“UNCAUS UNIVERSIDAD NACIONAL DEL CHACO AUSTRAL FARMACIA CLINICA Y ASISTENCIAL UNIDAD IV Prof. rédjunta Patricia YordanovichSST esa uf vis mcramascalae. Zn exe caso, iqudo se mas precancones de ssepisy el conzol igus ‘raciin en funn de! dempo, wsalmente puede ‘ y cine cin emery Seg en exc marc) a re SE i cist ab ao de as tjs de io cone Selena ‘Senas ene ne des muscular La sboricn calcam mese aeign ors mcs procs enc Abora bi en tno proceo de IE Smomay ere ccna, _ ra ix mae neo ee ae ege longue even a cava gue dete ls prt expen See er incamcamecn Panne eee {secon exons ras se oan en orden Sn po macs que eT reper ar ee ees (1) das oe logatmes de las eoncentaciones en sat absorben ma) por via orab (p. ej, aminoglucési- ‘ales deme ace | de sus valores muméricos (fig. 12). Aplicando logs os), que se degradan por via oral (ps penta “La ie tnerainfitico careos prictacamence ge maerés taro- ‘La velocidad de absorcion depende de una cons ritmos naturales o decimales ex le ecuacién (2) mes pon bape ym. Sees i pin i om oe tai tite develo arses enema, Geen ova os cones peronte ep pret ‘care o par gest smiles, (de proceso de absorcicn. K, representa I probabi- finer Ja ecascién de una recs Fi ostion son ias egos ay eS ay, SS Sali tene remo be aeorbeee slsiaycson on nse ONS sc cca gS tycoons ome ad de tempo. Relchona la cantdad o concent s0-Ks Yas 90 nin Las ance mobbles ode Suisrecaiam ‘Shane svar tong ci con ine nse ek Stas en vehi lot yas ors epec mo enone soe skits: sata one Se eee Die), Te rercina ceil ore ot Spero dy nor slaved oot 3 er ettbierconiconan a vance Megha Tes se Bectccrva se nares Bogen ca tempo crn ea (a pendent o nan ‘ad proce. Asi, si un firmaco tne una K, = 008 t ‘eguivale en valor absoluto & la constante de valoci- bout aproxiadanen coc pendent eae eoa . 8 tapiqo os om09 seonyUREE souoERMNIOS Sop (ony) samo mofo vom sumepeur ores SS Rpicnpe hms eo a odcones protein dl plasma. io editors en gran gre ous efecos faraacclgios. En ete sede ‘ue Sos peneran yse acumalan)y Sodas alas proce 1a alba es la protein rs important, a fqueeslans abandate 9 ose ane aor yes capa de neracinar con muchos fac de ‘aturaera Sida y cam algunos denature bce {uni de os fimnscosa ia slbarna es, engener reverble, y es favors por fs Lpossubiiad Aetalmence se reconocen an a alba has ch fo sitios eens pra la uni de os fmacos. «| Tee dldos ais se wen cast exiustament ar fomscante demo dean inele de vee plasma ‘capi paro el proceso es scrble 550 ar, (S poronaje de Semaco le sri mayor (Hg 1-15)ee ere ae oe eee e tis menos iad ome i pre. slo ‘medal st, ax como ls dopa xls (pros santo mecanisner de unporte active desde! LCR. sar) pido) os qu os frmses tune aent, i 42}. Elcompertiniet conralincuye lagu ams- Tos © tia intersticleinracilar atmente acs e e- ci adelostidos bien iadoscmocorani,pulmén, i 1) El compartnien perifrico upericalex ors sao po el agua inraelar poco ace es ec a a Tekosmamncceo rare kgesiacemees: =e Jape toe dla menbran os plsoo VTS 2 9] NLA fan. “SE masala econ ad cao G09 88 9 eepon angdei se 3 ener 20 ST Samnqenepred sn 2 vo Zoap 2 ‘srmonsesedncs Laban azennbe econ 8 oparna spre 5 ot ‘pune spa eno SER RTE mada pen poe ot SIR NT DEEN Fe jnoumanducng mB 9 OPPO 2 TENE?(Gin (V) quese oxien diviiendolacanisad {D Dipor i coacenrain en el empo ceo (Cp yet SG ‘Eivlumen parent de diseibocién sew pera cae cular In dei iil qoe debe adminsrare para alcn- Sa con rapes nies trapéuicos en smacones w+ tes (0.2. custo irc emparen ew one 0 ea para el SEE Se chcee er eileen ores cme oe Be eceromprenesal pr éelacomrias we Se steep etree apne erie sete) conten ae gi nn i a Sep nacre (0) 088 St CORN eg pence tps ge rome yee fara cane cain pe rd lent ta ec empriene oe ope SePautas de administracion de los farmacos @BETRCOREENTRUSORSSS a care el cao temporal de la soncenasn piss. (Nes ea yal de los tetas. que igtaient debe ener en uta ene deo de apa de ainsi. 2 Modes farmaencnscs Eliseo den pauiadeadminisvacin rguire re aieaar excl capmo 4 La eens ease ete modelo farmacocingtico que se apliqu yése varia ex 0 ncn > oy “Th de ads: incor 0 ea 5) a dibs: monncomerines ©) Preparado farmactuco que se wea wil. ta boonparimentlosicampertmental. pers mal soe gue panna aonb ule pre peda me Basco ase, co g i i % i g i | i iZermumeadesmrepunessso 01s ope em sp tm bg ero [sp appemp wf aimsumepapod “nop 59 SBOP 130 ‘unzeoy ep aigum souadep one op ENREN y x ‘mou-Cvae i It “ep tpoerage op aunsaas ep steeecoanrs wortoa a = dann wan seen eon sp DOR ANCE (>) masa expats appanosoco Hand 0 od | } I i | f appa. ay cgay) ssop map ome, p amsemssz 205d a SHY (a) apensTEoe Fe ea 0.) -pepeodsp (ayo) ae sara premio ema MNOS pepaME ext ofsod kr yeRatse) maa | rua) wey su apeenaccaoe apsep Apu —_-odspor ainae op apbeed r abo] sod UpROS apeenerace mane oo ep arb oduos eameps> ~ge.ny Ou (742g) ear OPEEAIIDE Ho ‘ED zewpodass oor [op apoemp CARO 203, aroma wgceasuuy Ve acappaguamp mp aeaRTr=ae|= "A —_sgundapoa ope ap BPR = 7 ena soanmememenaennny= Ll wae “ous oma ap appeanp a sap Beha AD ina anes ‘ygmageapoenveoey = "OE -tadop ab t 29 peppy an # spadsop opaaknarass 7 pate ‘am C3 cgeeman op manns SP YPN bp) och ee neem aaree| sys spend sub cows} op pepREED ey metho) oma mameee met tuome coe | a darmya) msec pp amma smd = "AO™ ‘Sioenttnemmonorsamn eg “3 9 wayne oppo aE Up oN op 2p magi openeIpE 9 ORSEL= 5 Seems opamde AC {WEERAURIPE oy Ay TEje HMMS ope | Tepe vemma- Id enone "men, | Tmapidace eae pa ESTHET eas CEE sme ond soca mee eemeere tie Sone wominated= CL moma mepmapaeee- dad Siocon tn) ppt nope seem romaine onmmenspameend=” Terbahpsmpmemepmied” Odd ions papa steommgjmnaprrensimpem=popsenguurery | ae Seeeceesreat 2 opsoten sess a ox sonymnn epee) = alg meg moan vies swromeneAagmseeay oun ssoq | pgea rane RN =P PPE a poe “ate segap noe =p PepaSe wees i -copmbeDops opm wo ram comme opememg: ff op rai one ye eo oT seanpased pasotspapeens | cxgoano ep omar 9 HOBIE) iY copeenmeng= q simone mnyom reise 8 apuodeuss epee | “Sora POURS sp ATENE = YR HP HEPES “F mueueld opoandooaae m9 fod vo ou #9 olin coun ogni! can sey | suosmzey so oe nee eocnsearope sy = ‘sogpedse mined won muss ezd (uompngensp 2p waar = joe Suporte sp stoesan Ona nes) uo yebos aed ip SeNpeSEDe geo BO ees | 3 aes} mp HEL es Rene fore {sue SO 6p OUI t = $3 [OAT ° senopegodoamros my izonssrouopaen E smote opens = ‘ogee sso 9p se v aren onse-spopzamorspsimpaa{~= + _oobaynieas suntan upeenssons>- a wet meueormes oe “Su eo igs mean passe (osm Jnonea ramapreenns Ropes eee pepe ss noe -apoad agep anb jot cnsedsa openpoud Ses mae 4 apexes ty ae onb ae soak so a feant ‘eq 2$ anb o1guzes) sopsiumar sop st © EME ‘pom pana ‘Wi epsrnguccceury sims uous =r 2015BREE teyecin inzavenas spiel mods sac pertncta nena el cam ena dos(A) 100 (haw ceca (2 )oobrelaconsnrase sinay indo ‘pain dl een. Cae=DN. yaa dela cnserecion depend de os ds pro. colo exponensses de apoio cy descats ex! capil mixin ene edo diane | dente A.B Coe oda es ‘tes procesos (fig. 6-3 B). 7 ont oct any ead cpg oe anne sale los nvee lamin depede de los procesas sbsercie elminsién GaBetacet onde Ay B soo at arenadas en rigen de ambos process (ig. 63 A). 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Iorace aeazar clave! nae 616A) (Cuando an rmaco tiene cinétianolineaeleunade 2 4 4 a aoe ess i Ps a sus constants de sbsorcin, dstibucién © elminacion i a ae‘apme(d opbenussoce Joeeu eon ante UPDETOME “apap eK mye a as ‘ee | pape ey mye seb mane ‘Sheps feomay ince ope anos BEETS esceoera sngenmn oan oma 4p) ammerepe 1 (q ofaon 9 rpm PENS SCRE em) yo pptnuses 2p yd ons ns INRIA a oF Ny NN) SEESSS oVooewsorwowswess 468 DETERMINATION OF RATE CONSTANTS tabolized), regardless of pathway of excretion, or due to metabolism. In the latter case we refer to it as the overall climination rate constant, often termed K. In the open two-compartment model, 8 is a hybrid constant for which everything discussed above applies in analogy. Addition- ally, we have an overlapping due to variations in the distribution process. The relation of the hybrid constants @ and 8 with the specific micro rate constants can be described as follows: at Baka t ka tke a + B= ka Ky @ ‘The hybrid rate constants a and f are given by Equa- tions 15.3 and 15.4. @ = 0.5 + [ka + ka + Kes) Ca + En Ea — 37 Es] @) B= 05+ [Oey + Ka + ks) Kat ka +R 47k Esl @) If a drug product is given extravascularly, the rate constant for the input or entry of drug into systemic cir- culation is described by the absorption rate constant k,. Different. drug products (from different manufacturers) containing the identical drug and administered by the same route of administration usually result in different biood levels due to different rates of absorption (see Chapter 36). However, the true absorption rate should be a constant for a particular drug and a particular route of administration, subject to biological variation only. Hence, the differences in rate of absorption of a partic- ular drug from different dosage forms are explained by the fact that we measure “apparent” absorption rates. ‘The true absorption rate would be obtained if the drug were in aqueous true solution at the site of absorption. Apparent absorption rates are observed upon adminis- tation of a drug product from which the drug must first be liberated (released) before it can be absorbed. In any case; where the liberation rate constant of a drug from a dosage form is slower than the unrestricted (true) rate of absorption, an apparent absorption rate is obtained. DETERMINATION GF RATE CONSTANTS 163, However, one has to be aware of the complications due to the anatce-ical and physiological factors involved, too, particularly in gastrointestinal absorption. An ex- ample is griseofulvin. With this drug, a solution resuits in a smaller total amount of drug absorbed than when it is given in the form of capsules or tablets. This is due to the faster transit time of the solution through the duo- denum where the drug is absorbed, in comparison to the slower transit time of the solid dosage forms. ELIMINATION RATE CONSTANT, OPEN ONE- COMPARTMENT MODEL, INTRAVASCULAR (See Figure 15-1) x, = BAS yoy ©) bh (0) = drug concentration at time 0, obtained by back-ex- trapolation of monoexponential declining line C,, G, — drug concentrations at corresponding times t, and t, k= overall elimination rate constant ELIMINATION RATE CONSTANT AND ABSORPTION RATE CONSTANT, OPEN ONE-COMPARTMENT MODEL, EXTRAVASCULAR (See Figure 15-2) ka = BOS ES eg © Pi te NUMERIC TIME. FIGURE 15-1. Determination of overall, elimination rate con Stant in the open one-compartment model upon intravascular Toute of administration using blood level data.-exep fone) pooig Sussn uoitensiunupe 30 exno4 seinosene stu) uodn . =) ump ocmas 30 £5 oun ehusuodysonow porto ~~ ate a eereanieotis t -denko-yoeq Uo UoReTUaSuOS om puE 5D oseyd ean Jenuss usanaeg mus}US> oye UOANALRS|p "UEIEUOD art -diosqe jo aod wuseid renioe vsom1sq souereID =" *D Nueisucs sie seeydeg feuruiar jo UoneuruueIeG “ESL BENDIS i 2 oum sures 1e 5 euTl penueuodxoouow! psre]o ~denko-y0eq uo uonthussuos ex pus ID esvud ean i “diosqe Jo 10tod vusseyd Tenase Usom9g saussagP = MIS { A pu 11 soum 2e odors 5 1 Buruysop jRUsuodxsoucU! paejodenxe-yoeq UO 8 i suonestueoues Srup fesnstaodsy punoy rp AWLLNSNOdx3ONON L i eaeuTE) ° ee | wppe adojs uondiosqe enusuodxeouom yordasisiut = asiviodvELxa Ove : | SenSios cap i oats woleatats fenusuodxoouou! parwjodesixs-soeq Jo jdaaiut = oD ses >p 20.9 jap Dejan 1p =a TwEISUOD arBi UONdosqe = St Jusisuos ses Uonwarume [Tezoso =H ou \ a», Bayuyoop Tenusuodxsouom Jo uonRIodenxs-soeq <4 en x L-a) aS ="y ‘ Peureigo ‘9 SUN 2 UORELUSOUCS Srp TeRemodsy = (0). ep oa @ fmarty = a = ©)D oA a5 i cy tam. 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DETERMINATION OF RATE CONSTANTS: C(O) = drug gopcentration at time 0 [obtained from A + B = €O) 8 = overall slimization (slow disposition) slope (rate constant) @ = distribution (fast disposition) slope B intercept of back-extrapolated monoexponential elimination slope @ with ordinate A _ = intercept of distribution slope a with ordinate S., C = drug concentrations at corresponding-times t, and t of the elimination phase Ci, Ci = actual drug concentrations at corresponding times t; and t; during the distributive phase Cy, Cl= graphically found hypothetical drug concentrations Sa back-extrapolated monoexponential declining Slope # at times & and Cium = difference between actual plasma point of distribu- five phase Ci and the concentration on back-extrap- Slated monoexponential ine Ci at same time t{ = difference between actual plasma point of distribu- five phase Ci and the concentration on back-extrap- Slated monoexponential line C3 at same time & Co ue kj, = distribution rate constant for transfer from central to peripheral compartment k,, © distribution rate constant for transfer from periph- eral to central compartment k, = elimination rate constant from central compartment ELIMINATION RATE CONSTANT, ABSORPTION RATE, CONSTANT, AND DISTRIBUTION RATE CONSTANTS, OPEN FWO.COMEARTMENT MODEL, EXTRAVASCULAR (See Figure 15-4) B= Bo-BS fh) an ew Sig = 1 Co a f- ue ho] aa) k= BS Se hy tas) (0) = A + Blug/ml] eo) ALB = oF yy ke Oe ed en IO%° "DETERMINATION OF RATE CONSTANTS 173 BACK-EXTRAPOLATED MONOEXPONENTIAL DECLINING LINE FIGURE 15-4, Determination of terminal 9-phase rate constant, ElShase rate constant, distribution rate constants between central SP Beripheral compartment, elimination rete constant from the Rescial Compartment, and absorption rate constant in the wo" SSikbaranent model upon extravascular route of administration Gaing blood level data. ky, = SLB B yy 2) CO) = FO py Bla + Bip — CO, ~ AGC HG eae AT@-B ik 5) Y. oy ku = 6) Ke. —. Dot @s) = £ = Be . @-—-«-V = hypothetical drug concentration at time 0 [ob- tiked from A B= C(O) = Sverall elimination (slow disposition) slope (rate constant) GiteiGation (ast disposition) slope absorption slope (rate constant) BEeee of back oxtrapolated monoexponen- fal elimination slope A with ordinate Enefospt of distribution slope « with ordinate Shug concentrations at copresponding times t Sheies of the elimination shase = Setusl Gus concestrations at corresponding Gimmes and t during distributive phaseee 2seesip 01 onp ‘(919 “y81qe2 oseoror poureisns “291927 Fomnsdes ‘aonmyos *"3"f) SuLIos aBesop oy1 Woy Sees OSEOT -21 Snip 2az9y;IP 02 onp wesoMP oq cus *y “sssvsurEr Ted onourjooeuzreyd pur camo oumy-uorenuesu09 Poolg Snip & Jo osznoo sy2 souSNgUr A[punoyoxd Aeur "x 10 ypue “4 ioRe wy oBueyo e ye~p ozteor 01 weyoduN St aT --oony pus eens ==4 BO > PUE “JO SUSMISUE (oe) L.-a} “e690 = QUT = DAL wy «zy wy See - mS) (sz) =~ a asxy om) re7ye WOHENUSOUOD YBNON oy Woy porETMTeS 3q tes “y ‘one: e “Butsop odpm wodn poyoeas st o7e1s Apeoys [Hun asop ISIY Sy] Wosy seremuMooe Snap e UST MA selpms UoRe;nunszy WoL "4 Jo MORASS Wut uondsosge Jo oun «we Gal a = (ez zxdeqD osfe 90s) poreur “nso 99 ues "y ‘poqiosqeun jussred | st sum wondiosqe aya Jo puo oy 3e pue paqrosqeun s} Bnip ay Jo ws9 trod oof orez 2um 3e ey UoNdumsse om Jepuy “Jopou queunreduroo-om1 942 UF oseyd uoRquisip Burpusss “ep agi Surreiue s10J9q s[qeUSMBunsIp THs sf 2M TAST poorg fenase oy? 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