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S£MINAR ON

DRLG DI$TRIBLTION & FACTOR$ AFFECTING
PR£S£NT£Ð BY S\BMIT TO
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DRUC D1STR1BUT1ON
ÐIsfrIbufIon Monns !ovorsIbIo Trnnsfor of Ðrug(s)
from Ono !ocnfIon fo Anofhor wIfhIn Iodv. Tho
dIsfrIbufIon of drugs from bIood fo fIssuo occurs nf
vnrIous rnfo nnd fo vnrIous oxfonf. IoIIowIng fncfor
ÐoformIno fho dIsfrIbufIon pnfforn of drug such
ns:-
AffInIfv of drug
AbIIIfv of drug fo pnss fhrough fIssuo mombrnno
IIndIng of drug fo bofh pInsmn profoIn nnd fIssuo
compononf
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ÐR\G ÐISTRIB\TION PATT£RNS
ÐIsfrIbufIon cnn bo fhrough of ns foIIowIng ono of
four fvpos of pnfforns
4
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IOÐY WATI!
IÞ VA!IO!S
O!CIÞ
SIICIIIC
O!CIÞ
TISS!I I.g.
Inf
ConornI Orgnn I.g.
!Ivor MuscIo
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ÐIsfrIbufIon Infforns
l)Tho drug Mnv romnIn
InrgoIv wIfh In fho
vnscuInr svsfom.
2)Somo !ow moIocuInr
woIghf wnfor soIubIo
compound such ns
IfhnnoI, & fow
suIphonnmIdos bocomo
unIformIv ÐIsfrIbufod
fhrough fho bodv wnfor.
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ÐIsfrIbufIon Infforns
3) A fow drug nro conconfrnfod
spocIfIcnIIv In l or moro fIssuo
fhnf mnv or mnv nof bo sIfo of
ncfIon.
4) Mosf drug oxhIbIf n non-unIform
dIsfrIbufIon In fho bodv wIfh fho
vnrInfIons fhnf Is InrgoIv
doformInnfIon bv fhoIr nbIIIfv fo
pnss fhrough fho mombrnno
&fhoIr IIpId/wnfor soIubIIIfv. Tho
hIghosf conconfrnfIon nro offon
prosonf In KIdnov, !Ivor,
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TORS T1NC DRUC D1STR1BUT1ON
Rute oI dIstvIbutIon
Mombrnno pormonbIIIfv (CnpIIInrIos Mombrnno
pormonbIIIfv)
IIood porfusIon rnfo
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Membvune µevmeubI!Ity
(CuµI!!uvy Membvune
µevmeubI!Ity)
Mombrnno IormonbIIIfv fonds fo rosfrIcf fho frnnsfor & dIsfrIbufIon of
drug onco fhov nro doIIvorod fo fho fIssuos
Tho cnpIIInrIos nro fvpIcnIIv IInod
wIfh ondofhoIIum whoso coIIs
ovorInp,. AIso, fho juncfIons bofwoon
coIIs nro dIsconfInuous. CnpIIInrv
wnIIs nro quIfo pormonbIo
!IpId soIubIo drugs pnss fhrough
vorv rnpIdIv.
Wnfor soIubIo compounds
ponofrnfo moro sIowIv nf n rnfo
moro dopondonf on fhoIr sIzo.
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Membvune µevmeubI!Ity
(CuµI!!uvy Membvune
µevmeubI!Ity)
!ow moIocuInr woIghf drug pnss
fhrough sImpIo dIffusIon
Ior compound wIfh moIocuInr
dInmofor nbovo l00 À frnnsfor Is
sIow
Ior drugs whIch cnn bo IonIzod fho
drug's pKn nnd fho pH of fho bIood
wIII hnvo n Inrgo offocf on fho
frnnsfor rnfo ncross fho cnpIIInrv
mombrnno.
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Thoro nro two devIutIons fo fho fvpIcnI cnpIIInrv sfrucfuro
whIch rosuIf In vnrInfIon from normnI drug fIssuo pormonbIIIfv
IormonbIIIfv Is
gronfIv Incronsod In
fho ronnI cnpIIInrIos
bv poros In fho
mombrnno of fho
ondofhoIInI coIIs,
nnd In spocInIIzod
hopnfIc cnpIIInrIos,
known ns sInusoIds
whIch mnv Inck n
compIofo IInIng.
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Thoro nro two devIutIons fo fho fvpIcnI cnpIIInrv sfrucfuro
whIch rosuIf In vnrInfIon from normnI drug fIssuo pormonbIIIfv
On fho ofhor hnnd brnIn
cnpIIInrIos soom fo hnvo
ImpormonbIo wnIIs
rosfrIcfIng fho frnnsfor of
moIocuIos from bIood fo
brnIn fIssuo. !IpId soIubIo
compounds cnn bo rondIIv
frnnsforrod Iuf fho
frnnsfor of poInr
subsfnncos Is sovoroIv
rosfrIcfod. ThIs Is fho
bnsIs of fho "b!ood-bvuIn"
buvvIev
l0
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Thnf monns Mombrnno IormonbIIIfv dopond upon PLysI¢o-
CLemI¢u! IroporfIos such ns moIocuInr sIzo, IIpId soIubIIIfv,
And IhvsIoIogIc InrrIors such ns..
SImpIo cnpIIInrv
ondofhoIInI bnrrIor
SImpIo coII mombrnno
bnrrIor
IIood IrnIn bnrrIor
CorobrospInnI bnrrIor
IInconfn bnrrIor IIood-TosfIs bnrrIor
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SImµ!e ¢uµI!!uvy
endotLe!Iu! buvvIev
AII fho Ðrug, IonIzod or
unIonIzod wIfh n
moIocuInr sIzo 600
ÐnIfon, dIffuso fhrough
fho ondofhoIIum nnd
Info fho InforsfIfInI
fIuId. OnIv drugs
bound fho bIood
compononf nro
rosfrIcfod bocnuso of
fho Inrgo moIocuInr
sIzo of compIox
l2
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B!ood BvuIn buvvIev
The hruin cupillurieo conoiot o[ endotheliul cell uhich
ure joined to one unother hv continuouo tiµht
intrucellulur junction comprioinµ uhut io culled uo hlood
hruin hurrier.
l3
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CorobrospInnI bnrrIor
l4
S io [ormed muinlv hv choroid pleruo o[ the luterul, 3
rd
& 4
th
tentricleo & oimilur in compooition to the o[
hruin.
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IInconfn bnrrIor
l5
The muternul & the [etul hlood teooelo ure oepuruted hv
numher o[ tiooue luver mude o[ [etul trophohluot
huoement memhrune & endothelium uhich toµether
conotitute the plucentul hurrier.
PR£S£NT£Ð BY AZIM ARSHI, 1
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PR£S£NT£Ð BY AZIM ARSHI, 1
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УPARTM£NT OI PHARMAC£\TICS
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HIgh porfusIon HIgh porfusIon
Modornfor porfusIon Modornfor porfusIon
Ioor porfusIon Ioor porfusIon
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TofnI bIood fIow Is gronfosf fo
brnIn, kIdnovs, IIvor, nnd
muscIo wIfh hIghosf porfusIon
rnfos fo brnIn,
kIdnov, IIvor, nnd honrf. If
wouId bo oxpocfod fhnf
fofnI drug conconfrnfIon
wouId rIso mosf rnpIdIv In
fhoso orgnns. CorfnIn smnIIor
orgnns such ns fho
ndronnIs (l.2 - 5.5 mI/mIn/mI
or 0.2 - l° CO) nnd fhvroId
(2.4 - 4 mI/mIn/mI or l - 2°
CO) nIso hnvo Inrgo porfusIon
rnfos.
As nn oxnmpIo; fhIoponfnI
gofs Info fho brnIn fnsfor
fhnn muscIo, whorons,
ponIcIIIIn gofs Info muscIo
moro quIckIv fhnn If gofs Info
brnIn
ThIoponfnI Is onIv pnrfIv
IonIzod nnd pnssos Info fho
brnIn or muscIo onsIIv.
IorfusIon IImIfs fho frnnsporf.
SInco brnIn hns n hIghor
porfusIon rnfo fho fhIoponfnI
cnn frnnsfor In nnd ouf moro
quIckIv
l8
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IonIcIIIIn Is quIfo poInr fhus sIowIv pormonbIo.
IormonbIIIfv IImIfod frnnsfor Is fnsfor In muscIo ns
muscIo cnpIIInrIos nro Ioss rosfrIcfIvo. Thus
frnnsfor of ponIcIIIIn Is fnsfor In muscIo fhnn brnIn
l9
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I!ASMA I!OTIIÞ IIÞÐIÞC
IIndIng of drug fo pInsmn profoIn Is mosf
common 50° of fho fofnI profoIns bInd fho
wIdosf rnngo of drugs. Tho ncIdIc drugs
commonIv fond fo bInd wIfh nIbumIn whoro ns
bnsIc drug offon bInd fo nIphn nnd gIvcoprofoIn
nnd IIpoprofoIn.
2l
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PROT£INS WITH POT£NTIAI BINÐING
SIT£S IOR VARIO\S ÐR\GS
Acidic Drug Basic drug
Binding sit¢ AIbumIns CIobuIIns, o
l
,
o
2
, b
l
, b
2
, v
ampl¢ Drug IIIIrubIn, IIIo
ncIds, Inffv
AcIds, VIfnmIn
C, SnIIcvInfos,
SuIfonnmIdos,
InrbIfurnfos,
IhonvIbufnzono
, IonIcIIIIns,
TofrncvcIInos,
IrobonocId
AdonIsIno,
QuInncrIno,
QuInIno,
SfropfomvcIn,
ChIornmphonIc
oI, ÐIgIfoxIn,
OunbnIn,
CoumnrIn
22
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IACTO! IÞVO!VIÐ
Croups on fho profoIn moIocuIos fhnf nro
rosponsIbIo for e!e¢tvostutI¢ Intevu¢tIons wIfh
drugs IncIudo
fho ÞH
3
+
of IvsIno nnd Þ
-
formInnI nmIno ncIds
fho ÞH
2
+
of hIsfIdIno,
fho COO
-
of gIufnmIc ncId rosIduos
Tho InIfInI oIocfrosfnfIc nffrncfIon Is roInforcod bv
vun vun dev dev Wuu!'s Wuu!'s Iov¢es Iov¢es nnd Lydvouen bondInu
23
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IxnmpIo
IhonvIIbufnzono nnd SnIIcvInfos dIspInco
foIbufnmIdo fo gIvo nn Incronsod offocf,
hvpogIvcomIn
Tho dIspIncomonf of wnrfnrIno bv phonvI
bufnzono Ionds fo nonrIv l00 foIds Incronso In
froo drug con. WhIch cnn rosuIf In cIInIcnI
sIgnIfIcnnf roncfIon.
Tho vnIuo of fho frncfIon of drug In pInsmn
fhnf Is unboundod fo pInsmn profoIns, fu Is
gIvon bv
fu = Cu/C
IACTO! IÞVO!VIÐ
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P£RC£NT \NBO\NÐ IOR S£I£CT£Ð ÐR\GS
Ðvuu Pev¢ent \nbound (100 * Iu)
ÐIuoxIn
??
GentumI¢In
90
TLeoµLy!!Ine
85
PLenytoIn
ll - l3
ÐIuzeµum
3 - 4
WuvIuvIn
0.5
PLeny!butuzone
l - 5
ÐI¢umuvo!
l - 3
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KIÞITICS OI I!OTIIÞ IIÞÐIÞC
Ð+I ÐI (compIox)
KA = nssocInfIon consfnnf
KA
KA = __ _ | conconfrnfIon bound] _ = ___|ÐI]__
|unbound drug] |unoccupIod profoIn] |I] |Ð]
r = Þo. of moIos of drug bound
TofnI no. of profoIn
r = ___|ÐI]__
|IÐ] +|I]
r = ___|ÐI]__ _
KA|I]|Ð] +|I]
r = ___KA|I]|Ð]__ _
KA|I]|Ð] +|I]
r = ___KA|I]|Ð]__ _
KA|I]|Ð] +|I]
r = ___KA|Ð]__ _
l+KA|Ð]
r = ___nKA|Ð]__ _
l+KA|Ð]
r = _nlKl|Ð]__ + _nlK2|Ð]__ +..
l+Kl |Ð] l+K2 |Ð]
26
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Af pInfonu r = n nnd whon
r = n , |Ð] = l
2 KA
!onrrnngod oqunfIon
r = nKA|Ð]- rKA|Ð]
Or
r = nKA- rKA
|Ð]
SIopo = -KA
Inforcopf = nKA
2?
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TISS!I IIÞÐIÞC
n) SpocIfIc profoIn In
fIssuos
b) AccumuInfIon In
ondocvfofIc vosIcIos
(I.g. ConfnmvcIn In
ronnI proxImnI fubo)
c) IIndIng fo nucIoIc
ncId
d) IIndIng fo CnIcIum
o) AccumuInfIon In IIpId
dopofs
rumple
Tho con. Of chIoroquIno
In fho IIvor Is duo fo
fho bIndIng of drug fo
ÐÞA. InrncofnmoI
bInd IrrovorsIbIv fo
IIvor fIssuo rosuIfIng
hopnfofoxIcIfv
30
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AIIA!IÞT VO!!M OI
ÐIST!II!TIOÞ
Tho oxfonf of dIsfrIbufIon Is IndIcnfod bv nppnronf
of dIsfrIbufIon
Vd = AI = Amounf of drug In bodv
Cp Amounf of drug In fho pInsmn
Tho voIumo of dIsfrIbufIon vnrIos from ?- 40,000l
por ?0 kg bodv woIghf
Tho nmounf of drug In pInsmn VpCp
Tho nmounf of drug In pInsmn VdCp
3l
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AIIA!IÞT VO!!M OI
ÐIST!II!TIOÞ
IrncfIon of drug In bodv pInsmn = Vd/Vp
IrncfIon of drug In bodv oufsIdo pInsmn = Vd Vp
Vd
Iorconf unbound In bodv =
fofnI bodv wnfor l00
Vu
32
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Ð.M.I!AHMAÞKA!, S!ÞI! I.JAISWA! I ?6-
90
Ðr.SHOIHA !AÞI , I l38-l50
!owInnd, M. nnd Tozor, T.Þ, l995 CIInIcnI
IhnrmncokInofIcs Concopfs nnd AppIIcnfIons,
3rd od., WIIIInms & WIIIInms. ModIn, IA
ShnrgoI, !., Wu-Iong, S. nnd Yu, A.I.C. 2005
AppIIod IIophnrmncoufIcs nnd
IhnrmncokInofIcs, 5fh od., McCrnw-HIII, Þow
York, ÞY
ÞInzI, S. l9?9 Toxfbook of IIophnrmncoufIcs
nnd CIInIcnI IhnrmncokInofIcs, AppIofon-
Confurv-Croffs, Þow York, ÞY pl0l
!III!IÞCIS
35
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!IfschoI, W.A. nnd Konrns, C.!. 2004 Hnndbook of
InsIc IhnrmncokInofIcs ... IncIudIng CIInIcnI
AppIIcnfIons, 6fh od., AmorIcnn IhnrmncoufIcnI
AssocInfIon, WnshIngfon, ÐC, pp369-40l
chIgnoII, C.I. l9?3 Ann. Aeu Yor/ AcoJ. Sci., 226,
p49, 53
Abornofhv, Ð.!., CroonbInff, Ð.J, ÐIvoII, M. of nI.
l98l AIfornfIons In drug dIsfrIbufIon nnd
cIonrnnco duo fo obosIfv, .P.1.T., 2l?, p68l-85
!owInnd, M nnd Tozor, T.Þ. l989 CIInIcnI
IhnrmncokInofIcs, !on & IobIgor, IhIIndoIphIn, pp
260-2?0
Thoso book nvnIInbIo on
hffp://www.boomor.org/c/p4/cl8/cl802.hfmI
hffp://www.boomor.org/c/pl/Chl8/Chl802.hfmI
36
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