1."".Ml.......on ' ...... s ..h. lUI....lio: 'n ...D....I I · oIl1" ini'I 1l>i.... To do so ...o.IM lllJt tI.Inll( " f hild> 1"1""lk . fo'nl"II .·.I. " ..hih ~' " f II.-alpn ""I"'. ..Iru~ . lm~ l t ....1 . valprotc add...1i. ..tilt' kinetic ('o ll<. ml l'" ot. n ~.. 2S l"'hr "l.. ~..l"'ml 'M' tI....· tl"I M . T h..la.1pl.nl-kn..A.' ......c... .41io:".) II 13.."S 1 .... tliminid.~n". ' >!"'·n -.. "'111..'t.'it).. rr.J io:..41 p1... II..l io:...l ~ S ~ 18 N.2.t"fltleIlCt 'S of di splao-nw-nt 0 11 appmadl 10 plateauunder the usual co nd ition in whi(......." _-alpl'loK' "".'an . pT'' '"Io' io ......and an N di spl al't'menl for d m "...·in " IJi".......• . llJt.1 \JIIIO mil: .plaex-s ph('1I~1 oill from allmm iu hill(ling silt-so As pn-dicn-d for a dmg of tow e-xtraction..Ii"".. acute events and t '\"(' lI tS al plnt eau Im\"(' 1)("('1\ d i..*I--I'I"''''~1''in 1 · ""·..41io:"..' n~l .."11ill Fi~.. S ..1 n "'· • ' ..n io lit .d.1 n Md......4 "nlll: uf .. " f ll..:1 hit. 17...1lI pl.1 pI"'"o . anothe r . A('(:unlinp.~ w -n 14 T otal " 0 ~ '-' 12 "0 ~ 0 ~ or s:.ot" thaI I.J.. 1"lal rgl .I.10. n ..In'l( iJ ~ n inlr. lutal . K.... '1Il II." C"l'T .1 wil h II .I....d n m· 1 .....nn·" lnal:io MlS ( J) .· u"I " 1 """". ./ . rt"{'('i\'ing calproic .•u II.n ..Tt ...10... C r..1..pL..lSlIIlI couceutranons of t ilt" lllltit'p ilt'ptic drug P"("1I~1 oill ill paueuts b efon.. I .....t C 1 <...l' I.."'." =v=' Unbound ~ ~ 0 D D D 0 900 1350 .2 74 CHAPTIIl 17 nil' events pn-dicn-d at plateau befon.ami aftN to l ~· n ·lillin4y small..1. iom r.4lin.." Iy..1.) ..lio:."" "'. ~t'Ji n ...In.. lr..r.. pL.·" ...rr. . .1o. i''''.· ...: 9 " '('(-it.m.. tilt' unbound couce-ntratiou is unahr-n-d.<Ihpt. n-r or..y Chll k-.).tot! oon.. C I..v.u l. .-to....uf" ..II"1(of pI"''''~1ui'' lo ''' C'R'll..l" .1wl.. 1 ..u... _>d .

In'lit .ai n '! \trt"" llr ". I'S) wi th di sp lill'('JTlt'UI F S rom pta~lIl a prote-ins..1if It . 1101 dmll!J. · " ' .'U u ~. IMJth dmg am] dt splacer ure mlm inisten.o'.0 T Oruo _ _ otal ~ 50 20 10 5 2 1 0.an' many l'M ...LsllIil drug concentration changes ill wrwly wi th that o f till' dis plao-r.· dn . :\otit"(.. . the total p l. 10-" '1{ half_lif" . l 11is is a l"(llloS('q llt'Il{'(' o f till. 111t' rutc of atl min is1 trutton (CI..1t. .ili"J. ahholl ~h there is a k ndc'nl'y fo r lilt' unbound dmg conce-ntrutlon Itl ri ~ ' aIM IIII' (UIII"("Jlt r. n . In 110. only nne rouunon situut um is ("(msidt·f("(I. .oo. pla1Cma COllct' lIl ra l io ll.run. ..10' 1 . Ht '(. h. hul tlllt'(' a~ai n Ihey lJablll't. inf".II . (" .d l:t!l¢ ng d l'grt"(.Tim e Profile .' made in C hap te rs 10 to 12.c·.. 111 this ('. ahhou ~h thl' unbound co nceut runou rcmains cs sennully unaltered . then.. for a d n l..·"'~ "'-tanl l~' .1<... · slow t. ~ 1.of d isl ribution . d isp tw('r I x"in~ slower than Ihal o f til(' d m~. 11m! is..r l"f. S wh ich I.' ki m-tics u f tht...II>la' llla .d hy constant.". in Fi g." .tI. .. of d isp lat:t' mt'n l. 111l" subv-qu e-nt poi nt s SUIll Ill'II. - ..infuskm and both an .{'. e ll . " c. I II contrast .tt slt'ady stall' d ll rill ~ I\'p accunmlat lon o f tht ' displacx-r.l::c' ill §.CHAPTfR 17 Di"IHJllil io n lUnd i n. dt'am m.7. n·H 1~ tlw .~plan_' ­ ment . .11. \\i lh rate u f l'limi natic m (CI. A{'(....f tilt' !' dt splacer results in ill si~lifil.I. til(' hal f-lift" (:hangl"S with volunu.!!." .05 0. rt'f1("{1ing tln. .1""""'1 '1. dIM.. (' (F ig . .II .5 0.t . .-. a 10". ~ Displacer Drug 100 1.02 0.......Io'l'Lot. hanl:<.l. Altho\l ~h then.1 0."(mli ngly. .rn-S M mtlingl. of low 1" t ract jou.o1I.. ell.1I. ~'''tr..I virtual slt-ltdy stutc-.~ rili. Gu ) would tlu-n t'x("('('t.di spl an 'r is d l'lII~ ng ~ ) sluwly relative to that of tilt' dmg thai at all times tilt' dmg is OIl .t' those. ".. . hillf-life either n-mainv 1"(11I staut [wlu-n \'" does not d l'lII ~t' ) o r sho rte lls (if \ '" tlt'l:n 'll... .. (-ha"I{<' in I'Jl. I"i'-I th at slnw al'('u lllulatio ll alJ(ll"( . IIIl' situalion d lOS{'1I dllt'S itlllSlrah' till' i mportance o f b oth k i l1t'ti(~ allllth(· mumu-r of d m g ad ministrati on on till' Ii kt 'l~' rln-rapc'lItic outconu-. 111t' ooncentratkm o f tln . T o s i lll pl i ~v mat te rs."1••. rollin 1or . b("('au st" uubouud clenrancc-. CI . 1111' n -verw h 'ntl l'lld e s 11('(. \ \11i1e th t'S{' o uxh tions an' somewhat n -stru-tive. un bound conceut ranon to fall be cause the rate of eltnuuution (e l.1 1r fin stopptug th e displao -r.. li-l ) tilt' di sp la('('r.1"....lt..' nt)· fo r tilt.mh iualions o f r-vents. 17--1.2 0..l.· .Inl): (.atin li .) nf . \\l .lt.. . ..) matdlin g Ihe ran.llIl chengcs in till' 1I111Mmmi d nl~ ('tllll'(' nimtioll and then-fenrt'SIX)lJ<. n·I..I".IT. -i.1. is mlllt'tllc i till' f(W lnt 'n of <I pauent stal..'(' of a lln lg with a high extraction rdtiu is IInafTl"(:h"(l by di.."(1 Oil a low ex trac tion ratio dmg.liminalio li t. 11.is an 0PI'MlS ill~ h'n d.".ssihl e ("(.~ a 111ll ~N '1IIl thau thut of till' t1m~.1M".ussuuu-d to aIWd)-S 1 1t~ at dist rilm lion t't illilih " riUIII. 1"Il'1l otl u-r out .\ transient dlan . ..01 ~ c 0 u u ~ c " E ~ ~ .. 1 r-~1l .o f ad m in ist ratio n. " 5 0 1234567 Time (halt-livesof drsptacen Drug Displacer '7 t-. .

ih lt·..·... I!it lll tlf Illt.. • • Theophylline Stopped • • •• - ro ~u ~ 0 4 ..o~ .... if only « 'S p U Il s(' wenc uuuutorex].· pl1.l-W just diSl-11.·"Ir...." hyl1 .il.Io llu-.. luul lx-eu th t· slowc'r.lnti dp.."~" t1 1<~'l"~·t1 "M' (~ II I<~· .....n ..t · is I n sc 10 a toxicle-ve]... · in th.J .·"I .u \·"1 l ~"·r"I0:' · i" . 111 i" I'il' ih t1 1< ~.<l i..·l h . I.. \\"It " So.. .. 0111<·.. 11. 1i-. p n ·. So""'''I<''' .. n~ ... "r 111<.(U "'WI.. ''''P''''1'~1.....'fh·(' qum(Jlim·..1c'tl........l~' t~... 1' ( ..11M' 1... n ". <:OIl'\('( jll(·lItly. I~!l l . r."... h.ll(...h" i".~ III1" · .. ~Ii A ~()-­ " I ~"'.. ..I1<n S"I'. t11<"'f>l~lIir"'''''I<>:\ati'' i"" ·... u" will.. •lal1ltl\( IJ6 I.·u .".'>I' "f •..II...· IIf 1 1 "'I 'I>I.'IO:t·.\S('t1. II.I ..1< . ( h i ..''''II I.l."I<. '1 '1<11 .. . INTE ~CTlNG ~S CHAPTER 17 IlliboUlld ('1 J1l('('nl r.n " .I"...\·(·lnp mUIS('a wln-n euocn-in. ""'alr I "..· .mo st dal\~t'rt m s 1~1)( ' lIf dm~ interne\ uou... a\llid IlJh 1)1)(' (If Interaction..~ lI"M" " ..· . 11<"'11)...Ij...din-I)' 11Il( ·OIll IllIll I . 'I< ' 1·limin.". unless a ll at ljusluwlIl nuuh-........ d DIMINISHID UNBOUND CIIARANCI 1 n -dncnou ill lillhllllmi ck-umnce is 1"01('1111.. · In II. opI . .~ i" "'n " il"''' l .'.. ·n". . .. TI I(' mlllst' a is a\s(K:ia h"tl with uu t'! t"'111t'(! ('Ull('(' IlIr.... ill II...' "to.· ' ''.•du .. .lIS('(l lly euoxaci n illhi hit ill~ tilt' nu-tal jolisru of t1l1. h pl.lo:li' " I<' " f r n ..'stl "'It 111<~ " h~ l1 il1<' lin II "I<' I"..~ I..'I..l:l· rt'¢lnt'n of l ilt' 1 t1m ~ is . I nlnbitfon IIf d m ~ metabolism i.· 1'1 "'. ...I" 'n or •.• • ••• 60 • • ••••• . a llli \\1\('n ' pll. l1M·T. .. II.h" ll f..·\lI I I< " . >I.1. 11< "to-r..·.. ... " Ili<. ..I. (l 1 "~'I>I ....l l'n H" R. 11. (.. >I..·r.r. >I I\II...· I. Iuri. A (ase Study Sllll\t· patient s n '('( 'i\il\~ t1lt·nplayllint· dt . is "ddt'l l 10 li lt' Iht'(lp lJyllim' r t'WllIt·n . J .21...·nn iJ II':'.· n · "'It. ... thi s situation is I'd. \\". II.· to i<!t·utify.llt'tl e-va-n I l.I. .... · In'n ...' n "Kin"·.· . ....1 \\".lf·li(. ~ ur. Indt'('tl .~ l h.'..Ihi" " .. '2 Enoxacin Slopped Started >'E 0 ~~ .(lphy'l[i 11(' .. 111( " " l<-nn.d OSll....." "1'1' ·d .... "..Io'''u ... rather than that of tilt' t1isp lal'(·r .·. .r..nl: in" ·I'\..rnl ..1.·""... uj( 1 ... •• • • 0 ' 20 ' 80 240 300 Hours 360 FIll.ll'l'llwnl 11.".:.. fur 4 <LI~"' . 110 dmll ~l' ill l'lTt"( a ndIn-no ....·. " . "" a"'r.I. li lt' nmjor ('auS(' o f n-dnc cdunbound ch-arunce.n·" lr.n ' ~.·' I< ..ttio ll ll1i~"t ocvur if th e kim-t ics of 11ll' d m~.... E""'..~ ~ ~ - 8 ~ ~ ro~ '" E :0 ~ '-' 0 - .~Il" . 11 e h.11<"" ' 1.· ..I< " ...I"'" "r 11.· I.l l.."..Io:..I" J R .5. T Ilt' unbound dm~ conce-ut ra nou <'. ..:.'I<.. ..II" " n · I.t11 111('11 ill d OS<. ·.· .·.\t~ I I.1i'1".h " ....I. .li..·1I1' '''OlTd tI. f" n n ) " .· " "I<~·"I ." .dM~I . (2"'''' hr ).."'"' ~ "u' .J uf 4.·n" · (~ 'nn·nl n... ..li."...T ito' " II.... .rv ' " f II. r G. li".. a n a l1!i·inft'<.I" m f"r ...n ". ~II. displaceuu-nt \\1I111 Ilo t !MH' !lt'('1l slIspt '<.In tlu.. 11"...'·"1 In ".. ). 1 n ... .. 11" ~ or'..II· int..~ . H~' 72 h r..' ' '' 1.· n1""..'f'II~i l. 1"'. n ad n 122 1.' ti l<' ' I< ." "' WI .. '1<. '1'(' In till' ('........0 ..oll ~h d ispl. I "'W .-\ o ou rn -d. K.... s n..\11)' tln. e lm..... 110\\..•t"'M:1·nlr..~ ~ \ I ) " \I .. \I e .: 11.~· lIi . characIt'ri u. r:" I ~ I.r:'" 1.."i.lifi..(lp l'yllim ' (·il.n.n.J "f ..... 12 .... f t11<..· .I"~ In ·"·. ti l<' In. """t 1"1'01' 11<~'n .l1~ ..Iall< >l i" .(" ( ." 1" """.. I"".1<.~ .... .. l~ ......" "f 4 .·h ....n nal " alf·lif.. .".'Io:....''''1' n . it is (·~trt·"l('lr impo rtant to he aliI. .·.il:""r 1'1 1""" (II'~'''''I:' ' inl.

5 mgtL ) 11' mid w. am] lower. Thi s calculation is h.."..I... t 3 TIll' u tl ll' r c'flua tio ll d d il1f's IIIl' III " \" (a llll lo IlW' r) hal f·lif(' of th t'f'p h )'Uillt· ( ' Ir.44 )."t"ll illlltlt'{liatt'!y Ullt lll \\.I and C ..1\1(' (CI'. As sll{k til t' ha lf-lift' of t h(>(lp hyllill(·. clea rance \1.. enoxacin reduces tilt' ck-anmee o f t11l>(lpla)·ltillt' h)' 56%.. a ppm\i lllat t'!~· H IllWL.... o f s t.Dose cr . :lIld th{' rt't um of Ilu>( Jp hyllim ' {1l!J{'('nlraliolJ til tl lf."o rl)('(t is IllI. whicb is usuallv well «I."lIob. it is 22 hr (8.inh ih itor...\ rti ll~ IIIl' t hl>(Thyllillt' 1"('J!illw n ...tlT{"{·!t"(! bv cnoxacin.. <lppnJ\i lllatt'I~' -1 IIIWI.. a mi ~J lllWL for C. . ....of tilt' events Illay lx.<~ • F . 11\1' slow return of the ph~lIla thoophyillnc ('fJll('('n tmt io n to tln. As expected.lI. 1 reach the I \l'W plateau.. its plasma conce nt ration rises to a new platr-au..~ 5 and on s n hst i t u ti n~ 4 lIIWI.../\' and fr om till ' know!e dgt. t1t' te n n ill{'t1 h)' t ilt' I W\\'.'1111 is ad d('{1to li lt' rt'J!illlell a nd t ill' n-tum 10 tilt' pre-euoxaci n vaha..I. wo uld ha\'t' f('\'l'rt('l1 had..orbed and illllll('{liah·ly lnhll uts Iht >(lp lJyllilll' lll(·ta lll ilislll wln-n admiutsten-d u n lilt' fifth day into Ihl' t h(>(lphyllirlt' n-giml'I\..' lIlt't<ll>s O!i Slil u f lllt>(lplly llilll' fllr a {1111sit!e mh lt' pt'ri()(1o fti llit' . 0 111'.aY• .. 111is lm l ~{' r h. " n f tl u..... in the al)S('!ll"l' and p n 's. that r-noxacin does no t alTl'("t tilt' \"(. rutlu-r than t lu. :\ uum.\<111 is SB IJr . til its l'(mlrol \'a lut'. I.s 4 day~ .1( E ll' S. is 1 rl' ae h t'tl \\it llin about 2 d.lI ~ (·llO\adn. \ Vil h conttnual administmtiu u o f tlu..llion.a fkr r-noxacin is . tln....i!~n"iI". i J.' prt'-('uoxadll \'lIh lt' \\"fluld ha\''l' Ill't' ll mudl q uit l t' r.. defill("!i Ih t.. 4 wlll' rt' CI."" aud Cl' lnl J.sa llll' t1ns a!!:I' n.. 1111' hal f-lifl' o f t1wophyllillt .-. ill th e ahst 'II{'(' o f ('110\.nlJ..conce-nt ration uf ('IlO\. thl· plate-au coucentrution (C . rt·"llt'l.11I1I1t' of d istrihutinll of t ll(>(lphylline ..\millf.ltie riw ill t ilt' trull ~h plasma concentration of 1!l( 'oph. t ilt' half-lift' o f Ihl 'f'phyllillt.11t'1I t'lI l1 xactn is \\11Iulra\ \l1 a rt' iIIustrah'{l in F i!!:. by n ·f(·f('Ill't· 10 Ell..).J.II>it .('p 10 return to t ilt' pl"(·-(·lJoxaciu vahu..Il'ill ill ph'illla !It·rsi.CHAP 1H 17 lN1[RACTING DRtX:>S 217 1111' d ra m. ('st illlah'ti from t!l(· d('d i ll i ll~ couce-utrution wlu-n th ('flpl..the clearance s o f th ('{)phyllill(.~ai ll('{ 1 Frorn twu equations... -moI C"'aY.quant itative pictun.. yllin{·mlminislmtion is stop !lt't l (d ay 13). 3..1.S hr.lifl'..pn--e-noxacin value U ti wi t hdrawal o f enox. A h hull~1a withdrawn.J)' . . :\oti('( ' that it takes appm ximal(·I)· 4 AI) '!' o f enoxacin admtn ' istrutiou for 111 hy llillt· concentration to rise to the new pla teau and a similar till\{' for it (.. t) in n-lation I" tln.lIill(' wll('l1 ('110'1(. H ad illhi bitiull ('(·. . ~j. Cl '. O il(' ohtams ..Jn'<T/ "" H...It·W half-li ft· o f tht'flphyllint ' in tl l(' prcst'n{"(' o f till' inhib ito r can now lx.". 1111' .. L X 1111.{lp hyllilJl' to ils pn'-(' Iloxad n {"llll('('nlr.l"t'tl 011 rhe a ssumption that th e bioavailability of theophyllmc.{'akulat('{1 hy apprnpriatl'ly s ll hs lit ll l i n~ tutu El l' -1. an.•~ . 111011 is...( ' C. h al <I sllffit'ie n l l)' hi~h \'allll' to ('tJll O ItI l(' to inh ih it tla(.l.u-iu re ma ins til Ill' exphuned...' .~llIt'n o f tllc'tlph yllil\{·. a dmg only w('ilkly hOllnd ill plasma and tissue.. A{'l'(mlillgly. w hid l ('fmt m ls t ill' rdum o f th(.tIf· lif(· ('spl a ins w hy it lakt.-ithdru.t1l{lnl\\.tIf.!y llf'twc't'1l ti ll' p revious and plateeus occurs I da y afiN atl min ish' rinl:( (·llfl:l:ad n. ...usual 2. C ha p ..".. rt' lltai llS t'1(O _ \':111"11 fo r Sll lll(' t illlt'.". \\111 \111'1 1 a sho rt h. prt'\111Ilsl) ' t'\.·!i\'d)·. Ii .4·1 Cl..no rmal !Ialf-lif(' (' II2. Equation 4 foll ows From t he equation k "" Cl. It is also 0 W llsistt-n l wi t h tilt' o h"t'I"\'alion t ha i 11 plas lIla coueeutm tum o f l llt'tip hyllill{' (6. Euoxacin is mpidly ab.. a\'l'rd!!:t· concentration of dOl!!: at plateau c . Ill"" .. k.t ).. ( '11(.

'11 illl·rt'll'..... . thai inhibition is (..· 1I. with inlnbi rion.10<. Role o f metcbcbte formotion = CLu/ ' Cu = fm · CLu ..ih.plasma ........ 'L~ Illustran-d in Fig....1.' and al sll' ad)' state d unll ~ n 'Wm. §.. .". O r.. .."I«'·..·llm\f.~' tl.. 1I0XiI<111 ('{)lI('t'llt ratioll falls afh-r ' a -4U O-lIIg .. Hccall (C hap.~ -.·r.... .. ~ 1 ale" .Jln-lIl ~ Tt. Lo~ "" ""'no "f 25' 1I11f (0).I ....~·li..I. (lI.K ntr. ·1.l-4110 Ill~ clf "'IlOXill'i ll ~H ' 1l I'\ "" f)' 12 h r.. h Illt'tahulit' Il<'thway Vm Rate of metaboli te formation .1..' .1l1!i: 1"'1.'0' 1m is till' Irucnou of thr. eli n ..".. ('\'l'1I Ihough the. ~opI...0 ...l l...doS(' uf ( ! nI ~ th<lt is ('(lIl\'('rft-ti to till. 1'....\ I ).I" " " !f j ......" ..f pI...R " ~Ima" .• ....·.1 il .lill· " f .. INIIII AUC am i Ilalf·l if..· .nd \\·~" ·r.".: n . W..l :.'tahu lift' .-r tln.. .Ii' p"'i lio .....·.· " .ll of a lIll. J C:. tioM" I.an n'It.. n..llf · d m~ conceutranon .. A ('(111I11I1111 IIIlx!... .L5 1ol .ll. M...e . in ...• {_I .7<'. 0" I 'jo~1 ' (I "'WI. I I) Ihal for .111.. ohstn.If.. The dl'}~Tt'l. . . inhihihon I)(~ rsists .-. is \\"1·11 "dow till' \l idl.~ lJ i ' .Tl II. Cu 7 ....uti" . CIl ..L C l.unbound C l.t.ti. .' a(. ' S" I0 ".. n "'r" ..... '-' ~ ~ 50 o o 12 24 Hours 36 48 o o 100 200 300 400 Dose (mg) !'·l l( ..oph~ lI i m· takeu alOl1l......· p n> lll(. \"4 i ? loo •••••lI..1:.t.. o f cuoxaci u. II. hul rather a ~radl'(l 0 111'.· .. 1>. W.'o phyllim· follc J\\ill~ a si ll~I . for some tillw then-eft.g. and IWIll't· <Ius......... "f . consider till' T o appn-eiate.... 'I.·n .• i" l. 1'I.l.2..olIM'" i" . As (·xlx ·l..Imlf-life of all Inhibitor.. ~I ...' o f inhih itio n varie s wi th the.. 0.· j. t 'C: lll) ". .. 11M."'11 the. I..) li"" ...~-tlill. alll. .s7U--. tln. . TIll' illh ihil ioll o f Ilwophyllim' hy enoxacin is 1I0t all <l1I -ur-noll!' n: spoIlSt·....i d( ·ut (.. .. i 0. of Ih"'Clphyllim· illl·n ·w.. !i l)..·.1l i" k r...L~ I stat euu-nt ru-eds St JIIl l ' amplification. r..rllls of IIl1l NJIlml clearuucc associated \\i th m(·taho litt· formation .· 5 . :-'. 10 \'ill)ing dl'}~n'l. h 'mling to "pp ma<:I1 all IlPI)('r Iimil i th tln.t it"' (Al .-It'l l for a d nl g of low clearance.. lu htl ution <I''l'O'..pmfil..· ._ · Cu Km 6 ..ptL~ nJ. fn >nl R.i " !Q" '" '''' '1)' 12 I" . H. Rr-sl'II('C I.('. lt·. ' duSt· ... Kill . I.'i..h~·lIi'"· .. t.Jis-!\!t'1lft'1I 1'{ llIstanl.. 100..·11 i lh 11<. Ck-arly.•.('S f A 4 150 B . ltl l.·. EfT t " f .1 til t1. . n . 2t....linm loy "Ill_ i n lO!fr t. .' lIU't alxllih'.s .J ....I...· thi s d T. ShO\ \1 \ · . tl.. ..'i-lIlg r-uoxaein n 'WIIlt'1l .·..·sc n lll.l .... T""th..ilion ' fully 111(' ~md('C 1 nalun' of illilibitioll o f me tab fulltl\\ i ll.~ 'I'I.n ..·lln~ 1 ..Yt'i .uKI 4t.111 hoth tI n.plasma conccut rutton-nuu.k.1...'WIll(·I1 .~ 'I>h~'1Ii1"· ...... ( I)". us o f 2. .I.of t l " ~ 'I"'l\lI i' .(llIl't·nlratiulI.md 1111..f rh..... '<-1 is <...llI1 i" j. 17--6. th e mo re persistent is Inhrlnt ion 011 \\i lh d m\\ing it.lNlERACTING DruGS Cl1AMf l! 17 AGradedlHeet Til l' ]. 17-6.s and AL'C u f tl1I.. ('\ pn'sSt'C 1 ill I.." ll. tilt' lo n~. r \ tI..

lu :2 lllWI.~ appm\i ma h' ly -I m w L and o nly IJ. tilt' impad of inh ih ition 01 1 d na ~ elinunanon dt . Is till' u nho llnd conee ntrution of lilt' inhi bitor lind h.. t·IT 1iwly co ne. E\idt'nlly. hytl mxytiesiprd lllille . t"Stimalt"tl hy tl i\id i ll~ tbt· dilily dns iug mit' hy ti ll' sh '..L\ anticip ated. Ilw ta1lo1i.Ullillt' . P!wn ylhu t. O ffl>n then.OIl4 10 O. di sp lac'('s warfa rin . aftN . 8 when. Qutnldrne.{'II al the hi~ht's l dost·.SOl (11.. ( rl.II-du(·UllWlllt"(1.( IrT\'lip0lJ{ li n ~ prolon~a ticm ill llalf·lift . /Q\'t'n h)' the unbound couceut rattou of inhih ilo r that dl'('n 'a. Tilt' antidepres san t d t'sip r. T wu main conclusions ma~' 1M d r awn fmlll Ell .1 highly IM mlJ(! d nt~ \\i th a Itl\\' ('xlnU:1ic lll m lio.\' ..O W'TH 17 INTf iACTI G DlIUGS N 27. athwa j-s.ltioll.unbound concentration u f fill' inhibitor rt'1al in ' to its h " Man )' compounds have b een ShO\\11 10 inhih it dm~ met ub ohsm /'1 ('Uro but fail 10 d o so JFI t: jtJ() .) is lllllxlIlnd ..lgt' rt'jQmt'n n f pht'II)'lhnla. .-rt s exte nsive nn-tabol el tzers of d eaipra tniue. 10 IXIIX metabohzers.<. is anothe-r examp le . is till' inhibit ion e usstau t .tr2 IllWl.l!t' ptLSIII.l p latt·'1lI o f app rm illla td y 11M IlIWL.l {'( Ill {'\'utm lion. fu :: ().Ind lIlt" ' Will' offll fur wOlrfari n rist'S appm \ im att'ly th rt"t·fold . a ~h 'ad~ stalt' for this d nt ~ is n -aclu-d wi thin the first 12 d ays .is ('t)lldminislt. E\. Iht" !owt'r the h " th e mo re POk llt is an Inhtl nto r. 13 . in whom this path way is a major nne. eunxaci n inh ihils u nly 'ilIIllI' n f tllt'st· p a thways. I.lpp ro\iTll. ri ll~ oxidation.'uetil"S ) 10 form :2.ont· is al'il) IXMJrly t'\ tmdt'll. D ll rill ~ thi s ) pt'ril)(l.e u. til t' dOM' ill exte nsive lIlt' taho li/.r('(1 h)' the <')1OC'h nnJl(' 1'~ .(k c:l as tilt' pri mary mt'l·ha nism fo r tlais tnteracnon. llu iniclim' h iL~ liUIt' t'lT nn tln. sho uld ht.lIt'ly 10 d Ol)". red uced to avold toxicity.t·..5() .'tJn l i n ~ly. Fi rst . Warfarin is laiglaly IXlIInd in plasma 10 albumin. wlu-n \\"llrfOlriU.1 lAir.l. is 11. thr. I M ~'i Warfarin is l'tJlIlp lt'td)" Olh'ilJrht'll.1 mit' is atl llliniskrt'( l. uncl ll<t\ a h. Inhihi lion IliL rlu\ mos t p rofou nd d T('{1 whe n till' alTt'l1 I"tI Il..wmc' is 110 longC'f wich-ly used .ll")' alit! toxicity. Ihe p]..dcgn-e of inhihition of a ' part icular p<llh\\ "d)' dt'IX'lll l~ on tlu.uly-st. l1woph)'lIint' is t.L SIllOl {'UIl(.'lt'll 2 p<ltll\\"ll)' is uo w u minor om-. is high ly IXllIllt1 (f" :: O.lsllla am i unbound concentmttons o f warfarin ill a suhjt'l'l who illgt'sh'l l 10 m ~ wa rfari n daily. t' nz:"'Jl('. T itus. AI this tinl(' lilt· \\1lrfarin p\.v. .p g. C ll'arly. fh l' pl.'r... 111l' int e-raction has {"lIU!\('11 st'rin us hlc"t'l ling 1 '1' i!\()(!t-'s. PIlC'nylh util1'JlIlt-'. Second.pha n na{. WlI mg Ihn't· ti ml's a day. i. c!t'\ u id o f inlat'n'n l anticoa gulant act ivity.\'nlmfi nll i.. with a pmnouneed reduct ion in d eanUl{1' of appmxillmlt'ly fOllrfoltl ant i {. and n-nal cxcret tou. a IXI!t'1l1 Inhtlutor o f C YP'2D6.ltl t\\"lty is f)hli~ator)' for tilt' eltnunutiou of til(' d r u Ihat is when fill . AMultifoceted Interaction Although lilt' antt-iutlu mmatory dmg p l\('nyllmt.!'It'mls on f m. l\ l't.rt'tl. \\'ilh desi p rumim-. if quinidun. Ftgurc 17-7 shows the temporal elTt'l1s of plwnylhllllvJlllt' admlnistru tion u n till' p]. S. C YI"'2 D6 (st·t· Chap.(lkillt'lks o f c't1 desipranun « in th e alrea dy poor C Yl"' D6 nu-tabolizer pht'llot )llt" bt'l"lUlSf' the alTc'(. Tilt' laalf-lifc' uf warfcrtn is 'lpp ro\ imalt'ly :2 days .lilllillalt'll hy dt·lIIetll )'I. llSllOllly n 'l'tlllllllt'mll'll c!OS. <Iisp la{'('llIt'nl has 1I t'('n adH)('.rJllll'. am i the-refon .e {'tm trilm tions o f d nt~ an d 1llC'laholitt· to efli t'. w llt'll 01 1 d ay 13 Ih{' !iuhjl'l1 {"IJl11 1llt'll('('S tlit. In such caws.n ·lali\. \m rfarin is . Role of metabol ite Iormetion = Clllf ' ClI 1 + ClI/K.llf·lift· (app ru ximalt'ly 3 days) t'\ '('11 In ll~e r than Ihat flf \\" drfa rin .L\lIIa \\1Irfari n falls slt'ad ily in half. \'alill' .t's CLuJ by tw"fold. the clmk-al conseq uonces of an interact ion dC 'l'It'nds o n tln. alJ(1 tlll'ft'fo ft· ils d t'ardll{. As Ill i ~ht Ill' cqx-ct cd.'adlt·s . CIIll!\('(IIIt·nlly.l\ llla ('tlllt'('nimlinll o f tbis t1nt~ rist·s am i t·\l·ntually n.art' mult lph. ht'l"lUlw the uul xuuul concentrutions iL\'illliah"tl \\it" f!JC'flIpt'lIlic rt'/QlIlt'IIS o f th« inhibilion lIrt' wd l lll·low the h .OIOl. t' no~ldll is o llly ah le 10 reduce lilt' (tulal) dt'a m nl1' of t1lt'o pltyllillt' hy app m\imat d y "mfold \\i d l U t"(IrT\'slx mdi ng dOllhl i ll~ of d ll"()pllylliltt' half-lift'. its interaction with warfari n is \\'t.

.1 ".n" ..&r{.' o r inalti\.. n."1"1". 17-4 fora pun' t1ispl.. d ldt h ..1 11M ml 1". . pI M 'n. tlC· 17.· 1 ..d III at'l'Ollll t for til(' d l'\'i1!t'l1 \.. 11III 2..... · IIlt"tah uluJ'l! in dK" liw r In t'ifh t'r "1 ~a k1...~ II" 'I"" " "·. " ."".·. ... ( ~ . illtlt"t'l l. (''fInfin llt'l l d ldt.• in tiM' a hi lit..' t1...."". .d sccoents for 11K" d illie' tl p Kt ll A.fhulaznn e and warfari n is ("\''11 IIJUA."• • '" In . GIIlIIIM. D"II... " .nlrn.. ~ _ I'II<lr..'R'(1 .." " '" eI"·. ~ ~ ~ .1tr1" "'~ D "'I.... //) f. ..'(1 sustaim"(1 <l u': " lt' lIla lio ll of til«" d T a."n '~" " .~ ....ot" "..I. ca r eful ·r. H j." illftoraltiull ht 'h\' 'l'1I pIK'II. H ( '(·.. I'.. \1 ..02 ~ ~ "'''''''rod"".rdal warfarin b it racemate. nit" uuboaud wa n ..'l1. W a rfa rin i\ alllKJ"lt t·WIIL\i\l·I.' r 11... k)fl ~ ('(1 a.to O W l H 17 AI Clli<." .ll must ha"l ' (k"lTt·iL"t. . III .. \IIIN "IIUt'IlII. 1I0w('". I "·~rl. ~ . ...\ ' .Ilipl..2. N tt'n . Ih t' ("'I'nb ill p l<l.....1 rn. IIf IlIIhl"lII11 ll m~. 1 d t'\ .n " ......l 1 tIl '"~ ( I'I. t' itl w.k1iIl1l. ami w:.: \\ ·.pI.tiOlI..o f t"IlIf)' of dm j?.1. e c.. 1 " ·.III. l ilt' (it _ J.h..1IMlhlJlllll' inhibi ts warfarin dimin. R..l or III(' va lue of C l"l' is decreased .\1) . 1. e 0 ~ ~ u ~ => e 0. • • 0 0 0 0 •••• 0 e 0 0...llll p!t"ll.ll. i'i nf "' ''\'t"rtl n""tal lll ll i h~ o f warfilrin in llllllh pk\lI ld a lKlurilM'" .. '-.""' ".(·I1..· llM ·f....c 'IIM 11 M' les .• tilt' t'fTI"C.. I..u'l·tnt·1I1 in h ·r.. a !tM" r \.... .. " " I."~.·. this \ 11.n .n....· o f Iht· liw r to IIIt·tdhufi7~ · wa rfa riu .) Isome r is fiw lillK~ murt" al ti"..-. \ \ '.lI. (S )-h........1..1. . W I •..L". "" . 2 i IK lil.\.....tt.1'10."....2 ......1. . tht'n' is run.."n onTh.::t' nw nwII (If w..1..fl illll)I M~ a dt '(Tt'a...... 11111\.ufarin is IIl1ah." 11.. Examina tion of f AJ. .. ~f.. ... tl tt· ll101jor IItt1al 1llllih' uf Il.&1. 1. 0 = 30 40 Warfarin Phenylbutazone . . than purIra' l 'll ah u\(·...I "lI.m ~.\ n'I~ . IIlll 'lI ) lImt..... \ 1.\:0.1 " .7... f. u ml...1.. .uf a rill it. iulo 11M" hotl)' i.r.. . 111" .arl..&r{M1n--phrft.-rt.. . '....• mtl tilt· S( ..1 tlwo rL<-"'" 'IO'.nll is d t'a t': () m~ inh'ral'f HMllO call ht · l''Ump Jt.1 of warfarin i." \ ")( " '-' ~ E " 3: e 0 ·C e 0 ~ ~ ••o • 2 0 120 80 40 0 0 10 0 0 0 0 o~ 0 0 • 0 0 0 ~ ~ e 0 ~ 3 -s.ullt" for C I....~ n" 'I"""""·"'''''PT1u~u. fully hill.1.uw \I· i" 1"l).03 ~ ~ 0.. . 1 I "'WI.04 000 ....01 0 4 0 0 0 o 0 0 ••••• • 'n"'.Important tlifT.. .lIl m in i"h'rt"C."l---n ':" 2...• l.. 11 ". . t ...lIIlt·llllmilli"l r...~ . iIK'n'a.t· lIIu tt · 'K'fi\l · i-.... I lll '''l .. . t han fltt' R( + H ~ 'IIII·r.. I."n'I K'l'.. ·C e '" 0.. a 50:5() mixtu re of R( + ). lh llla7u llC' p rimarily inhihi ts tIM'" fo n liOltiulI of 7.. II ....·•. 1\... 1 1 <I~i •.• r1..ahnn.. " Wn n "."lt·~ th.. ." ra....... l Y'... · itC:'( i\.. uf<ln n..·~U"...·hlni". C l ..".. cla:-' ...lhulih..·IIIK" (ali s.l..)-"-drfa'.IUI"... Innn it '~' un ) .rf~ nn ..1.. • ..I\-ailahlt·. .Itt< .unt .ttklll i!i in at'{'(ml with til(' o h<.\1I101 appl'ar n' lI larka"I~' \imilur 10 th o"4' dt1lid'''l1 in Fi g.ami S( ...... point.... IIIN ·n ' ltiulI\ an' n"lillin'li to lIurJ. 1 tu ib unbound (1)m 't'lIlmliclII..lalt..... r.· (l......) warfari n. 1. 0 0 • 20 Days • 0 0 00 . ~1 ..1".. a ud it i\ th i' inhihi tHIIl au(l llut (li\plal"f"lrwnt fh...uf.nn \ . ( \1.... E..ui n concent r anon rise-s and rt'maim l'11"\"aktl dllrill~ pl lt'lI)-lhul aJ'.":I~ ..... · . .

II.lI\t'(. . ln" l'. ·' r ..i" l it' im ip< 'Ilt'lll loy il1 h lh i\i " lt IlM.lt·y o f imipenem. ( "t.the ('ffit'. BjI\n . it is market ed in t'o lllbillalioll \\.ntt''( dT('(1in' treatment of urinary · truct infect ious. metabolism is til(' majo r route uf us t'!imillalitlll. the major compon ent of total d t'amll('('. in. K II . J.1)).p rnIJt'lIt'('id com hiuatkm t h(' rJ. 11-Ji."'I.'n t o~~etl\(. 1...tf. Z1 ::!U l-. .n.(llllpd iliwly illilihii s the renal secretion of penicillin tlwn'hy suh sta ntially n 'l illdll ~ Its n 'na l deanmct'. 80 Administe red with Cilastatin HJC.u!-: ill'l'laJ'ulam idl' or sodium bicarbonate increases the renul clearance uf sali(·."'a lin marl<.l "rl. . . II dOl~ hi!!:hly ('xlnu...~..:. ad m ini\t . Beneficiallnteroctions Pt'n id llin."·I. .llt'll at lilt' hnlsh Iltlrt!t'r of tilt' p roximal tubular ('(."'~'in .~ .. A h h oll~h prolx-ncctd is also a<-1i \"t'i S('(.)' .• lI ulM . l'Il'a" -S lh..s ma coucentrarions of pcrnctlhn an' achieved full(J\\i n~ a nonnal dOS<I~t' ft'Wll1l'n of tilt' ant ihiotic.. n "{!Ut1'S til(' d ('anlll<. llti"l k r oh . Th· llri n . unhke pt·nid llin. -ta. a t1t'l... " .t...('(1 t'xlt' ns i\ l'i~' in the kidn ey hy ...l...~i. Propranolol diminislll'S cardiac ou tput and IWllt't. whic h mark('(lly Increases til(' uri nal)" exen-tion of Illwhan!-:t'd imipeucm (Filot.I.T with pm pmnolol.(' til(' dt~n't' " f ~-adn"l('rgi c blut:kadt' is it ~nltlt'(l n's!'ltlllst'.1.H~' n-cov. . · i nhi h it " u . Iht' interaction wi th lalocaim. Pn-sumubk-. the urinary excretion of intal"! Iuupenem is low am] u ftt'n insuffid l'llt 10 j. is an ex ample of a ph ysiologk ally lIll"{li. F . .11 " il l. o f noll' is tilt' lad.'t' of lidnt:aillt'.-· in til(' ~itlr .'rb l" . d Pmbe-m-cid t. I·S..l mll('pt i t!lL'i<-' Iuhihitnr. . -. . ill tum.'mt ol l.M.. (Rt.. " .It'l1 into y thr.rt.-:. M.. Cila.Ii(' . Both of till'se acidic d rugs arc n -nally secrete by an anionic tr. J"'l<'o.' when ~hl." II:.~ " 1<...1 . a ~ '<It1 n' lIer!-rjt' hlnd.tit. l ..."...Ia.. it is Iipophilit· and tn{)sl l~' reabsorbed.. .l..u interact ion is thai hl'rn't't'li lila.I!t'(1 phurmacnkim-ttc tn tcract tou .J u..\'.-i•.• H u r m an . . (If a dr u g interaction...1. The..m ... R ilisi ll ~ urine pll M.."jI j()..) ."..".~l.1.lrni ni... of 51_' 11111: M"r . Couv-queutly...: . I. I<"'hJl:. l n 'l"Tot..l uf s·r.1 s"I. a n 1. ElEVATED UNBOUND ClIARANCI TIlt' un lltlllm] dt"tr.' hy W\. fnTln i mit~ ~1 o l" it'naHl~. ).tati n and th e antihioti e .l.CHAPTE ~ 17 211 Other (ouses of Reduced C1eorOlice Inh ih ilioll of metabolism <lml secretion an' examples of t·lw m il~dl1~· II1t"{liall"{l plumnacokinet ic mteracttcns.l1~· ill' uri na l)-' t'\(.. n ". in the (In 'St'llt'(' of prnIJt'llt'l:itl.1l"{! by thellvr-r. Imipenem Alone 1.m l il.... tlt'h~tl n'P'l>l itL.1 alt. r~· u f umpenr-m io f".. UrilW)' Tl'l''''l'ry of . Tn itnprovr. Auotln-r example of a IJt'Ill' fk i .in (M" O!"7 ) "-. 8 . J(:.p~' is an example of Ih(' sUl"l'('SsfuluSt." . Cl. hepatio blood IInw.. of a dnl~ can 1 iU(·n "L'>t'l! in numerous \lllp .:~) anti 10 _ !:.1tlarJ.. ito 1t .tr..kidlll 'y tu bu lt'.tl.. Silll.a.nni mi · .1I1I"..II. 1""'1.' nt .. IllI' n 'na l ch-amnce of pmIJt'lJ("(id is low ... F. 1 I..111 dhsta lin..1 dl' hytlmpt'pt idlL~·.. iuupeneru.l...~~ lhit'n.J.\.mspo r! S~"!i l e m . COIISt. ~ ". 11 'R •• d lll'llili n ( (~ .. of a major d Tt't1 of pt' llicillin nil prolx-mctd ehuunation. whict.. lmipem-m is IIIt. lI i ~IIt'r tha n usual pla.dlll!: t1 m~..t"lltJlil. CllllSt'iplt'lllly. 1.is dt'I)(>I1(I('nt 0 11 IlIl' pllL 'ima conceutmuon of propranolol.ff''(1.l U7 ..-tit•• of tilt' .11 afk r a .'(I" t'lIt1y.. -. Kn'I'P.lower hepanc clearance of lidoc'aim." fro m :""r1 ~ S R..'\ .'r..l'i l>l<..

•...1 '''' Un' lt A ).9 illustran.r Uml: R. a\nitlt't l by t1l1uhlinp.Il l('l a"oli:d ng e nzynu-s..J. and th at ti ll' l'fT('(1: il1l1J't'tliately tli.~~ r . previ ously 2U of lotal clea rance .. A ) also n '('('in'S unot her (D m p.: .. ...ar. .••: . II.Imini<lr. A is IIl1t d l. ·iw. IM-<.. if this clea mno.lssul.9.'. m it.... l'Sj)('(ially for a <I m~ of Inw ext ml"lioll ratio..]l.\'T. " f 1>"'1: II i. d... "..l.llIiltlt' ill l·tlll..:.. .. .tJ.tU i~ k ~......UlV.. (( illl . nul " ....ti<: l'C IlIS('C llIl'IIn's of an iUert'iL 'i{"(lml'taholit.: ill thf' lm~.i\. T he fall in conceutrationcan 1)(.'lt ml1:i ll~ ti ll' vu rvvs in Fi ~.hJ.. In th is illustntti on iI patient st.~ tiMl·k~. (' I) .· tinn .ul('(-'...ar. nallll'l)' tltat till' 1.: rate is maintained when I) m p.. Gi\ing ammonium < nt l.•.tilll(" t"I''''11 tn n-ach a platean is IHll~1'f ill tilt' ahsence th an p fl'M'lll't' of D m~ 8 .. If th e t!osinp.sappt 'ars npoll its \\i thdfilwa l.212 CHAPltR 17 ad d and otlw r ad(l~ who'i(' n-nul d ear-lllct' is p H sensitive. th e S rate flf atl mi nistmtion of D nt~ A for . "t.0'1'(1 of Drug B is 'll·h il'\'(".. T Il(' events dt'pit1('(1 ill Fi!-':.S( tlu. :-'< 0 (·hanp. 11 am i 12....'ia!t"..< 'ents that . lI o\\'t'\ . in l!. pn'S<·.K"'. ' ill tilt" doS(' is .uw(' WN t ' d isclls...lll('t.. were to iUert". K. oJ"" 'K" "f 't· 1 n n' l( H i..K ..:hl 'r t1osin!-..l1ll't ' of ti lt' g afTt'<-1:t"...r).: B (Ca.contribu tes Hnly I lk to tota l d l'a r....1 Instantly and remains constant as l(l l\~ as it is ad lllinish'n'(I.I.''1 '1.. Iln-u its l'tllll't' ntmtioll falls by nne. a probh-m o f t'xl'('Ssi\"(' al'<." n..\.llls(' tot al d m j{ d t·i1r.half at a mit' dl'l t'nnilll'tl l.. ""t.. :-.1 20-fuld .lh ili7.ri _ if ... l') IIII1l(ml~' hy ind ud llg tilt' dnl ~.i". n i l' im pliedtiollS u f tlu-sc dmllges Oil dO~lgt' requirr-ments nnd Ihe.<I ..1 fl .' n!l·d .. ti"..\lf·Ii\t "l> " f U m-.. Twn major assum ptions wen.. if fnllow~ that rln.f I>m lt A i.n 'a tly illl·r\'. 1in h.llil' hloc)(llIow "i and t1wreby iucrvaw the hepatic clearance or drugs thai ure highly ext rurted h~' lht' liver. I'Lt .l' IOll!-. (".1ch-arS uuee .ltt"..(' urine mo re ad tlic tncn-ec.l\("..·. An exc eption anws when tilt' Illt'taholi tt' fnn m".. Iikt· glu(:agoll . t1m !-.(01..<IK''' " r Dn.. a dnS<Ij{I' n'lQllw n adjust ment is ""(luin"(l finly whe-n tilt' dl'.-.11l 11 11latioll of I)nt~ A l'xi ~ ls if till' h i!-. b("(.. tIll''' Incn-aw hl'l ).. even if de. -.!Ialf-lifl' o f D m~:\ is ~I' l ll'fiIl1y IOll!-(I'r when ~ \"" II u ' alum'.salie nt ('tIlISt"fl" I'III"l'S of an ilwn "l.lSt. ·IK. follow Iht' itd d itiull or ui thdmwa l o f dm j{ l"a us i ll~ tht' alh 'n-<I d l'am lll't' an ' li llW p rl'!it..• lot':4l<· in h"tI . n or p".1. 1\0. T!I... a 1It"t". (k1.Hf pll ' S('lISilh l ' I "l~ i<: drugs.... tha t t · patll\\-dY im 'ft". 0 1 23 4 0 2 3 4 5 Druo A + DruO B DrugAAlone Dosing Time (hall-lives) Rate ~ J.<r· ' lUll'" of Unl~ . Unlit H. I'K.It-".·l.. s.lIItidp<lh-<1. B is witbd ruw . (Cit.·nlr...I't1.9 ... 11.1\\i tl..( Mf.aI. H) that doubles Ihe d l'ar..1. ' In II.I 10 Ih.1is l'itllt"f th e adin' spt'('il's or is to \ k·.."'1..< 1 'nl «I"hili7t. In p ract ice..' tilt' !Ialf-lifl' of tIlt.lt" f.1 if tilt" <:!('anllll't. .l'lSO(1alt". . ' pn~i.1 to d liUl!-... (Ol'" II lln~ Ii..tIM II .IUS(' its plaxmu coucentmucn can he p. hut tilt')" lIIay also ad i\" alt' ('1lZ)11WS or n -tanl ('nZ)ll ll' degrmbtinll..1 pa thway is o r bt'<-'tJlllt'S a siWlifk a nt Iructinn of to lal dru ch-arunce. " 1" 'n ...1 on Olll' dm~ (I)m p.. SOllie drugs Increase tht· lIleta ho lic d t·:lr.K II"".. . ·.. I. ....:t' the doS(' is antid p.· pn ·.wncf' of Vnlf.ui"n . -d ill C haps.IlIl'l' of otlwr 11m"' TIlt')' dn so most 1\. " .. tI. tI.I . BI'('lII. I j . til(" renal ck-aram x....uK"...' .(".of D m p. l i .• ''''1'""". d hIRrAh' i . .1 ti M lin In n·.m".tr..n 1".1L o lia lly ....1 with a particular pathway.. .la'" ' . a elm): tlwl inc:n-. III !{I'nt>faJ.lSt' sixfold . bolh ll'sump t ious Ml' ill\1llitl..' is % then doubled.> or :illo ascorbic add to make 11. 11...-1 01 Drug A o Drug B .: us ()nt ~ B is ¢\l' 1\ (C tSt' Il l. <:!t'. .1II11:' uf D rug A..

lTl t it.. Turnover Concepts."t'i\ill ~ dicumarol ch rou ieally (F ig....ul ( e ) "".. 2.1"1'1) ( I illWI-• • . Phan naml. ( tt."111' tnvolvcd ... 30 60 120 Days 150 180 210 Flit. a measun-o f its .' .~.r.naml mnlfliodl~" ( ~ mK n." 11 . Thi s last possibihty may exp lain the effect o f plu-noharhitul on the temporal chun ges ill till' plasma conce nt ration o f dicumarol and p roe<.rinlt '·ff.I~u la ll t efT 1 . I 2I1--429.' u"" " f its .il M'11. the ohst' l"vations a n' 1. th e clea rance of the afT("<. 0 90 c..L..: ~ ~ . pl.n ll: . .ll... . r.is a d elay in tilt' decrease in clearance of the afTe<.\o takes app mximatl'ly the same peri od of time to reach a plateau in the hod y and to he " d illlinah -cl."t.ml "" Oll t1iph.J r...n ~ e<. . likt. 19l15. on thl' kiuet ics o f the d rugs and tilt' ('IIz:..1 '01 ' tiM " MK.'ll1e is the slowest p n K"t'ss. I'-JU).... Both tIll' fall ill the concentration and efT 1 o f this tlnl g follO\\. of Inducer art' t11('11 n 'I1I"11('(1almost instantaneo usly hy changes in tilt' amount of ('n7)"llt· and h('nl'(' d ear..... A(:m n li n~ly. Fur a furt llt'r dist:'ussioll of tlJ(' kinetic llSpt"l.. u d liUl~(' in dl'arall(o'(' is an indin"<."''1M "..)""l' 1 ·t. 40 40 .'n~n.O .1 measure of the effect o f an ind \l('('r.l . plll'Iloharbital treatment liav(' hl"l'n att rihuh"ll to the b arbiturate ind ud ng the t'n7)111l'S n 'spo llsihl(' for d il'un mrnl llwtaholism. 17. "r tI. in a patient re<. S". \1 S .Ii< "".ly ccustan t. eli" ." H .1('(! dru g on removtng till' Iuducer.. It takes app roxilllutely 3 to" weeks for the plasma ot dicumaml b h to fall to a mhumum du ring phe-nobarbi tal admmistratiou and to n-t urn to the p rdlilrbitu rate value after phenobarbital is disco ntinued . changes in tilt' roucentratiou t'r. Pln-noba rlntal (t l/ Z of .'" pt.1 i s all Increase ill the synthesis mho' of the drug-llIt"tahoIi7jn~ enz:..'". th rombin time. (" 1Ut Similarly_ tln-n .bi l~' ) '-." " mini' tmti" " "f ph"'H~rhi'a1 (fi(l mil: daily) 10 it palil'lll n'O'.')"..l"n . all" 8u m•• IJ. l1 UlS. .3 0 11 M )..IW \\i tl! tiuu..u.... '''''ntraliou " f tI.\ tilt' ('I17.I p".) . Irwl.in. til(' din-ct ('fT("<. ma '''H .••!t" L... \\1lt'1l elimination of enz:.tn O('t11r (" ·('U tlIOU)!:!J the coucentra tm n of the inducer is rL'latin . (. then cha nges ill d('anllll'(' of till' drug llIa~' contnuu.·ff..m.' lln>mhin ti ". \\111'11 .\'('n if tilt' pJ. <If .. there is " ck-la h('tWI y 'C1l the di rect e ffect and its refll"<. 1111' tum.( )."llw induct ion \\~LS men ttoru-d as tll(' prime cause of increased metabolic d earunre.: la. it " .. Ih. aUlk.fk-.CHAPTE ~ 17 INTERACTING oacs En z:. lI o\\'I'\ t"r.(l P] a~' d('I)('I\(Is..· (OJ. TIlliS. n.°llle.'utralil"...· "Hamill ":r<I. dot tin( (. . 'it'(' C hap.1 t'(! d rug would illtTl'.1 riws from 011(' plah 'iUl \11 ' to anot her..10. .. ot her sys te ms in the hotly. howt" O elimination o f tilt' induce r is slow .".2- zs 10 Phenobarbital ~ e ~ E '5 / o ..1s of tnducttou ..1 <If 1 J<" IH " .harh it.. s .1 io n in the IIlt'iL \lIrt'(l rt"Splm ~ ' ..n (ru m ' I.L\ IllU concentru t jon o f tilt' Inducer \\'('n' at taillt'(l insta ntly ami the n maint ainer] constantly.. days) al..()lllpat ible \\ith the hypothesis that till' indlll"l ll pidly to changes in plasma phenobarbital couce ut ra('1I0 °IllI' spte m responds rdati\"t'ly rA 1 tion .. u 0 ~ 30 ~ E 20 ..n .lll('(' of tilt' afTl"CtN I d rug.

Displacement tnteracttons are g('lwmlly not tllt'rrJl'nJtlc dnl f!. oE 0 ~- 2 - 2 1 E ~ ~ f£ 0 0 J"IJt.. All a increase-d risk arises . d. Drug Interactions a rc o fte n de tec t ed when an interal1ing dmg is Inlnan-d or with- drawn.i1. Bnefly comme nt 0 11 the aC(:uroll. Each gra ph sll1mld d('arl)"Indicate tilt' con. mola r concent ranou of Drug H approaches th at of the protein that hind!' Dmg A.L phel" ' nob ar bital is slowl)' elim inated. C. infusion ' 5 ~ 0 ~ 4 3 c u ~ 8a.' of the follO\\ ng statements.Ilant is not reduo-d when phcnobarhilal is dlscontmued. )' e. \'. i a. perhaps. l lit· barbiturate until.'rtletiOlU. 17. Dm g interactions art' ~(' nemll)" WlI<!t"(l. however. The grap hs below show tilt' conce ntration. luhlbttiou of metabolism ill of primiU therapeutic important't' . a hemorrhagic crisis occurs.tune rurvt-s follU\\i ll)!. STUDY PROBLEMS (Answers 1 Study Proble ms ore in Appe ndix 1 0 1. tilt' lIlt'thod of administratio n gh't' u . Displacement of ()m~ A by D m~ B occurs when llit.10 sU " AAt'sl that prothrombin tunc Illay 1"-· maint ained at lilt" p rt·· b rbit urate value by rdisillF.. dntg (low clearance. S!wt(·h the expected plasma concentratio n-time profil(' (If ('ad.S("f jlwlll't' of a d langl' in C/. 111 plasma dicumarol conceutration 11\('11 rises insidiously. 111t' pa rau J('!l'r gin'll is uln-n-d twofold. ". h.) I. ph enoharhital aduuuistration.'I'liLS("'(I. cons tan t-rate i. 17. 2. jil ill(.t.. a.214 111l data ill fi~. brgp volume uf distriburion ) if ad minish' J'("(! again du ring tht. the dose o f d icu mam l duriuF. coadministration of anot he r dnl)!. and ' 112 (o r il l"f)mhination ). j. of the various rncchamsms of drug intcructkm. .Jl . if th e dose of ant iC'tKtj. and may ~o unnoticed for seve ral weeks aftN di st'o lltilluin.v. 6 12 Hours 18 24 . tllat is at slt'ady sta te.

llW" and itlt'ltli ~\' !loth l·.11l1" .7A'Jlfnjtlt. tlu..· I. 20 230 ~ cwo _ ""'""""' '"a. f " T' Cl.. IllSuffid t-nt information W 'i provided to conclude whether or not IlK"u lcti llt" aIn-red 11K" half-lift' Oi~If thl'liphyllilll'. . l . I . ~I l'an \'1iIIlt"S of C(o ) and t II! for dllonliil.K1illll of l l·tO (1millt ..v..lxldde ? J lIsti f~' a ll)' aasum prious thai ) UII 1II...i\ 'I·1I tlMt ('hlonlia7A'!xnitlt.(· time COUnt· of the concenrnmon of I ht>( lflh~11i1li' t1 l1 lin~ treatment with all oral 30U-IllF: sustamed-n -k-asc dosa~~· fonn ('\1' ''' 12 hr.. W <L\ a<llll i ll i~lt>n·d 10 ~i\ I... 11K-' oral ahsorpti llll of Iht'l'PI I~1 Iillt' is \i rt ually complet e (F = I ) ami G" IC is appnnimah. W I/dr:l<TOOo A I .11\\11 ill Tahlc' 17-1.) C I ..lml)1hmic a~t"llt. dllnnliillA.111)('1 hott. ) is reslxlII.. r.fflll( l\\i ll~ !.I" t ".v~ 'PI\itlt ·.rn·.Iurtli..1i\1" anti. an' . Chlo nli.... in till" pn 'S!'lll'1 ' and absence o f keroconazole....is eilmiuated by luotrau. J7'l9O-191 t Q ~ ~ 20 43 ' a. 111t" data ill Tablt ..'ihio ll alone or 0 11 th~· fifth day of a tLily -IfIO"ITI~ ~ In\(' of !wtUlUlI 'W III·... (l A Ir) h. Ketoc onaz oh\ '( I... t' lIliloKaritlllllil' plot o f lIlt" mean (1I1ll'1 'lltmtio ll-lilllt' p mfill'" of (·!.. one' \ e unp arnneut 1Il()lld charact eri stics ..fu rruatiou in tin: hvr-r. an allliflln~al agent .l· nu-chan i.I. .. Prr-pan.m (s) (Qu.3 1Il~.---. \ \'itllI1111 Kctoconazoh\\'ill. o 12 24 Hours 36 48 3. COll1plt·tt. what p"rsilll f)~.. a Ill'Il/AltliillAl)int>. 17-5 silo\\" tt.VA'IXI\idt. tilt" d nl~ ha.01 .alt l l~' \ul ll ll h't' ~ (-1.llll pl i n~ 011 day 6 ). 17. n. "II llral l~' ~·lT("l.i bl~' for tilt" inlt·r. 1. is l''Omllllinislt"n "'l1 { 2ntl lll~ ('\1'''' IS hr \I arti n~ a t tilt' tim e of hlcJOlI \. -I..II' \\i ll.-post· of th is probk-ru.... ho lu\ ) ill l·rn\\O\ "(·r fil..-----. f"..1. 2. (. For tl R pu. IIM'dldilll' .. O n days fi alll i 7..( HAPTff/ 17 2IS 40 o +--~---....

..o1iin.)11W ind uction ..~..0 4 tIM M_I. . 6.. Dr u A is ¢\'('ll by infusio n ot a rute o f 2'5 mWllf to mainta in a con stant pkeuia cong centrarion.. h.(! Oil a d mllJ.the interacnon.u subjt'l1 l hlll t~]li fy what is known ab out til(' interuc tiou b etween Ijuin idint ' a nd d i ~u'(i n ....._ 2 3 7.(1lt'(l when tlwrapy with t his dm ~ is ini tiate-d in a ' palit'lll who is lImlt'rgoin g auttarrhyth mie tll('rapy with quuudiue-.. ~ O . 17-5. b.lHoll r.. TIlt' Iht'rape uti{' l1l1ll't'ntr.IetI .ah st'lIl't' alit! p n S('lll't' of D m~ B (il.. Table 17.. Give.' til(' paramete r mvokr-d a nd im lilw ti ll' din"('tiull of its dmll ~c...tII_ e... a.. Det ermine till' IIlt"(·I..\idt·!lt't· fo r DnI ~ A I It' i ll ~ st"(·N. 5O?Q9-Xll.. 01 03 12 8 G in ' u t his illfonlliltioll am] tilt' ob serva tlonthat tilt' ('f(' a tinillt' e!t·. .._1... G W .M I ..'lt'1l a nd/ ur n'a hsu rllt'1l in tilt' kid nt"')"S.probable "lo adtug" dose of digoxin nl. calculate tlu. Dt. 1200 "'9 -v 8 lwl a. .. J..~ 'Mo.... """-'oed n.IDY Sl Art:~1 HALF tJ! 0 """ 100 07 15 ..2.(.ltle 17-e. 0 75 075 ~"" C. '" v".t M <li"'d"""""". com potuiou for ad i\'t' reabsorp tion in ren al tuh ull'. 1001 s. u 5.. PI.-_.lIlll·tN \'alut's in Ta bl t' 17..·•.-. h rit·f1y di scu ss (i n te-rms tlf tilt' di~u1iill l1lIll'l'lltral ion) II\(' Ilwrapt·lltit· . 1-3~ " 0 72 101 51 500 '40 077 079 a.. The da ta in Tahk.li\'t'S o f digo\ in a m i fjllini tl im' an' ahou t 2: days a nd S h r.. Brit·fly di sc uss Iht" explanation in (lut~ti nll "a" aiM)\"(' ill terms of 111\(' physioln¢ c.d It> 3 cb..A OON """'" ""'"" ~1:«:if TK:lN fRACTI()N ~ lATIA' STt.1i\'l' ly... oo/IooctI""'~o.· mechanism (e.. .tll ~l'. <J ~ . c...• 0' 02 7' PI.ltl.... .q. '00••....a nism (s) by which DnI ~ B interact s wit ].7. M __ r INTUACnNG DRUGS CHA... DnI ~ A.. n ·spt'l. . Using th e a pp ropriate d i ~o'(i n par...:nu..'h 'n nill(' if thr-re is t./Irt:AU PlASM' DAT AJO OOJGA CONCENTtATK:lN """ '" reoo e 20.ving that tilt' Imlf.* J l floooo<o<o.0 CONCE N!R..1 of mcxtletme (Ill t1ll'u p hyllilw kinetics .' I"l-O. 17. «><>:J-. (·1I7. The explunati on should hc. f ll T' Cl"h" Q". Brielly comment o n how q uin idilw alTl'(:ts til(' d istri hutio ll of d iv... .7.. 112 hr .0 117 80 o~ fooor.g ..mUl('(· inlhis SUhjl"( 1 is 120 m llmiu .-. De_. h . dh" .A ...PTH 17 1t n. Discu ss the therapeutic implicat ions of l'o'l( l lIli n isft'ri n~ DnI~ A wi th D rug B. 1 to 2 IJWl.. n-uuuns tilt' same for <IiKu\ in ... Give an explanation for till' (·ff('(. U lI1 l· tha t it is it! sh·atl~· sta te when pn·st·"I).-p1t.. . "''''' ItfA... c. . N ""'"" . . lnluhit ion of biliary to 'n -lion ) that couk] pr oduce.7 contains pharmacokmctic \ 11I m 's fUf lU I im li\idu... . 0.17--6 a n ' o hlailU'11 ill a sllhjt'l1 who is infuSl'11at t his rail' ill tlu...T/VtNT 5 8 125 Q 10 55 Concentration lmg/U 0 00 07 7. h.:(Oin only 0111' of till' rol1 o\\i ll ~ pa mlllt"lt' rs : j ll .

and that tilt' "well-stirred" model of ht'jl<ltie r-liminunon applies... ..I' ·"...hltIl Il.m~ "ral d.."I ..._ AI••• and . 1 :l: 103 19 7 . of desipramine (50 lIlj?. 111is is Iht· more rtmunon situation ill \\'hk-h Ihe interaction is observed. II. Fig-lin' l i -1 3 ami Tahlt...at iun aile! nlt'( .tareti O_11y I•• Iln.1 9 .."hn..I ~ . 17.. au d 1..I. d. .19--2-11>.kl_tlcs.j fnlln Bt·l'K'frum.ht Dally Da_....1">I" e ll"... 1!J!J:2.. Bt' ~S lrull l 11 £II.( H"'no"i.f D••lpra.1 54 16 52 168 398 2110:l:Q()() 23..\t. Do ~ Ull thi nk lluiuidill(' would affec the dosage requirements for digoxin in a pat teut t \\111..) ".l alone am l3 h r aftt"r the eighth tWily dns(' o f IIl1o\t'tiTw (fiU 1lI~ t·at·h ).fto-r .t't l llllly ill tlu.an n... US(· tlu... uu-taboli .. h. .. ( ~ ."'.t1i!-:(Jxill pa ranWlt"r values in Table Ii-i and consider tilt" events upon lxuh initialin J!.) o T.r. " " _ • • H_- 28.8 :!: 19 3 27. Suggesl (JI lt' nu-chamsru (comhinarion o f mec hanisms is nol acceptable) for the phannacoktnottc interact ion observed.1..."'. .1f_ t . ~'n'n' renal [unet ion impaim lt"nt? Briefly di scuss.CHAPTH 17 '" umS ('tlllt'llt"t' of ad ministe ring quinidine 10 a pat it'1I1 \\'110 is rt't"ti\illg di ~(Jxi n tln-r' ap~· . 51:2.O..i\"t'll that tlu. lw·'1l'·r... and d is(. 1 Ie 100 1'-11/:. Document how ~1l11 arrived at ~l l1l r conclusimi.')1u" .t> tilt' ollSt'rva tions folliMing a singlt· ural doSt.. ( . 50.H er-r.1 .4 53 16 1 289 77 1 :!: :!: :!: :!: :t :!: 2..-••eh) . M t..13 ..""."'...o:tllu . (I>lade. Itt'" 1'.L.. l i --8 sunuua n .". TIlt' ccucentrution of f111o.. calculate tilt' value of e Li"l '111 in I!I£' pff"St'Il(.m " f tI"" Ihll"""I.. 77 a. . slu dit'tl till' pharmacokmeuc interaction of the antidepress