Clinieel PharmacokinetiCI 1; 135-155 (1976) ClA DIS Preh 1976

Altered Hepatic Blood Flow and Drug Disposition' A. S. Nies 2 , D. G. Shand and G. R. Wilkinson Division of Clinical Pharmacologv. Departmenlt of Medici ne end Pharmecologv. Vanderbi lt Univerlity School of Medici ne. Nashvi ll e. Tannenee

SummDry

For JQm~ drugs. dtlil'uy to th~ /i1'U by th~ h~ptltic ciTcuktion il on importont dtttr· miMnt of rt",C1\'ol by this orgon. Ckuical phormocokinttic onoly., CIlnnot prtdict tht cluU/g~s prodUCld by olt~ring ony of tht biolQKiCilI d~ttrmiMntJ of drug tliminotion by tht /i,'u; htpotic blood flow. m~tobolic tnzym~ octMty. drill binding ond rour~ of odmini· Itrotion. Ho~vtf, wllh tht uu of 0 physiological nwdtl of h~ptlric drug ~limiMlion. such predicrions CIln ~ m«J~. This nwdtl has bun ttsltd tx~rimtntally ond OppttlfS to ~ valid. Htpatic blood flow COli "ary ov/'r about a 4-[01d rang/' from holf norfTUll flow to twict 1I0rmDi flow. Thtu voriDtiont or/' produced by physiologlcol, potho/ogicol or pharmoco· logical chongI'I offtctinl tht circulotion. For drug c1taronct to ~ afftcttd signifioantly by thtu changtl in flow, tht dMJg must ~ avidly rtmo~td by th~ livtf os rtf1~cttd in 0 high htptltic txtrtlction ratio OM in,rinfic htptltic c/tflrtlnCl. This kfttr ttrm il a uuful WIly to cJrgrocttriu lh~ obility of tht lil,tf to irrtl'tflibly rtmovt drug from tht circu/otion in tht obunct of lIny flow limitation, Tht cftoronct of drugs with low intrinsic cftlUonctS wilf not IH lIfftcttd significontly by chorrgtJ in fivtr blood flow.

Intuitively, drug delivery to the liver should be important to hepatic drug elimination in vivo. However, until recently only minor attention has been given to the fact that the ra te limiting step in the removal of some drugs from the circulation is the blood flow to the eliminating organ. Classical pharmacokinetic teaching, even when directed toward clinicians (Greenblatt and Koch·Weser,

1975a,b), has considered drug elimination in te rms of compartmental models, which despite their desc riptive accuracy, tell us nothing of the biological determinanls of drug disposition. Such models cannOI be readily manipulated when disease, drugs or individual variation results in allered phys.iological conditions.

1. Clearance ConceplJ 1 Supported in part by the US Department of Health Educatio n ilnd Welflll'e Grant; GM 1543 1. 2 Dr Niel is il Bunoughs WeUcome Scholar in CUnical Pharmaco lolY .

Recently, a few invesliga tors have discussed the advantages of describing drug eliminalion from the body in physiological terms (Branch el aI ., 1973b;

,,.

Altered Hepatic Blood Flow and Drug Dispolition

Rowland et aL, 1973; Wilkinson, 1975; Wilkinson and Shand, 1975). With this approach drug elimination is described as a clearance. This clearance (CI) is the volume of blood from which drug is completely removed per unit time and is equal to the product of blood flow (Q) to the eliminating organ and the extraction ratio (E): G=QE

(Eq. I)

Clearance is thus an index of the efficiency of drug removal from blood and is not dependent on the distribution of drug outside the vascular compartment nor on the model one chooses to describe pharmacokinetics. Although clearance describes drug elimination in measurable biological terms, it still has limited predictive value due to the fact that the extraction ratio is not constant but is dependent on three fundamental biological determinants: I) The blood flow to the organs of elimination 2) The inherent ability of the organs of drug removal to irreversibly clear drug from the circulation, and 3) The binding of drug to plasma proteins and cellular components of blood. With an appropriate analysis one is able 10 predict changes in drug disposition induced by changes in these fundamental variables. Although this discussion is primari ly that of the influence of hepatic blood flow on drug dispoSition, the con· cepts developed can apply to analysis of the other basic biological determinants of drug elimination.

2. The Perfusion Limited Model

The most useful analysis incorporating the biological variables important to hepatic drug disposition is based on a perfusion limited model of hepatic drug elimination (Branch et aL, 1973b; Gillette, 1971; Rowland et aI., 1973). In this

Glossary of symbols CI CIH CIEH CII Clint Cl'int C1 CHV

maen blood clearance 01 tOUlI drug hepatic elurance of tOUlI drug eKtrahepatic cluranca of total drug IVltemic cl&llrallCe of total drug intril'l$ic clearanca of total drug intrinsic cl&llraf1C8 01 unbound drug IVIt&rnic concentration of total drug hepatic venoUI conc&ntration of tOUlI

d,,,,

IB fraction of drug unbound in blood VmaK & Km Michaelis consunu for drug removal proceuel E hepatic eKtraction ratio a hepatic blood flow area unde< the blood concentration AUCHV VI time curva 01 hepatic venous blood AUC, area under the blood concentllltion VI time curve of IVltemic blood area under the blood concentration AUC o VI time CUI'Vtl of Ivltemic blood aher an oral dose F Ir.c1ionallVlt.mic .....,I-,:>,I'ty o drug doM I inlulion rille of drug at steady state apparent volume 01 diltribution Vd half.liI. of elimination

"

mOdel, drug is removed from blood as it passes through the liver such that drug in the liver is in equilibrium with blood leaving the liver. Thus the unbound concentration of drug in hepatic venous blood is the same as the unbound drug in the liver, which in turn, is available to the drug removal processes of metabolism and biliary secretion. Based on this model a number of relationships can be derived. During an infusion the amount of drug removed by the liver from blood per unit time at steady state is: VrnaxfBCHY GHC, = v='ti~c; Km + fBCHY

(Eq. 2)

Where Vmax and Km are the Michaelis constants for the removal processes, CIH is hepatic drug

Altered Hepatic Blood Flow end Drug Disposition

clearance from blood, Cs is the drug concentration in systemic blood and fa is the fraction of drug in blood which is not bound to proteins or other blood constituents and is thus free to equilibrate. Under conditions where drug elimination is firs t orde r, the concentration of drug in the liver (fBCHV) is much less than Km and equation I simplifies to:

(Eq.3)

It is convenient to combine the constants V max and Km into a single clearance term , the intrinsic clearance (CI'int). The intrinsic clearance is a characteristic of each drug and represents the maximum possible hepatic clearance of that drug when flow is not rate· limiting and is thus indica· tive of the int rinsic ability of the liver to remove drug irreversibly rrom liver water. Substituting in equat ion 3 and rearranging:

, CHV rBO int .

--c;-

(Eq.4)

137

(AUC s) are substituted for the respective (Xmcen· tralions during steady state. Thus as in equat ion 4: fa' . . AUCHY b Int AUC s

(Eq.8)

and since AUCHV! AUC s F :: I E then the same relationship as equatio n 7 is derived. The usefulness of this perfusion limited analysis is that the clearance of drug from blood is described in terms of the three biological variables: (I) hepatic blood flow; (2) binding of drug to blood, and (3) the intrinsic removal process of the liver. For the purpose of this discussion, drug binding will be assumed to remain constant and readers interested in the changes in drug handling with altered binding should consull a recent review where this is discussed (Wilkinson and Shand, 1975). Ifdrug binding to blood is constant then fB can be incorporat ed into the intrinsic clearance term to give a new constant Clint which is the intrinsic ability of the liver to clear drug from blood rather than from liver water thus: 0::

(Eq.9) Now CHv/C s is the rraction or drug escaping extraction by the liver , F, and is equal to I - E. where E is the hepatic extraction of the drug. Substitut ing in equations I and 4:

OE = fBO'int (1 E ::

(Eq.5)

- E)

fBCI'int , Q + fBCI int

fBO'int aH = QE:: Q [ Q+ fBO'int

(Eq.6)

1

(Eq.7)

This ba sic relationship can also be derived rrorn considerations of single doses where the areas under the concentration vs time curve in the hepatic venous (AUCHY) and systemic blood

Overall drug clearance from the systemic circu, lation is the sum of the hepatic clearance and all other clearances, so that if extrahepatic clearance is negligible then equat ion 9 will also describe systemic drug clearance. A basic assumption underlying the perfusion limited analysis is that drug equilibrium is reached between the liver and the blood emerging in the hepatic veins. During an intravenous infusion of drug at steady state,

(Eq. 10) where I is the infusion rate and CIEH is the extra· hepalic clearance. Combining equation 4 and 10:

(Eq. 11)

Altered Hepetic: Blood Flow.nd

Or~

It should be noted that the concentration of drug in the emerging hepatic venous blood should be independent of hepatic blood flow and indicates changes in infusion rate, intrinsic clearance or extrahepatic clearance. Similarly, with intermittent parenteral doses (D) at steady state during a dosage interval or after single acute doses

o

= Ow AUe, • OEH . AUe,

(Eq.12)

and from equation 8

AUCHV = 0 - OEH • AUe, Oint

138

Oi,positlon

(Eq.13)

Thus the area under the concentration vs time curve in the hepatic venous blood should also be independent of hepatic blood flow. The assumption of perfusion limitation has been tested experimentally with lignocaine (lidocaine) and propranolol in the isolated, perfused rat liver (Shand et aI., 19 75). In this experiment drug was administered into the reservoir and perfUSion

rate was altered. Whereas drug clearance from the reservoir was dependent on hepatic blood flow as predicted from equation 9, hepatic venous amcentrations were independent of fl ow.

2.1 The Effects of Hepatic Blood Flow on Clearance

Assuming minimal extrahepatic metabolism , the relationship of system ic drug clearance to hepatic blood flow as described in equation 9 is shown in figure I. In this figure, blood flow and systemic clearance are ploned as multiples of intrinsic clearance. When flow is infmitely large , actual clearance approaches the intrinsic clearance and flow has little effect on systemic clearance. When fl ow is small relative to the intrinsic ability of the liver to remove drug. then actual clearance is dependent on hepatic blood flow. Since liver blood flow is not infinitely variable in villO but must remain within certain physiological limits, only a portion of the curve in figure I will be operative for each drug, depending

•~

u

l

~ 0 .5

o Flow

4 7 2 8 5 6 101,., multipl" of intrinsic: cleerloll« ICiint'

9

10

Fig. 1. Theoretiul r.lationship t.t_n Ii ...... blood flow .nd .ctual dr~ cl .....nee. Both flow Ind actull cl..renee t.ve been uicuilled 1$ multiples of Intrinsic hepetic cl .... nee using equation 9 in the tlltt (Ifter Br.nch et.l. : Drug Meteb. Disp. 1: 687, 1973b; with permissionl .

139

Alt.red Hegetic: Blood FIow.rod Drug Di.poti tion

15

" °o~---Oo~..•C-----C,.

oL-______~~--__--~--------~ 50 100 Intrinsic; metabolic; c;lear.nc:e Wtre/min)

150

Fig. 2 The re lat ion,h ip, eecording to t qul1ion 9 , bttwttn the intr in.ic; c;:INranc:t, hepat ic;: extrac;tion e nd .tt .... r hepat ic; duran te assuming a liver blood lIow of 1.5 U min. The inset ind icatas on an ellplnded seere the relat ion.hip 11 low va luft of Cl int 'alt.r Wilkin50n and Shand: Cli n. Pharm. Ther. 18 : 377 , 1975; with permiuion ).

on its intrinsic clearance. Drugs vary widely in their intrinsic clearances and lhis is evidenced by Ihe variabililY in hepatic extraction ratio at normal liver blood flow (fig. 2). When Clint is equal to liver blood flow , extraction is 0.5. With lower intrinsic clearances the extraction is less than 0.5 and at higher Clint hepatic extraction is greater than 0.5. Figure 3 describes the family of curves repre· senting actual clearance versus flow for drugs with different intrinsic clearances corresponding to extraction ratios of 0.1 to 0.9 at normal liver blood flow. The magnitude of the change in clear· ance produced by a change in now can be found by moving along the appropriate line. It is clear from figure 3 that the lower the intrinsic ciear· ance, the leIS dependency actual clearance has on blood flow. In contrast, clearance is highly flow dependent for drugs whose Clint is greater than liver blood flow (E>O.5). The reason for the independence from flow for drugs wilh low Clint

is that the extraction ratio for such drugs is sensi· tive to changes in flow (Eq.6, fig.4), and an alteralion of hepatic blood now will result in a nearly equal change of the extraction ratio in the opposite direction . Thus the product of flow and extraction will be relatively unchanged. This is not true for drugs with high inlrinsic clearances where changes in extraction do not compensate for flow changes. Experimental evidence is available 10 substan· tiate this Iheoretical analysis. Using the isolated perfused rat liver where now can be precisely controlled, we have found that propranolol clear· ance is dependenl on flow as predicted by the model (Branch et ai., 1973b). Similarly in a series of dogs, propranolol clearance in vi", has been found to follow the predictions of the perfusion limited model with differences in hepatic blood flow being the parameter responsible for the inter· individual variation of propranolol clearance observed in this species (fig. 5).

140

Altl'red Hepltic Blood F low and Drug Disposilion

"

I" ~

"

i

'0

i

0'

°° 3~

2.2 Effects on Enzyme Actillity on Drug Clearance

ER

" " "

/

"

0.

-~ "

0' '0 '0 Uver blood lIow Wlr./min)

0' 0' 0> 0' 0'

"

______________________

~

Uver blood flow (Htr./mln)

4L-__________________

Changes in the drug removal processes of melabolism and secretion will be reflected by changes in the inlrinsic clearance, and this will affect aClual drug clearance (fig. 2, Eq.9). Such changes wiU make the largest difference if the Clint is small. Thus a change in Clint from 167ml/min to 37Sml/min will result in a change in hepatic ext raction of 0.1 to 0.2 al a liver blood flow of 1,500ml/min and a doubling of hepatic drug clearance. In contrasl a change in Clinl from 6L/min to 13.5L/min will increase extraction from 0.8 10 0.9 and increase drug clearance by only 12.5% at normal blood flow. In figure 3, a change in intrinsic clearance is represented by moving from the cur\'t for one extraction to anolher at the same value for flow. In summary, Ihe perfusion limited model allows prediction of the effects of ailerations in flow and/or enzyme activity. The hepatic clearance of drugs with high intrinsic clearances and extraction ratios will be very sensitive to changes in hepalic blood flow, whereas the clearance of those drugs with low Clinl and consequently low exlraClion ratios ",;11 be independent of flow. JUSI Ihe oppo· site is true for the effeCIS of altered enzyme ac· livily: the clearance of drugs with low intrinsic clearances will be most sensitive to changes in enzyme activity.

~

Fig. 3. Th. rMllionlhip between liv.r blood flow and

cleJfopnln' o lol lclosed circled or d-p ropranolol (open c ircles).

141

Conversely, a change in Clint gives large changes in half-life of drugs with low Clint and small changes in half·life of drugs with large Clint (fig. 7 upper panel). However, when given orally, the situation is different. Under these circumstances if ext ra· hepatic clearance is nil, systemic clearance:

as

FDo = - - ' = QE AUe"

(Eq. 15)

where F is the frac tion of the oral dose (Do) reaching the systemic circulation. This is seen to be ident ical to Eq. 14 where F = I d uring intra· venous administration. If the drug is completely absorbed from the gastro·intestinal trac t then F is the fraction removed by the liver during transit to the systemic circulat ion. Since F'= I - E, substi· tuting in Eq. 5 and IS:

~= AVCo

QE ---= Clint I - E

(Eq . 16)

This interesting relationship indicates that the area under the concentrat ion time curve after an oral dose (AVC o ), and hence the average drug con· cent ration, is independent of fl ow and depends instead on ly on the dose and the Clint, rega rdless of whether the drug has a low or high clearance. Changes in Clint will give reciprocal changes in the area under the concentration vs time curve after an oral dose. The mechanism whereby this occurs, however, is dependent on the Clint. For drugs with low intrinsic clearances and extraction ratios, the fraction of an oral dose (F) reaching the system ic circulation is high. Consequently changes in intrinsic cleara nce result in litt le change in peak concentration and the area under the curve changes because of an altered half·life, pro vided absorpt ion is rapid (lower left panel, fig. 7). Indeed the ora l and intravenous curves are similar. Thus it has been shown that for tolbutam ide, anti· pyrine and warfarin, d rugs with low Clint, changes in eliminat ion half· life will generally re nect differ·

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Alterkl Hepalic Blood F Iow.nd Drug Dbpotition

,, ,

1.0

,,

,,

,,

0 .1

. i

•~

,,

1.0

" ,,

,, ,

,,

0 .1

0 .05

0.05 E 0. 10

a


ssibility of Significantly altering drug clearance in this group.

6.3 Pharmacological Agents - Haemodynamic Drug Interactions 6.3.1 Drugs that Decrease Hepatic Blood F1cw Several drugs are known to decrease hepatic blood flow and hence have the capacity to interact with drugs having a high intrinsic clearance. The active I-isomer of propranolol decreases cardiac output by 25%, and in the unanaesthetised monkey has been shown to decrease hepatic blood flow by some 35%. The inactive d-isomer of propranolol on the other hand, does not alter haemodynamics (Nies et a\., 1973a). Since propranolol not only has effects on liver blood now but also has a high Oint, the pharmacological action of the drug affects its own clearance (Nies et aI., 1973b). This was demonstrated by comparing the clearance of the d-isomer with that of the racemate. In vitro it had been shown that d- and dl-propranolol were cleared with equal efficiency by the liver (Branch et al., 1973b). However, as predicted, the clearance of dl-propranolol in vivo was 25% less than that of d-propranolol although the calculated intrinsic clearances were identical. The differences were due entirely to the change in hepatic blood flow produced by the I-isomer in the racemic mixture . dl-Propranolol clearance is, in fact, a type of drug-drug interaction where the pharmacological effect of the I-isomer to decrease liver blood flow affects the clearance of both isomers in the racemate (Nics et al.. 1974). This haemodynamic

Altered

~tic:

Blood Flow Irld Orug 01J1)Osition

explanation appears more attractive and consistent with the data than stereospecificity in drug clearance by the liver and may account for the observed shorter half·life of d·propranolol than either dl· or I·propranolol in man (George et ai., 1972). Just as propranolol influences its own clearance by its haemodynamic effect, it has been shown experimentally to decrease the clearance of other flow dependent drugs given Simultaneously. Two drugs which illustrate the principles involved are lignocaine, with a high intrinsic clearance corre· sponding to a hepatic extract ion ratio of 0.8 , and oxyphenbutazone, with a relatively low Clint corresponding to an extraction ratio of 0.15 in the dog. When dl·propranolol was given to a dog simul· taneously with lignocaine, the clearance of the latter drug was reduced by an amount approxi· mately equal to the reduction in liver blood fl ow as would be expected for a drug with such a high Clint (Branch el ai., 1973c). Oxyphenbutazone clearance, on the other hand , showed much less change with the administration of dl-propranolol because hepatic extraction rose to partially compensate for the decreased hepatic blood fl ow exactly as was predicted from the perfusion limited model (Branch el ai., 1973e). d-Propran0101, which is without effect on hepatic blood flow, did not alter the clearance of either lignocaine or oxyphenbutazone. These two drugs. lignocaine and oxyphenbutazone, illustrate the practical application of the perfusion limited model. Drugs with high intrinsic clearances such as ligno· caine will be susceptible to such haemodynamic drug interactions while drugs with Clint equal to or lower than that of oxyphenbutazone will not. Alpha-adrenoreceptor stimulating drugs are known to constrict the splanchnic vasculature and decrease hepatic blood flow (Bearn et aI., 195 I). Such vasoactive drugs assume importance because they often are given in situations when hepatic blood flow may be already compromised such as during shock or circulatory collapse. Under these circumstances, drugs with high intrinsic clearances

150

will certainly have a decreased clearance and should be given cautiously. Experimentally, noradrenaline (norepinephrine) has been shown to decrease the clearance of lignocaine in the rhesus monkey, presumably by this mechanism (Benowitz et aI., 1974). Anaesthesia is also known to decrease hepatic blood flow (Cooperman, 1972). In anaesthetised man with controlled ventilation, splanchnic vascular resistance increases, probably as a result of the mechanical consequences of artificial venti· lation (Epstein et aI., 1966). Additionally, the anaesthetics themselves can alter hepatic blood flow. Cyclopropane increases sympathetic tone and decreases hepatic blood flow by 33% (price et ai., 1965). Halothane causes a similar decrease in liver blood flow but much more hypotension than cyclopropane (Epstein et aI., 1966). The decreased splanchnic blood flow with this agent is likely to be the result of the decreased cardiac output since there is no evidence of vasoconstriction of the splanclmic bed (Amory et al.. 1971; Wyler and Weisser. 1972). Methoxyflurane causes a larger decrease in splanchnic blood flow than cyclopropane or halothane, and there is active splanchnic vasoconstriction (Price and Pauca, 1969). Hypotension produced by spinal anaesthesia can result· in a reduced splanchnic blood flow. The higher the level of the spinal block, the more marked are the effects (Cooperman, 1972). There is little evidence that morphine , thiopentone, pentobarbitone or nitrous oxide has any effect on splanchnic blood flow. If hypercarbia occurs, however, splanchnic vasoconstriction may occur with most of the anaesthetics except with halothane, which appears to paralyse the vasoconstrictor responses (Epstein et a1., 1966). Evidence as to the effects of these haemodynamic changes on hepatic clearance of drugs is unknown , but it is reasonable to assume that the perfusion limited analysis (Eq.9) would apply, and the clearance of drugs with high intrinsic clearances given during anaes· thesia, such as lignocaine or propranolol would be reduced .

Altered Hepatic: 8100d Flow and Drug Oilposition

151

6.3.2 Drugs that Increase Hepatic Blood Flow and antipyrine being used as prototypes of drugs Few drugs are used commonly which produce with moderately high and low intrinsic clearances large increases in hepatic blood flow. Although respectively (Branch et aI., 1974b). The clearance dopamine has been said to increase mesenteric of both drugs was Significantly increased by blood flow it probably does not do so when given phenobarbitone but by different mechanisms. intravenously in usual doses (Branch et al., With antipyrine. which has an intrinsic clearance in 1973d). Glucagon has been found 10 increase the monkey approximately 30% of liver blood splanchnic flow in the unanaesthetised monkey flow. the increase in clearance caused by pheno(Branch et al., 19731). That such an increase in barbitone was largely due to an increase in intrjn· flow can increase the clearance of drugs was shown with the combination of glucagon and d-proprano101. In the monkey, glucagon produced a 2-fold Antipyrine l oo • Control increase in hepatic blood flow and resulted in o PhenObarbitone precisely the predicted increase in d-propranolol clearance (Branch et al.. 1973f). likewise, isoem prenaline (isoproterenol) in the monkey has been shown to increase the clearance of lignocaine (lidocaine) by an increase in hepatic blood flow (Benowitz et al.. 1974). Whether such a manoeuvre to increase liver blood flow would have ,~L~_=-,,,,"""---,, potential to enhance the clearance of drugs taken Q '00 lOQ )QQ