7 Effect of Liver Disease on Pharmacokinetics GREGORY M. SUSLA' AND ARTHUR J. ATKINSON, JR? "hia Consubing Services, Freferick, Margfant 2 hint Center, Navona iestutes of Healt, thes, Margland HEPATIC ELIMINATION OF DRUGS Hepatic clenrance (CL) may be defined a3 the vol: ‘ume of blood perfusing the liver that iscleared of deug per unit time. Usually, hepatic clearance is equated ‘with nonrenal clearsees and is ealeulatad as total body clearance (CL) minus renal clearance (CL): Cy = Cbs ~ Che way Accordingly, these estimates may include a compo= nent of extrahepatic nontenal clearance ‘The factors that affect hepatic clearance include boca flow to the liver (Q), the fraction of drug not bound to plasma proteins (f,), and intrinsic clearance {Chg} (1, 2) Intrinsic clearance is simply the hepotic slearance that would be observed in the absence of blood flow and protein binding restritions, As dis- cussed in Chapter 2, hepatic derrance usually cin be considerad to be a firstorder process, In those cases, intrinsic clearance represents the ratiooF Vir Ree ate this relationship has boon used as the basis for cor- relating én 1370 stuclies of drug metnbolism with i itv resulls (3). However, for phenytoin and several other crags, the Michaelis-Menten equation is needest to characterize intrinsic elearance, ‘The wellstirred model, shown in Figure 7.1, is the model of hepatic eluaranice that i used most com ‘monly in pharmacokineties, lf we apply the Fick equa tion Gee Chapter 6) to this model, hepatic clearance scan be defined as follows (2), ety = of ==] “The ratio of concentrations defined by the terms withie| the brackets ss termed the extnictans ealio (ER). An ‘expression for the extraction ratio also can be obtained. bby applying the following mass balance equation to the model shown in Figure 7. Vid dt) = OG ~ 2G ~ fabian At steady state, 7) Also, ray (2+ fuCLin) Co ER G Equation 7.3 can be divided by Equation 7.4 to define ‘extraction ratio in terms of Q. fa and Clin? os By substituting this expression for extraction ratio int ‘Equation 7.2, hepatic clearance can be expressed as 78) Two limiting cases arise when fyCLay <= Q and when foClin => @ (2. In the former instancea Principles of Cinieal Prarmacslngy Blood Fow (2) FIGURE TL The wellatired emoded of hepsi clewance, in nhs Iho Ivers ete a single eoenpartinen having a tok une 1 and bod dow (9), Brug onssotatos ashing the iss sin the hepa avery ard portal vein ae derignted by Cj, ane fees in serge weno Baul by. Dy conse crihin he Hyer nce sidered tbe x agelibriom with thors in ‘ergent venous Hod, Enric clearance (Chg acts be eliinne Ihe frclon of drug nat Bound la pln pacts G,) Equation 7.5 can be simplified to Chay = feCloe en Hepatic clearance is termed yesirttiow in this case, since itis limited by protein binding. This situation is analogous to the elimination of drugs by glomerular filtration. Drugs that are restrictively eliminated have ‘eeleaction ration <03, When fCLig: => O, Equation 7.5 can be reduced to Cle a) In this ease, Nepatic clearance is flow Jontted, similas to the renal tubular excretion of puaminohippurnts, Because protein binding does not affect their clearance, drugs whose hepatic clearance is flow limited are sai to be nowtestritiety sliminated and have extraction ratios > 0.7, In addition to the well-stirred model that is the basis for Equation 7:5, several othor kinotic models of hepatic clearance have boon developed (4). However, the following, discussion will be based on the relation- ships cofined by Equation 7.6, andthe limiting, cases rophsentad by Equations 7.7 ate 7.8 Restrictively Metabolized Drugs (ER < 0.31 The product of fy and Cy is small relative to liver blood enw usually about 1500 ra. min) for drugs that ss eesiilively mielabolized. Although the extention ratia ofthese drugs is less than 03, hepaticmetabolism, Cften constitutes their principal pathway’ of elimina tion and they frequently have long slinination-phase halFlives (ee diazepam fj2 = 43 be. The hepatic clearanceot these deigs is alleced by changes in their binding to plasma proteins, by induction or imbibition of hepatic drugametabolizing enzymes, and by age, nutrition, and pathological fctors. However, a8 indie sated by Equation 77, their hepatic slearance is not alfected significantly by changes in hepatic Blood flow. Effect of Changes in Protein Biniting an Hepatic Clearance Tr usually ie assumed that the free drag com eeniration in blood is equal to the drug concentra luon to wikieh hepatic drug-metabolizing enaymes are exposed. Although protein binding would not be fanlicipated to change hepatic clearance sigalficantly for restrctively metabolized drugs that have, > 80%, displacement of highly bound (fy = 20%) drags from their plasma protein binding sites will eoult in a sig- nificant increase in thei hepatic clearance. Howeve steady-state concentrations of unbound drug will be sanchanged as long as there is no change in Clie This occurs in some drug interactions, as diagrammed in Figure 7.2. This situation alsa is encountered in. pathological conditions i which plascia pooteine or plasma protein binding i decreased, as described fn Chapter 3 for phenytoin kinetics inpatients with impaired renal function, Sinse pharmacological effects soa & Tats ;, 22 Fe 83 a Hr one ars FIGURE 72. Tio course of an terostion in which watt, a restricts mieten rg fe deplced fom i panna poten Tending sles tbh Tre sean conccations ee lilly as result ofthe interachon, they subsequently return t pee tection levels x a nol Ie neesne psc tie fly tnnsient, Besause fy ietexed, wal Ghowrd plus ec) Athinoe Aj ey Reldenborg AM, Thompron WL Claicl pharaa seligy. bv Gresherger Net MKSAP UL Syllko,Phadl pa ‘Amare Celoge of Physi 190. p .}Rh conte Eis of iver Disease SS are related to concentrations of unbound drug, pure Gsplacementype drug interactions put patients at ‘isk for only a brief period of time. Serlaly, dose Adjustments are not needed for patonts whose Pro- tein binding is impaled. Infact, as pointed out in Chapter 5, measurement of total rather thin unbound drug levels in these patients actually may load to Inappropriate dose incteases con Hepatic Drug Clearance Both hepatic disease and drug inoractions can alter theintrinsic clearance of esrctivey eliminated drugs Drug interactions wil be considered in more detal in Chapter 15. The effects of liver disease on drug elimination will be discussed in the following sec tions. Although a number of probe drugs have been used to characterize hepatic clearance, analysis ofthe factors influencing the intrinsic clearance of drugs Is Inampered by the fact that, in contrast tothe wse of ‘eatinine earance to assess renal funtion, there are zo simple measures that can be applied on a routine 0.70) ‘The product of fy and Cli is lange relative to liver blood ow for drugs that are nonsestic- tively metabolized These drugecharacerstialy have short elimination-phase halflives (eg, propranolol fa = 39 he), and changes in hepatic blood flow Ihave # major effect om their hepatic clearance (Equa- tion 78). Accordingly, hemodynamic changes, such as congestive heart failure, that reduce liver blood Mow wil reduce the hepatic clearance of these drugs and may necessitate appropriate adjustments in intra venous dosage, Changes in hepatic bod flow will also affet the first-pass metabolism of pral doses of ronrestnctively metabolized drugs, but the eects of ‘this on patient exposure are not intuitively obvious. First-Pass Metabolism Because nonrestrictively metabolized drugs have an extraction ratio that exceeds 017, they undergo fextensve first-pass metabolism, which reduoes their bosvailablity after oral administration (Chapter 4). I'there is no loss of drug due to degradation or ‘elabolism within the gastrointestinal tract or to incomplete absorption, the relationship between bio- availabilty (F and extraction ratio is given by the following equation: F ER 9 ‘case Equation 78 implies thal ER = 1 for non- restrictively metabolize’ tnugs, yet the oral route of ‘administration can be use or many draga inthis ct gory (eg, F> 0 for morphine and propranotl), iis apparent that Equation 79 represents only a rough approximation, By using Equation 75 to subsite for ER in Bquation 79, we obiain a more precise cstimate of the impact of first-pass metabolism on Bioavailability: Orch co Considering the case in which a drug is_elimi- rated only by hepatic metaboisin, Equation 42 from Chapter 4 canbe rewniten as follows: Dani (Chi AUC Using Equations 7.6 and 7.10 to substitute, espe Lively, for CLy and F yields the esl that Dans fxn - AUC ow 1 can besten from Equation 7:11 that orl doses of onrestcively metabolized rugs should not need to be adysta in response to changes im hepatic ood! flow Equation 711 also forma the bat for ting AUCygs messorements 1 cacuate socalled orl earn” ab a estimate of Jali. HOWEVe, iP renal excredon contibuts to deg eminatio, it ‘wll reduce AUC and ead to overestimation of {eClruiless the contibubion of ronal clearance i vou fo ; Biliary Excretion of Drugs Relatively few drugs are taken up by the Liver and without father metablism exereted int ble, which, a5 an aqueous solution, generally favors excretion of ‘more watersoluble compounds (9). On the otherhand,