SPECIAL POPULATIONS Clin Pharmacokinet 1999 Nov; 37 (5): 399-431

0312-5963/99/0011-0399/$16.50/0

© Adis International Limited. All rights reserved.

Effects of Liver Disease

on Pharmacokinetics
An Update
Vanni Rodighiero
Department of Pharmacology, University of Padova, Padova, Italy

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
1. Liver Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
2. Hepatic Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
3. Cytochrome P450 (CYP) System and Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 401
3.1 CYP1A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
3.2 CYP2A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
3.3 CYP2C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
3.4 CYP3A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
3.5 Relative Changes in CYP Enzyme Levels and Activity . . . . . . . . . . . . . . . . . . . . . . 404
4. Cardiovascular Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
4.1 Angiotensin Converting Enzyme (ACE) Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . 405
4.2 Angiotensin II Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
4.3 Calcium Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
4.4 Ketanserin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
4.5 Antiarrhythmics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
4.6 Hypolipidaemics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
5. Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
5.1 Torasemide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
6. Psychoactive and Anticonvulsant Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
6.1 Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
6.2 Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
6.3 Tiagabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
7. Antiemetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
7.1 Metoclopramide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
7.2 Serotonin Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
8. Antiulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
8.1 Proton Pump Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
9. Antimicrobials and Antiretrovirals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
9.1 Grepafloxacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
9.2 Ornidazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
9.3 Pefloxacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
9.4 Stavudine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
9.5 Zidovudine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
10. Immunosuppressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
10.1 Cyclosporin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
10.2 Tacrolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
11. Miscellaneous Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
11.1 Naltrexone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
400 Rodighiero

11.2 Tolcapone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420

11.3 Toremifene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
12. Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
12.1 Altered Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
12.2 Altered Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
13. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427

Abstract Liver disease can modify the kinetics of drugs biotransformed by the liver.
This review updates recent developments in this field, with particular emphasis
on cytochrome P450 (CYP). CYP is a rapidly expanding area in clinical pharma-
cology. The information currently available on specific isoforms involved in drug
metabolism has increased tremendously over the latest years, but knowledge
remains incomplete.
Studies on the effects of liver disease on specific isoenzymes of CYP have
shown that some isoforms are more susceptible than others to liver disease. A
detailed knowledge of the particular isoenzyme involved in the metabolism of a
drug and the impact of liver disease on that enzyme can provide a rational basis
for dosage adjustment in patients with hepatic impairment.
The capacity of the liver to metabolise drugs depends on hepatic blood flow
and liver enzyme activity, both of which can be affected by liver disease. In
addition, liver failure can influence the binding of a drug to plasma proteins. These
changes can occur alone or in combination; when they coexist their effect on drug
kinetics is synergistic, not simply additive. The kinetics of drugs with a low
hepatic extraction are sensitive to hepatic failure rather than to liver blood flow
changes, but drugs having a significant first-pass effect are sensitive to alterations
in hepatic blood flow.
The drugs examined in this review are: cardiovascular agents (angiotensin
converting enzyme inhibitors, angiotensin II receptor antagonists, calcium antag-
onists, ketanserin, antiarrhythmics and hypolipidaemics), diuretics (torasemide),
psychoactive and anticonvulsant agents (benzodiazepines, flumazenil, antide-
pressants and tiagabine), antiemetics (metoclopramide and serotonin antago-
nists), antiulcers (acid pump inhibitors), anti-infectives and antiretroviral agents
(grepafloxacin, ornidazole, pefloxacin, stavudine and zidovudine), immunosup-
pressants (cyclosporin and tacrolimus), naltrexone, tolcapone and toremifene.
According to the available data, the kinetics of many drugs are altered by liver
disease to an extent that requires dosage adjustment; the problem is to quantify
the required changes. Obviously, this requires the evaluation of the degree of
hepatic impairment. At present there is no satisfactory test that gives a quantitative
measure of liver function and its impairment. A critical evaluation of these meth-
ods is provided. Guidelines providing a rational basis for dosage adjustment are
illustrated.
Finally, it is important to consider that liver disease not only affects pharma-
cokinetics but also pharmacodynamics. This review also examines drugs with
altered pharmacodynamics.

This article updates a 1987 review[1] and pro- with liver disease. Other reviews on this subject
vides an overview of developments in the under- have been published previously.[2-5]
standing of how drug kinetics are altered in patients The capacity of the liver to metabolise drugs

© Adis International Limited. All rights reserved. Clin Pharmacokinet 1999 Nov; 37 (5)
Effects of Liver Disease on Pharmacokinetics
(hepatic clearance) depends on hepatic blood flow
and enzyme activity. Factors that affect liver blood
flow and enzyme activity can substantially alter
drug disposition and the therapeutic response to a
drug. Liver disease is clearly a factor that can mod-
ify the kinetics of a drug by changing hepatic blood
flow and reducing the activity of drug metabolising
enzymes. These changes can occur alone or in
combination. When they coexist, their effect on
drug kinetics is synergistic, not simply additive. In
acute liver disease, the major alteration is in
hepatocellular function; in chronic liver disease,
such as cirrhosis, the major abnormality is in liver
blood flow and/or alteration in liver function.
1. Liver Function
Drugs with a low hepatic extraction are not sen-
sitive to liver blood flow changes. The fraction of
these drugs removed from the blood during a single
passage through the liver, that is the extraction ratio,
is small, so hepatic clearance is not limited by the
amount of drug carried to the liver. Their clearance
depends on the activity of drug metabolising en-
zymes. Thus, hepatic failure can reduce the capacity
of the liver to metabolise the drug, resulting in a
decrease in hepatic drug clearance, an increase in
the area under the curve of plasma/serum concen-
tration versus time (AUC) and a prolongation of
the half-life (t1⁄2) of the drug. It is evident that if the
liver metabolises less drug, more drug is present in
the systemic circulation and more time is needed
for its elimination.
In blood many drugs are bound to plasma pro-
teins, mainly to albumin and/or α1-acid glycopro-
tein, whose synthesis can be decreased by hepatic
failure with consequent reduction in drug binding.
The effect of hypoproteinaemia on drug kinetics
depends on the type of agent and degree of protein
binding. Drugs with a high extraction ratio are re-
moved by the liver as rapidly as they circulate in
hepatic blood because the liver is capable of meta-
bolising all the drug reaching the liver.[6] Thus, the
hepatic clearance of bound and unbound drug is
not sensitive to changes in drug protein binding but
is flow-dependent. If the unbound drug concentra-
© Adis International Limited. All rights reserved.
401
tion increases because of hypoproteinaemia, the
liver will remove all the drug anyway.
Very few studies consider the effects of decreased
plasma proteins on drug kinetics in patients with
liver disease.
2. Hepatic Blood Flow
Several drugs are subject to a significant oral first-
pass effect which leads to a reduced systemic avail-
ability. Liver blood flow can be reduced because
of pathological alterations caused by liver disease,
as in cirrhosis. There can be spontaneous or surgi-
cal portacaval shunts. After oral administration of
a drug with a high first-pass effect to patients with
portacaval shunts, a fraction of the drug enters the
shunt, thus bypassing the liver and reaching the
systemic circulation directly without being ex-
posed to the first-pass effect. This results in greater
systemic availability, which may be increased
many-fold depending on the proportion of portal
blood flow shunted. Although drugs with a first-
pass effect are sensitive to changes in liver blood
flow, this is not the case for drugs with a low he-
patic extraction because the fraction of these drugs
removed from the blood during a single passage
through the liver is small.
3. Cytochrome P450 (CYP) System
and Liver Disease
There are numerous pathways of drug metabo-
lism in the liver, each affected to a different degree
by liver disease, oxidation being more sensitive
than glucuronidation.[3] Oxidative metabolism plays
a fundamental role and it is largely catalysed by
enzymes belonging to the CYP family. One of the
most rapidly expanding areas in clinical pharma-
cology is the study of hepatic drug biotransforma-
tion by the CYP system, and the identification and
characterisation of individual CYP isoforms. The
information currently available on specific CYP
isoforms involved in the metabolism of a variety
of therapeutic agents has increased tremendously
over recent years. However, knowledge remains
incomplete and for many agents the CYP isoform
has not yet been identified. In humans the 3 fami-
Clin Pharmacokinet 1999 Nov; 37 (5)
402
lies predominantly involved in hepatic drug meta-
bolism are CYP1, CYP2 and CYP3.[7]
Hepatic disease is associated with reduced me-
tabolic capacity for drugs that undergo oxidative
biotransformation, but information on impairment
of individual CYP isoforms is still limited.[8] Sev-
eral probe drugs have been used to investigate this
point, but when drugs metabolised by CYP are used
as a probe a common drawback in study design is
the fact that CYP isoenzymes can be variably ex-
pressed, being subject to inhibition and induction
by a variety of agents, as in the case of drug
coadministration to patients. In addition, CYP iso-
enzymes can exhibit genetic polymorphism. Thus,
the presence of these factors may lead to erroneous
conclusions when using a drug as a probe.
3.1 CYP1A
Caffeine is almost completely metabolised by
the liver; it is mainly demethylated by CYP1A2.[9]
The drug has been used as a probe in patients with
liver impairment, showing a decrease in CYP1A2 ac-
tivity proportional to the severity of liver disease.
Holstege et al.[10] studied 27 patients with liver
cirrhosis who were given an oral dose of caffeine
7 mg/kg. The degree of hepatic impairment was
determined using the Child-Turcotte classifica-
tion[11] and the Child-Pugh scoring system[12] (7 class
A, 8 class B, 12 class C). The apparent caffeine
clearance decreased with increasing impairment of
liver function, the correlation being highly signif-
icant. The demethylation of caffeine was severely
impaired in these patients.
Scott et al.[13] obtained similar results in 19 pa-
tients with cirrhosis (10 with Child-Pugh score ≤7,
9 with score 8 to 12). Upon oral administration of
caffeine 400mg a significant linear inverse corre-
lation between the degree of hepatic impairment
and salivary caffeine clearance was observed. Sim-
ilarly, in 34 patients with mild, moderate and se-
vere alcoholic liver disease who were given an oral
dose of caffeine 300mg, salivary caffeine clearance
strongly and inversely correlated with a modified
Child-Pugh score[14,15] (10 class A, 10 class B, 14
class C).
© Adis International Limited. All rights reserved.
Rodighiero
3.2 CYP2A
Coumarin undergoes hydroxylation by CYP2A6
to 7-hydroxycoumarin, which is conjugated with
glucuronic acid and rapidly excreted in the urine.[16]
Coumarin has been used as a probe drug for mea-
suring liver function.[17] Oral coumarin 5mg was
given to 36 patients with alcoholic liver disease
classified as mild, moderate and severe according
to Child-Pugh score and histological diagnosis (11
class A, 14 class B, 11 class C). The urinary excre-
tion of 7-hydroxycoumarin was decreased and in-
versely correlated to Child-Pugh scores. However,
the coumarin test is not applicable in patients with
impaired kidney function because the excretion of
7-hydroxycoumarin is compromised.
Kraul et al.[18] measured the activity of 7-eth-
oxycoumarin O-de-ethylase in liver biopsy speci-
mens from 23 patients with alcoholic liver disease
and different degrees of structural liver damage
(fatty liver, chronic active hepatitis, cirrhosis). The
activity was reduced in proportion to the degree of
liver damage.
3.3 CYP2C
There are 4 identified members belonging to
this subfamily: CYP2C8, CYP2C9, CYP2C10 and
CYP2C19.[7] The CYP2C9 isoenzyme is not sensi-
tive to liver disease. Tolbutamide[7] and irbesar-
tan[19] are substrates for CYP2C9/10 and CYP2C9,
respectively. Mephenytoin is a racemic drug: the
R-enantiomer is metabolised by CYP2C9[20] and
the S-enantiomer by CYP2C19.[21] Liver disease
does not affect the disposition of irbesartan,[22] tol-
butamide[23] and R-mephenytoin, but it impairs the
metabolism of S-mephenytoin.[21]
S-Mephenytoin is a specific probe drug metabo-
lised by CYP2C19, a genetically polymorphic en-
zyme.[21] After oral administration of racemic
mephenytoin 100mg to 18 patients (poor metabo-
lisers excluded) with mild or moderate liver cirrho-
sis (9 class A and 9 class B according to Pugh scores
and Child class) a marked decrease in the apparent
oral clearance (CL/F) of S-mephenytoin was ob-
served with a corresponding reduction in the uri-
Clin Pharmacokinet 1999 Nov; 37 (5)
Effects of Liver Disease on Pharmacokinetics
nary excretion of the metabolite 4’-hydroxymephen-
ytoin.[21] The decrease in clearance was related to
the severity of the disease and exhibited an inverse
relation to Pugh scores: patients with moderate cir-
rhosis were affected more severely than patients
with mild cirrhosis. Thus, CYP2C19 appears to be
very sensitive to hepatic impairment. These results
are consistent with those obtained in a previous
study[24] which showed reduced elimination of S-
mephenytoin in patients with chronic hepatitis.
Adedoyin et al.[21] simultaneously evaluated in
the same group of patients the effect of liver im-
pairment on CYP2D6, a genetically polymorphic
enzyme, with the use of the specific probe drug
debrisoquine (10mg orally). In contrast with S-
mephenytoin, the metabolism of debrisoquine was
not affected by liver disease. Thus, this study showed
a selective effect of liver disease on the activity of
specific CYP enzymes, CYP2C19 being more sen-
sitive than CYP2D6. This study has the advantage
of simultaneously evaluating the effect of liver im-
pairment on 2 isoenzymes in the same population.
Because of the multiplicity of CYP enzymes, mul-
tiple studies are needed to assess different enzymes,
making it difficult to compare the results from in-
vestigations using different study design and pop-
ulations.
A new method (the ‘Pittsburgh cocktail’), based
on the simultaneous administration of low doses of
multiple probes of drug-metabolising enzymes
(caffeine, chlorzoxazone, dapsone, debrisoquine
and mephenytoin) with the absence of metabolic
interactions among the drugs used, has been re-
ported.[25] This method provides simultaneously
independent estimates of respective individual
metabolising enzyme activities in the same popu-
lation and it may be useful for the evaluation of
differential effects of a particular disease state or
drug therapy on CYP activity. However, there is a
drawback in the coadministration of probe drugs
as ‘cocktails’, since they can result in complex in-
teractions.
© Adis International Limited. All rights reserved.
403
3.4 CYP3A
The isoenzymes belonging to the CYP3A sub-
family are the most abundant form of CYP.[26] They
are generally referred to collectively as CYP3A be-
cause of the inability to readily distinguish among
the various isoforms, especially in vivo. High levels
of CYP3A are present in the gastrointestinal tract
and liver. Accordingly, the route of administration
of a drug becomes an extremely important factor.
CYP3A is involved in the oxidative metabolism of
many important drugs. Although the activity of
CYP3A is subject to large interindividual varia-
tions, genetic polymorphism has not been demon-
strated.
The metabolism of drugs involving CYP3A is
affected in patients with liver disease: a reduction
in activity (30 to 50%) has been reported.[26] Sev-
eral drugs metabolised by CYP3A have been used
to evaluate the effect of liver impairment on
CYP3A. Huang et al.[27] measured serum mono-
ethylglycinexylidide (MEGX) concentration 15
minutes after intravenous administration of a sin-
gle dose of lidocaine 1 mg/kg to 24 patients with
chronic hepatitis and 47 patients with liver cirrho-
sis (16 class A, 13 class B, 18 class C Child-Pugh
classification). Lidocaine is metabolised to MEGX
via oxidative N-de-ethylation by CYP3A. The se-
rum MEGX concentrations were inversely propor-
tional to Child-Pugh classes and directly propor-
tional to galactose elimination capacity, although
there was no correlation with serum albumin or
total bilirubin levels. There was a large variation in
MEGX concentrations, but this probably reflects
the wide variation in CYP3A activity found in
healthy individuals. Patients taking drugs affecting
lidocaine metabolism were excluded from the
study. Of course, lidocaine administration is not
suitable for patients with cardiovascular disorders.
In conclusion, the MEGX formation test reflects
the severity of hepatic impairment and may serve
as a simple and rapid quantitative liver function test.
Similar results were obtained by Shiffman et
al.[28] In their study, serum concentrations of MEGX
were determined 15 minutes after the intravenous
administration of a single dose of lidocaine 1
Clin Pharmacokinet 1999 Nov; 37 (5)
404
mg/kg to 225 patients with chronic hepatitis (107
had biopsy-proven cirrhosis). A liver biopsy was
performed in all patients to assess liver histological
condition, which was scored according to the clas-
sification of Knodell. The severity of cirrhosis was
further graded by Child classification as mild,
moderate and severe. MEGX production declined
in parallel with deteriorating hepatic histology. A
decline in parallel with worsening Child class was
also observed in patients with cirrhosis. The range
of MEGX values varied widely, probably in keep-
ing with the wide variation observed in healthy
individuals. The possibility of interference with the
metabolism of lidocaine can be ruled out because
patients taking known inducers or inhibitors of
CYP3A were excluded from the study.
The results reported above were confirmed by a
study of Sotaniemi et al.[17] in 36 patients with al-
coholic liver disease (11 class A, 14 class B, 11
class C Child-Pugh classification) after intrave-
nous administration of lidocaine 1 mg/kg.
These findings are in agreement with the studies
that have shown reduced clearance of drugs meta-
bolised by CYP3A in patients with liver impair-
ment.
3.5 Relative Changes in CYP Enzyme
Levels and Activity
George et al.[29,30] examined 50 livers removed
for transplantation from patients with end-stage
cirrhosis (18 with and 32 without cholestasis) to
determine the levels of CYP1A2, 2C8/10, 2E1 and
3A, their catalytic activities and the corresponding
levels of mRNA. The severity of liver disease was
assessed using the Child-Pugh classification (4
class A, 17 class B, 29 class C). The total content
of CYPs was decreased but there was a selectivity
for individual enzymes, some being more affected
than others. Moreover, the effect was related to the
type of liver disease (cholestasis or no cholestasis).
However, there is little information in the literature
about cholestatic liver disease. The reasons for
these differences are unknown. It would be impor-
tant to identify the mechanisms underlying this se-
lectivity of effects. Large interindividual variations
© Adis International Limited. All rights reserved.
Rodighiero
were noted in the CYP enzymes and CYP-specific
mRNA content of hepatic tissue.
CYP1A2 appears to be particularly susceptible
to the effects of liver function impairment. The
level of CYP1A2 was significantly reduced both in
cholestatic and noncholestatic cirrhosis, with a lin-
early correlated decrease in its catalytic activity
(ethoxyresorufin O-de-ethylase). CYP1A2 mRNA
levels were correspondingly reduced.
CYP2C and tolbutamide 4-hydroxylase activity
were not reduced in either type of cirrhosis.
CYP2C activity was determined by the 4-hydrox-
ylation of tolbutamide catalysed by CYP2C9/10.[7]
The levels of mRNA were diminished in all cir-
rhotic livers. However, the authors used a polyclo-
nal antibody to identify CYP2C8/10; this antibody
is not specific and probably recognised other mem-
bers of the CYP2C subfamily.
CYP3A4 was significantly reduced with a par-
allel decrease in catalytic activity (testosterone 6β-
hydroxylase activity) in cirrhotic patients without
cholestasis, whereas in patients with cholestasis
there was a reduction but it was not considered sig-
nificant. Similarly, CYP3A4 mRNA was decreased
with a significant correlation with CYP3A4 content.
CYP2E1 and the related N,N-dimethylnitros-
amine N-demethylase activity were reduced only
in cirrhotic patients with cholestasis, whereas CYP-
2E1 mRNA levels were lower in patients with both
types of cirrhosis.
In conclusion, the studies showed that the extent
to which liver impairment affects drug metabolism
depends on the specific enzyme involved and the
severity of the underlying liver disease. Some CYP
isoforms are more susceptible than others. There is
a range of sensitivity in the presence of liver dis-
ease, even though the mechanism responsible for
this differential effect remains unknown. It is im-
portant to have a detailed knowledge of the partic-
ular enzyme involved in the metabolism of a drug,
of the impact of liver disease on that enzyme and
of the degree of liver impairment. An adequate
amount of information on these factors can provide
a rational basis for dosage adjustment in patients
with liver disease. Dosage adjustment depends on
Clin Pharmacokinet 1999 Nov; 37 (5)
Effects of Liver Disease on Pharmacokinetics
which specific enzyme mediates the metabolism of
the drug involved and the severity of the disease
itself. Since information is limited, studies are
needed to investigate the effects of different de-
grees of hepatic impairment on the activity of spe-
cific metabolising enzymes so that specific guide-
lines for dosage adjustment can be developed.
4. Cardiovascular Agents
4.1 Angiotensin Converting Enzyme
(ACE) Inhibitors
Most ACE inhibitors are prodrugs, esters of the
active form, because the active drug is poorly ab-
sorbed from the gastrointestinal tract.[31] The esters
are readily absorbed and converted in the liver to
the active form, which is usually excreted in the
urine. It can be assumed that hepatic conversion to
the active form can be impaired by liver dysfunc-
tion. Although few studies are available, it is clear
that the conversion of the prodrug is significantly
reduced in patients with impaired liver function.
Quinalapril is a prodrug converted in the liver
to the active form, quinalaprilat. This biotransfor-
mation is impaired in patients with compensated
alcoholic cirrhosis (as shown with a single oral
dose of 20mg),[32] producing a 3-fold higher AUC
of quinalapril than in matched healthy individuals,
a 2-fold lower AUC of quinalaprilat and a 2-fold
longer t1⁄2 of quinalapril (AUC for quinalapril 744
vs 257 μg/L • h and for quinalaprilat 1558 vs 3410
μg/L • h; the t1⁄2 of quinalapril was 1.4 vs 0.7h). The
t1⁄2 of quinalaprilat was not changed in these pa-
tients because quinalaprilat is largely eliminated in
urine.
Similar results have been obtained in 9 patients
with compensated liver cirrhosis given a single
oral dose of cilazapril 1mg, a prodrug biotrans-
formed in the liver to cilazaprilat, because of a re-
duced clearance of cilazapril.[33]
The conversion of enalapril to enalaprilat is re-
duced in patients with well compensated liver cir-
rhosis and impaired liver function compared with
healthy individuals.[34] The biotransformation of
enalapril to enalaprilat was considerably impaired
© Adis International Limited. All rights reserved.
405
in patients with decompensated cirrhosis[35] [7 pa-
tients given a single oral dose of 10mg, all with
varices, splenomegaly and 37% retention of indo-
cyanine green (ICG) at 15 min] as shown by a
marked reduction in the CL/F of enalapril resulting
in a higher AUC and peak plasma drug concentra-
tion (Cmax), while the AUC and Cmax of enalaprilat
were lower (CL/F for enalapril 39.2 vs 91.6 L/h in
healthy individuals, AUC for enalapril 276 vs 122
μg/L • h, Cmax for enalapril 123 vs 66 μg/L; AUC
for enalaprilat 173 vs 375 μg/L • h and Cmax of 16
vs 46 μg/L).
The above studies demonstrated that the con-
version of the prodrug to its active form is reduced
when liver function is impaired. It is probably bet-
ter to avoid the use of ACE inhibitors, which are
prodrugs, in patients with hepatic dysfunction
since their dosage may need to be increased to en-
sure adequate concentrations of the active metabo-
lite. The use of non-prodrug ACE inhibitors, such
as lisinopril, a lysine analogue of enalaprilat, may
be advocated in these clinical situations.
4.2 Angiotensin II Receptor Antagonists
Angiotensin II receptor antagonists are a new
class of drug for the treatment of patients with hy-
pertension. Losartan was the first agent of this class
and has been followed by valsartan, irbesartan and
others. The number of studies on these drugs are
still limited and information is incomplete.
4.2.1 Losartan
Losartan is a nonpeptide angiotensin II receptor
antagonist[36,37] which binds competitively and se-
lectively to the angiotensin II subtype 1 receptor,
thus blocking the physiological effects of angio-
tensin II. The oral bioavailability of losartan is
about 33% because of a considerable first-pass ef-
fect. The protein binding is >90%. It is mainly me-
tabolised by hepatic CYP2C9 and CYP3A to sev-
eral metabolites. The metabolite E-3174 is active
and largely responsible for its antihypertensive ef-
fect.
In patients with mild to moderate alcoholic cir-
rhosis,[37] the total plasma clearance (CLp) of
losartan is decreased by approximately 50%, the
Clin Pharmacokinet 1999 Nov; 37 (5)
406
oral bioavailability is doubled and the plasma con-
centrations of losartan and E-3174 are increased 5-
and 1.7-fold, respectively, as compared with
healthy individuals. Therefore, a lower dosage
seems justified in patients with liver impairment; a
25mg once daily dose could be appropriate. It
should be noted that the effects of losartan,
valsartan and irbesartan are dose-related.
4.2.2 Valsartan
Valsartan, a compound structurally related to
losartan, is a selective competitive angiotensin II
antagonist which binds to the angiotensin II sub-
type 1 receptor.[38] The fraction of the oral dose
absorbed by the gastrointestinal tract and systemi-
cally available is 23% for the capsule and 39% for
the solution. Binding to plasma proteins (albumin)
is >90%. Valsartan undergoes little hepatic meta-
bolism and is largely excreted unchanged in the
bile. The main route of elimination is biliary excre-
tion.
Patients with mild and moderate liver impair-
ment (6 class A, 6 class B by the Child-Pugh clas-
sification) with different types of disease (primary
biliary cirrhosis, alcoholic cirrhosis, alcoholic hep-
atitis, hepatomegaly and extrahepatic biliary ob-
struction) were given a single oral dose of valsartan
160mg.[39] Exposure to valsartan, measured as
AUC, was increased approximately 2-fold com-
pared with matched healthy volunteers. The possi-
ble mechanism explaining the altered pharmaco-
kinetics is the impaired transport of valsartan into
the bile. A lower dosage seems advisable in patients
with liver impairment. However, this study has
drawbacks, since it grouped together patients with
very heterogeneous diseases and the number of
patients is small.
4.2.3 Irbesartan
Irbesartan is a nonpeptide selective and non-
competitive antagonist of angiotensin II receptor
subtype 1. Oral bioavailability is about 60 to 80%
and binding to plasma proteins is approximately
90%.[19] It is primarily metabolised by hepatic
CYP2C9 with the amount of the drug excreted un-
changed in the urine being about 1%.
© Adis International Limited. All rights reserved.
Rodighiero
The effect of hepatic impairment was assessed
in 10 cirrhotic patients with mild or moderate he-
patic impairment (Child-Pugh class A and B) given
oral irbesartan 300mg once daily for 7 consecutive
days.[22] The pharmacokinetics were not signifi-
cantly altered; there were no significant differences
between healthy individuals and patients with cir-
rhosis. This is in keeping with the fact that CYP-
2C9 is not sensitive to the effects of liver disease.
Irbesartan could be a good choice for the treatment
of hypertension in patients with impaired liver
function. However, more studies are needed to
evaluate the kinetics of irbesartan in severe liver
disease.
4.3 Calcium Antagonists
Calcium antagonists are widely used for the
treatment of patients with cardiovascular disease.
They have some common pharmacokinetic charac-
teristics:[40] they are subject to a high first-pass ef-
fect in the liver resulting in a low oral bioavailabil-
ity and are metabolised almost entirely by the liver.
All calcium antagonists reported in this review, ex-
cept for gallopamil, are biotransformed by CYP3A.
Hepatic disease alters, possibly markedly, the
kinetics of calcium antagonists, the pharmacokinetic
alterations depending on the severity of liver im-
pairment. If given in normal dosages to patients
with liver disease, the pharmacological effect could
be excessive and dangerous. Dosage modifications
are advisable in patients with significant hepatic
impairment, as for most calcium antagonists there
is a relationship between plasma concentrations
and effect.
4.3.1 Felodipine
Felodipine has a bioavailability of about 16%
and protein binding of >99%.[40] In 9 cirrhotic pa-
tients with impaired liver function after a single
dose of felodipine 0.75mg intravenously or 10mg
orally, the AUC and Cmax were almost twice that
found in healthy individuals as a result of a reduced
CL/F (one-third of that in healthy individuals).[41]
The bioavailability in patients with cirrhosis, in-
cluding 2 patients with a portacaval anastomosis,
was almost the same as in healthy individuals. The
Clin Pharmacokinet 1999 Nov; 37 (5)
Effects of Liver Disease on Pharmacokinetics
most likely explanation is that the intestine plays a
major role in the first-pass metabolism of felodip-
ine.[42] This study did not specify the degree of liver
impairment and included heterogeneous diseases.
A reduction in dosage is recommended in patients
with liver damage; a starting dosage of 5 mg/day
seems appropriate.
4.3.2 Gallopamil
Gallopamil is a methoxy derivative of verapa-
mil. Although it is almost completely absorbed af-
ter oral administration, oral bioavailability is low
(15% after a single dose, 22.6% after repeated ad-
ministration) because of its extensive first-pass he-
patic metabolism;[43] protein binding is about 93%.
It is largely metabolised by the liver. Liver disease
markedly alters the kinetics of gallopamil. In 6 pa-
tients with Child-Pugh class B cirrhosis who re-
ceived a single oral dose of gallopamil 25mg, the
CL/F was greatly reduced (1.82 L/min compared
with 8.2 L/min in healthy individuals).[44] Conse-
quently, bioavailability increased to 60% and t1⁄2
was prolonged to 11 hours (compared with 3 to 6h
in healthy individuals). The changes in pharmaco-
kinetics were accompanied by a greater drug effect
in patients with cirrhosis compared with that found
in healthy volunteers. Based on these findings, I
suggest reduction of the oral dosage of gallopamil
to 25 to 50% of the normal dosage.
4.3.3 Nicardipine
Nicardipine has a low bioavailability (about
11%) because of an extensive first-pass liver me-
tabolism.[40] It is 98 to 99% protein bound. After a
single oral dose of nicardipine 30mg, 9 cirrhotic
patients with impaired liver function (abnormal
routine laboratory tests, antipyrine AUC reduced
by 65%) showed a reduction in drug elimina-
tion,[45] demonstrated by substantially higher AUC
and much longer t1⁄2 than that found in the matched
control group (AUC 432 vs 97 mg/L • h and t1⁄2 13.7
vs 1.6h). The pharmacological response to the drug
was also greater, which is in keeping with the
higher plasma concentrations. These findings indi-
cate that the dosage of nicardipine should be re-
duced in patients with liver impairment.
© Adis International Limited. All rights reserved.
407
4.3.4 Nifedipine
Nifedipine has a bioavailability of about
45%.[40] The protein binding is 96 to 98%. Its kinetics
are grossly altered in patients with liver cirrhosis.
In 7 patients with cirrhosis, all with varices and
mostly with ascites, the capacity of the liver to me-
tabolise the drug (a single intravenous dose of ni-
fedipine 4.5mg) was reduced, as shown by a de-
creased systemic clearance (CL) and an almost
4-fold prolongation of t1⁄2 (CL 13.98 vs 35.28 L/h
in healthy controls; t1⁄2 7 vs 1.85h), while the oral
bioavailability (after a single oral dose of nifedi-
pine 20mg) was almost doubled (90.5 vs 51.1%).[46]
In 3 patients with surgical portacaval shunts the
bioavailability was 100%. The unbound fraction of
nifedipine was almost doubled (8.5 vs 4.4%).
The capacity of the liver to metabolise nifedi-
pine was reduced in those patients with cirrhosis,
as shown by a decreased drug clearance. However,
this reduction alone is not sufficient to account for
such a high bioavailability. Other factors include
the presence of portacaval shunts, with their syn-
ergistic effect on bioavailability.
Another study[47] reported a marked reduction
in the elimination of nifedipine after a single oral
dose of 10mg in patients with cirrhosis (all patients
had portal hypertension and were largely decom-
pensated) as shown by a 4-fold increase in the t1⁄2
and a 2-fold increase in AUC. Clearly, patients
with cirrhosis are at risk of nifedipine accumula-
tion and a dosage reduction (to half the normal dos-
age) is required.
4.3.5 Nimodipine
Nimodipine has a low bioavailability (of about
11.6%) and protein binding of about 98%.[40]
In 6 patients with cirrhosis after a single oral
dose of nimodipine 60mg, CL/F was decreased by
almost 60% and AUC was 4 times greater than in
healthy individuals.[48] It was not reported whether
or not the patients had portacaval shunts, so it is
not possible to determine the relative contribution
of reduced clearance and blood shunting to the
greatly increased AUC. It seems that the decrease
in clearance alone cannot account for a 4-fold in-
crease in AUC. In the patients with cirrhosis there
Clin Pharmacokinet 1999 Nov; 37 (5)
408
was a significant reduction in mean arterial pres-
sure, which was significantly related to the nimodi-
pine concentrations, while there were no signifi-
cant changes in the healthy controls. In this study
no data are reported to assess the degree of liver
impairment.
Considering the marked changes in pharmaco-
kinetics, the dosage of nimodipine may be halved
in patients with liver impairment. However, more
detailed studies are needed.
4.3.6 Nisoldipine
Nisoldipine has a bioavailability of about 3.9%
and protein binding of >99%.[40] The pharmacoki-
netics of nisoldipine are markedly affected in pa-
tients with liver disease. In 8 patients with cirrho-
sis,[49] mostly with ascites and 2 with a mesocaval
shunt, after a single dose of nisoldipine (as either
an intravenous dose of 0.37mg or an oral dose of
5mg) there was a 42% decrease in CL (29.64 vs
50.82 L/h in the control group), a prolonged t1⁄2
(16.6 vs 9.7h in the control group) and a 4-fold
increase in oral bioavailability (14.7 vs 3.7%),
probably because the portacaval shunts and the re-
duced hepatic function had a synergistic effect on
bioavailability. Because of these alterations, a re-
duction in the dosage of nisoldipine was recom-
mended in patients with cirrhosis. However, in this
study very heterogeneous diseases were grouped
together.
In another study,[50] major modifications in the
kinetics of nisoldipine were observed in patients
with chronic liver disease. AUC and t1⁄2 were in-
creased, and clearance was decreased.
4.3.7 Nitrendipine
Nitrendipine has a low oral bioavailability
(about 16%) and a protein binding of about
98%.[40] Liver disease considerably modifies the
kinetics of nitrendipine. Nitrendipine was given to
11 cirrhotic patients with impaired liver function
and to 5 patients with chronic hepatitis (a single
5mg intravenous dose and 20mg orally once daily
for 7 days).[51] Impairment of liver function was
quantified using antipyrine clearance (patients with
cirrhosis 1.07 L/h and with chronic hepatitis 2.18
L/h; healthy individuals 2.50 L/h). After intrave-
© Adis International Limited. All rights reserved.
Rodighiero
nous nitrendipine the patients with cirrhosis had a
significantly altered drug kinetics; patients with
chronic hepatitis had similar alterations but to a
lesser extent [CL 51.2 L/h in patients with cirrho-
sis, 50.4 L/h in patients with chronic hepatitis and
77.4 L/h in healthy individuals; AUC to 24 hours
(AUC24) was 128, 118 and 61.8 μg/L • h, respectively,
for the same groups; t1⁄2 was 7.67, 3.79 and 2.19h,
respectively, for the same groups]. Following re-
peated oral administration, significant accumula-
tion of the drug was observed in patients with liver
disease.
Accumulation of nitrendipine after repeated ad-
ministration was also found in another study.[52] In
6 patients with alcoholic cirrhosis (after a single
10mg oral dose on day 1 and then 10mg twice daily
for 6 days) there was a marked increase in AUC on
day 1 (119 vs 29 μg/L • h in healthy individuals)
and at steady state drug accumulation was evident
(AUC 165 vs 47 μg/L • h in healthy individuals),
while the t1⁄2 and the elimination rate constant were
not significantly different in the 2 groups. These
data were considered consistent with a marked in-
crease in the systemic bioavailability of nitrendip-
ine, probably as a result of portosystemic shunting.
As a result of the altered kinetics of nitrendip-
ine, dosage adjustments should be made in patients
with liver disease according to the haemodynamic
response.
4.4 Ketanserin
Ketanserin is a serotonin (5-hydroxytryptamine;
5HT) 5HT2 receptor antagonist with a weak α1-
adrenoceptor antagonistic activity used for the
treatment of patients with hypertension and vaso-
spastic disorders.[53] After oral administration it is
subject to first-pass effect in the liver (bioavailabil-
ity of about 50%) and is extensively metabolised
by the liver, only 1% being excreted unchanged in
the urine. Ketanserin is about 95% protein bound,
mainly to albumin. In 26 patients with cirrhosis
after a single intravenous dose of 5mg, or 20 or 40mg
orally, CLp was decreased by 48% compared with
healthy controls, and the AUC was 3-fold higher
with the 20mg dose and 2- to 4-fold higher with the
Clin Pharmacokinet 1999 Nov; 37 (5)
Effects of Liver Disease on Pharmacokinetics
40mg dose.[54] The t1⁄2 was similar in the 2 groups.
The decrease in clearance is not sufficient to ac-
count for such a large increase in AUC. It is likely
that the increase in AUC may be because of the
existence of spontaneous portacaval anastomoses
in patients with cirrhosis. Unfortunately, the authors
did not report the degree of severity of cirrhosis.
These findings suggest a reduction in the oral
dosage of ketanserin or an increase in the adminis-
tration interval; the dosage should not exceed
20mg twice daily.
4.5 Antiarrhythmics
4.5.1 Flecainide
Flecainide is a class Ic antiarrhythmic agent. It
is not subject to presystemic metabolism, the bio-
availability being approximately 95%.[55] Flecain-
ide is 30 to 40% bound to plasma proteins. It is
metabolised by hepatic CYP2D6,[7] with about 25%
being excreted unchanged in the urine. Liver dis-
ease markedly affects the kinetics of flecainide.
Six cirrhotic patients with impaired liver func-
tion[56] (i.e. with abnormal values of routine labo-
ratory tests, antipyrine clearance 0.852 vs 3.192
L/h in healthy individuals) were given a single in-
travenous dose of flecainide 2 mg/kg. Liver im-
pairment resulted in a decreased CLp for flecainide
(0.23 vs 0.55 L/h/kg in healthy individuals), an in-
creased AUC (12 868 vs 3805 μg/L • h) and a
greatly prolonged t1⁄2 (49 vs 9.5h). Thus, in patients
with liver disease, flecainide can reach unaccept-
ably high plasma concentrations with the usual
dosage regimen. Caution should be used: therapy
should be started with a low dosage while monitor-
ing the therapeutic response and plasma drug con-
centration.
Flecainide is partly excreted unchanged in the
urine and elimination is reduced in patients with
kidney function impairment.[57] Thus, in patients
with liver disease both hepatic and renal function
should be assessed. If liver and kidney impairment
coexist, the use of flecainide is dangerous and
probably best avoided.
© Adis International Limited. All rights reserved.
409
4.5.2 Mexiletine
Mexiletine is a class Ib antiarrhythmic drug with
an oral bioavailability of about 90%.[58] It is exten-
sively metabolised by hepatic CYP2D6 to inactive
metabolites.[7] The plasma protein binding of mex-
iletine is about 70%.
The elimination of mexiletine is markedly im-
paired in patients with advanced alcoholic cirrho-
sis after a single intravenous doses of 200mg.[59]
This study involved 6 patients with abnormal rou-
tine laboratory tests and antipyrine clearance
(0.013 L/h/kg vs 0.028 L/h/kg in healthy individu-
als) and showed decreased CL, a greatly increased
AUC and prolonged t1⁄2 (CL 0.139 vs 0.496 L/h/kg
in healthy controls, AUC 21.6 vs 6.25 mg/L • h and
t1⁄2 28.7 vs 9.9h). On the basis of these findings the
usual loading dose, if it is needed, can be given to
patients with cirrhosis, but the maintenance dosage
should be reduced to a quarter or one-third of the
usual dosage. In this study the number of patients
was small and only patients with severe hepatic
impairment were included.
4.5.3 Propafenone
Propafenone is a class Ic antiarrhythmic agent.
It has a low and variable oral bioavailability (rang-
ing from 5 to 31%) because of its hepatic first-pass
effect[60] and protein binding of about 96%. It is
extensively metabolised by hepatic CYP2D6.[7] In
8 patients with moderate to severe hepatic dysfunc-
tion caused by alcoholic cirrhosis (severity of dis-
ease assessed with routine laboratory tests, pres-
ence of varices and ICG clearance) given a single
dose (intravenous 1 mg/kg, oral 150mg), an in-
crease in bioavailability, decrease in CL and ten-
dency for an increase in free drug was observed,
the changes being more marked with the increasing
severity of liver dysfunction.[61] On the basis of
these findings it is recommended to reduce the dos-
age of propafenone, depending on the severity of
hepatic impairment and to start with a low dose
with ECG monitoring. Thus, at least a 50% reduc-
tion in dosage is recommended.
Clin Pharmacokinet 1999 Nov; 37 (5)
410
4.6 Hypolipidaemics
The HMG-CoA reductase inhibitors (statins)
are reversible competitive inhibitors of HMG-CoA
reductase, the enzyme responsible for conversion
of HMG-CoA to mevalonic acid, thereby reducing
endogenous cholesterol synthesis and lowering
plasma cholesterol levels.
4.6.1 Fluvastatin
Fluvastatin, which is almost completely ab-
sorbed (98%) from the gastrointestinal tract, has an
absolute oral bioavailability of between 20 and
30% because of its extensive first-pass metabo-
lism.[62] Fluvastatin is 99% bound to plasma pro-
teins, mainly albumin, and is almost completely
metabolised to inactive metabolites, perhaps by
CYP3A.[7] After a single oral dose of fluvastatin
40mg, 11 cirrhotic patients with hepatic insuffi-
ciency (Child-Pugh score ≤10) had a plasma CL/F
28% less than that of matched controls and a 2.5-
fold increase in both AUC and Cmax, with no dif-
ference in the t1⁄2 between the 2 groups (AUC 795
vs 304 μg/L • h and Cmax 683 vs 269 μg/L).[63]
Lower dosages of fluvastatin are recommended
for patients with hepatic insufficiency.
4.6.2 Pravastatin
Pravastatin has a low oral bioavailability (about
17 to 18%), which is attributed both to incomplete
absorption (34%) and extensive first-pass metabo-
lism in the liver (extraction ratio 0.66).[64] About
50% of the drug is bound to plasma proteins. Both
renal and hepatic routes are responsible for the
elimination of pravastatin and its metabolites, ac-
counting for 47 and 53% of total clearance, respec-
tively. It is probably metabolised by CYP3A.[7] The
2 major metabolites are active: 75% of the inhibi-
tory activity of pravastatin is attributable to the par-
ent drug.
Patients with biopsy-proven alcoholic cirrhosis
and hepatic insufficiency have an AUC 34% higher
than that of matched controls (dose not speci-
fied).[65] This increase in AUC is attributed to re-
duction in hepatic clearance. The impairment of
hepatic clearance resulted in a compensatory in-
crease in renal excretion. The dual routes of elimi-
© Adis International Limited. All rights reserved.
Rodighiero
nation, renal and hepatic, suggest a potential for
compensatory excretion by alternative routes in pa-
tients with renal or hepatic impairment. In patients
receiving pravastatin both renal and hepatic func-
tion should be evaluated. Caution should be used
in administering pravastatin to patients with he-
patic disease; I recommend that they are started at
a lower dosage of 10 mg/day. In such patients, both
liver and kidney function should be evaluated.
5. Diuretics
5.1 Torasemide
Torasemide is a new loop diuretic used for the
treatment of patients with oedema caused by con-
gestive heart failure, renal failure and cirrhosis and
for the treatment of patients with hypertension.[66]
The absolute bioavailability is approximately 80%.
It is highly bound (>99%) to plasma proteins. Torase-
mide differs from other loop diuretics because it is
extensively metabolised by the hepatic CYP2C9;
only 20% of the drug is excreted unchanged in the
urine.
Several studies have shown that the kinetics of
torasemide are altered in patients with ascites
caused by cirrhosis. After a single intravenous or
oral dose of torasemide 10mg in 12 patients,[67] a
higher bioavailability (96%), decrease in CL and
nonrenal clearance, increase in renal clearance
with a greater percentage of the dose excreted in
the urine and prolongation of t1⁄2 were observed [CL
2.28 vs 2.58 L/h in healthy individuals, renal clear-
ance (CLR) 0.546 vs 0.384 L/h, nonrenal clearance
(CLNR) 1.752 vs 2.196 L/h and t1⁄2 8.1 vs 3.6h]. Pa-
tients had a diminished response to the drug.
Although this seems paradoxical, patients with
cirrhosis usually have a resistance to loop diuretics
because of a pharmacodynamic abnormality.[66]
Because of the decreased CLNR of torasemide, a
greater amount of drug was delivered to the kidney.
Since renal function was preserved in patients with
ascites, there was a greater excretion of torasemide
in the urine, the fraction of the dose excreted being
about 70% higher than in healthy individuals.
Thus, more drug for a longer time reached the renal
Clin Pharmacokinet 1999 Nov; 37 (5)
Effects of Liver Disease on Pharmacokinetics
site of action, offsetting the diminished pharmaco-
dynamics of response. In fact, the natriuretic effect
was essentially the same as that in healthy individ-
uals. Therefore, the pharmacokinetic changes of
torasemide in patients with cirrhosis compensate
for the pharmacodynamic abnormality.
No change in dosage is needed in patients with
cirrhosis unless there is concomitant impairment
of kidney function. It should be noted that in this
study individual data were widely scattered. The
authors did not measure plasma protein concentra-
tions in the patients; the presence of hypoprotein-
aemia has important effects on a highly bound drug
such as torasemide.
In another study,[68] altered kinetics of torasem-
ide were also observed in patients with ascites
caused by decompensated liver cirrhosis.
6. Psychoactive and
Anticonvulsant Agents
6.1 Benzodiazepines
6.1.1 Alprazolam
Alprazolam has an oral bioavailability of about
80 to 100%[69] with protein binding of between 79
and 83% (mainly to albumin). It is extensively me-
tabolised by hepatic CYP3A. In 17 patients with
alcoholic cirrhosis without ascites (abnormal rou-
tine laboratory tests, ICG t1⁄2 10.5 vs 2 to 4 min in
healthy individuals)[70] given a single oral dose of
alprazolam 1mg, the impairment of liver function
resulted in a 54% decrease in the CL/F of al-
prazolam with a corresponding increase in t1⁄2 and
AUC as compared with healthy matched individu-
als (CL/F 0.034 vs 0.073 L/h/kg, t1⁄2 19.7 vs 11.4h,
AUC 529 vs 220 μg/L • h). A reduction in the daily
dosage by half is suggested.
6.1.2 Midazolam
Midazolam has an oral bioavailability in the
range of 34 to 68%, because the first-pass effect
depends on the dose.[71] It undergoes significant
presystemic metabolism in the small intestine by
hepatic CYP3A;[72,73] high levels of CYP3A are
present in the intestine.[26] The plasma protein
binding of midazolam is about 95%. Midazolam is
© Adis International Limited. All rights reserved.
411
almost completely biotransformed by CYP3A.
When patients have moderate liver impairment the
changes in midazolam kinetics are modest.[74] Af-
ter a single intravenous dose of midazolam 0.2
mg/kg in 10 patients with alcoholic cirrhosis and a
moderate degree of liver dysfunction (routine lab-
oratory tests), CLp decreased by 37% compared
with the control group, AUC increased by 57% and
t1⁄2 was prolonged by 25% (CLp 24.12 vs 38.22 L/h,
AUC 649 vs 414 μg/L • h and t1⁄2 2.8 vs 2.25h).
The situation is different when patients have se-
vere liver cirrhosis.[75] After a single intravenous
dose of midazolam 0.075 mg/kg, 7 patients with
severe alcoholic cirrhosis (evaluated according to
routine laboratory tests, antipyrine and ICG clear-
ance) had a 2-fold prolongation of t1⁄2 as a result of
a significant decrease in CL (CL 0.32 vs 0.62
L/h/kg, t1⁄2 3.9 vs 1.6h). The patients experienced
greater sedation than the control group. Psychomo-
tor function was also evaluated (reaction time and
critical flicker fusion time); there was a decrease
in this function, which was attributed to an in-
creased cerebral sensitivity to midazolam.
Similar results were obtained in 7 cirrhotic pa-
tients with advanced impairment of liver function
as assessed with routine laboratory tests, antipy-
rine and ICG clearance.[76] The patients were given
a single intravenous or oral dose of midazolam (7.5
or 15mg, respectively) and had a decrease in CL
(55.7 vs 93.8 L/h/kg in controls) with a consequent
prolongation of t1⁄2 (7.36 vs 3.80h) and increase in
AUC (543 vs 298 μg/L • h). The bioavailability was
76 vs 38%.
Midazolam should be used with caution in pa-
tients with cirrhosis, and the dosage should be re-
duced by 50%.
6.1.3 Triazolam
Triazolam has an oral bioavailability of be-
tween 44 and 53% and is about 89% bound to
plasma proteins.[71] It is extensively metabolised
by hepatic CYP3A. Eight patients with cirrhosis
were given a single oral dose of triazolam 0.25mg
(the severity of liver disease was assessed accord-
ing to ICG clearance, partial thromboplastin time
and albumin concentration).[77] Liver impairment
Clin Pharmacokinet 1999 Nov; 37 (5)
412
reduced the CL/F (0.299 vs 0.401 L/h/kg in healthy
individuals), the clearance being correlated with
the severity of liver disease. This was accompanied
by an increase in AUC (15.5 vs 9.51 μg/L • h). The
values of CL/F and AUC varied widely. Psychomo-
tor performance and memory tests were adminis-
tered; the patients with cirrhosis showed greater
psychomotor impairment than healthy individuals.
Similar results have been found in another
study.[78] Eight patients with stable cirrhosis treated
with a single oral dose of triazolam 0.25mg (sever-
ity of disease assessed with aminopyrine breath
test, galactose and ICG clearance) had a significant
increase in triazolam free fraction (16.9 vs 13.8%
in healthy individuals), reduced CL/F of the un-
bound drug (0.888 vs 0.143 L/h/kg) which corre-
lated with the aminopyrine breath test and pro-
longed t1⁄2 (9.7 vs 3.9h). In patients with cirrhosis,
excessive sedation was observed and attributed not
only to impaired drug elimination but also to brain
hypersensitivity. The psychomotor capacity of the
patients was assessed with different psychometric
tests (flicker sensitivity, pursuit rotor and digit
symbol substitution test) when plasma concentra-
tions of unbound triazolam were the same in
healthy individuals and patients with cirrhosis (i.e.
2.25h after administration). The results of the tests
showed that the average impairment in the perfor-
mance of patients with cirrhosis was 30% greater
than in healthy individuals.
Because of pharmacokinetic changes in patients
with cirrhosis, the dosage of triazolam should be
adjusted: a 50% reduction of the dosage is advis-
able.
The oxidative pathway is more sensitive to liver
damage than glucuronidation, even though glucuron-
idation is not spared when liver disease is se-
vere.[79] Thus, in patients with liver disease it is
better to avoid benzodiazepines undergoing oxida-
tion and to use, in preference, benzodiazepines me-
tabolised by conjugation with glucuronic acid.
6.1.4 Flumazenil
Flumazenil is a specific benzodiazepine antag-
onist which reverses benzodiazepine-induced CNS
depression by competing with these drugs for the
© Adis International Limited. All rights reserved.
Rodighiero
benzodiazepine receptor.[80] It is indicated when
the central effects of a benzodiazepine need to be
attenuated or terminated. It is 40 to 50% bound to
plasma proteins. The oral bioavailability averages
16% because of a high first-pass effect. Flumazenil
is extensively metabolised by the liver to inactive
metabolites.
Eight patients with moderate alcoholic cirrhosis
(Pugh’s score ranging from 5 to 11) had impaired
elimination of flumazenil[81] after a single dose of
flumazenil (30mg oral or 2mg intravenous); this
was caused by a decreased CLp with a consequent
prolongation of t1⁄2 and a more than doubled AUC
[CLp 42.3 vs 72.06 L/h in matched healthy volun-
teers; t1⁄2 (intravenous) 1.4 vs 0.79h; t1⁄2 (oral) 1.3 vs
0.88h]. The oral bioavailability is more than dou-
bled (65.2 vs 27.8%).
In conclusion, patients with liver function im-
pairment have a reduced elimination of flumazenil.
Acute intravenous administration of the drug to
these patients only results in a longer duration of
action. Since the drug is well tolerated and has a
wide therapeutic index with a short half-life, no
serious problems should arise. If long term oral use
is anticipated, somewhat lower dosages are sug-
gested, especially if blood shunting is present be-
cause flumazenil has a high first-pass effect. The
effects of this drug are dose-related.
6.2 Antidepressants
6.2.1 Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs)
are antidepressant drugs with a common mecha-
nism of action.[82] They selectively and reversibly
block the reuptake of serotonin, binding to the pre-
synaptic serotonin reuptake carrier in the CNS. All
SSRIs are extensively metabolised in the liver. The
SSRIs discussed below are all biotransformed by
CYP2D6, although they have different chemical
structures and different pharmacokinetic charac-
teristics.
Fluvoxamine
Fluvoxamine is subject to a significant first-pass
effect, with an oral bioavailability of about
50%;[83] protein binding is about 77%. The meta-
Clin Pharmacokinet 1999 Nov; 37 (5)
Effects of Liver Disease on Pharmacokinetics
bolites are inactive. In 13 patients with alcoholic
liver cirrhosis [severity of disease assessed with
routine laboratory tests and bromosulphophthalein
(BSF) clearance], after a single oral dose of flu-
voxamine 100mg the AUC and the t1⁄2 were about
50% higher than in healthy volunteers.[84] This in-
crease is evidence that fluvoxamine metabolism is
reduced (CL/F 54.8 L/h) in this patient group.
There is great interindividual variability.
It is recommended that patients with liver dys-
function should be given a lower initial daily dos-
age with a longer interval between doses and this
should be followed by careful monitoring.
Fluoxetine
The absolute bioavailability of oral fluoxetine
in dogs is about 72% (human data is not avail-
able).[85] The main metabolite of fluoxetine is
norfluoxetine, which has a similar potency and se-
lectivity as the parent compound. The kinetics of
fluoxetine are nonlinear. Binding to plasma pro-
teins is 95%. In 13 patients with stable alcoholic
cirrhosis (characterised by routine laboratory tests
and ICG clearance) given a single oral dose of
fluoxetine 40 or 60mg, metabolism was signifi-
cantly reduced,[86] as shown by a 56% decrease in
CL/F and prolongation of t1⁄2 (6.6 vs 2.2 days in
healthy individuals).
The kinetics of norfluoxetine are also altered:
CL/F is decreased by 30% and t1⁄2 prolonged (12 vs
6.4 days in healthy individuals). Therefore, upon
repeated administration, excessive accumulation
of the drug can be expected, thus increasing the risk
of toxicity and exaggerated pharmacological re-
sponse.
Based on the pharmacokinetic modifications
observed in the patients with cirrhosis, a lower dos-
age (about a 50% reduction) or prolonged interval
should be used.
Paroxetine
Paroxetine has an oral bioavailability of about
50% and protein binding of approximately 95%.
The main enzyme, CYP2D6, involved in the meta-
bolism of paroxetine is saturable. Its saturation ac-
counts for the nonlinear pharmacokinetics ob-
served during repeated administration or after
© Adis International Limited. All rights reserved.
413
dosage increases.[87] The kinetics of paroxetine in
12 cirrhotic patients with moderate hepatic impair-
ment (routine laboratory tests) were investigated
by giving a single 20mg oral dose;[88] no signifi-
cant difference was found as compared with
healthy individuals. However, a single dose study
is not very meaningful because paroxetine is ad-
ministered to patients for an extended period of
time: a multiple dose study is clinically more rele-
vant. In 12 patients with alcoholic cirrhosis and
reduced liver function,[89] repeated oral adminis-
tration of paroxetine 20 mg/day for 14 days re-
sulted in the doubling of AUC and t1⁄2 compared
with healthy individuals. The patients had a re-
duced clearance of antipyrine and galactose (1.74
L/h and 78 nmol/h, respectively, vs 3.66 L/h and
150 nmol/h in controls). The data had a great inter-
individual variability. These findings suggest that
in patients with hepatic impairment the initial
dosage of paroxetine should be at the lower end of
the range recommended for those with normal liver
function, starting with a daily dosage of 10mg.
6.2.2 Nefazodone
Nefazodone is a new antidepressant agent with
a mechanism of action different from that of cur-
rently available antidepressants.[90] It potently and
selectively blocks postsynaptic serotonin recep-
tors. It undergoes extensive first-pass metabolism
(oral bioavailability of about 20%) and it is largely
metabolised by hepatic CYP3A, the main metabo-
lite (hydroxynefazodone) being active. It is highly
bound to plasma proteins (>99%). Because of im-
paired hepatic function in patients with cirrhosis
(12 patients, 6 class A and 6 class B Child-Pugh
classification; single oral dose of nefazodone
100mg),[91] systemic exposure to nefazodone and
hydroxynefazodone is about 2-fold higher than in
healthy volunteers and approximately 25% higher
after repeated administration (100mg twice daily
for 8 days), probably because nefazodone inhibits
its own metabolism. The data have a large interin-
dividual variability.
The results with the single dose reported above
are consistent with those reported in another study
by the same authors.[92] 12 patients with cirrhosis
Clin Pharmacokinet 1999 Nov; 37 (5)
414
and 12 healthy controls (antipyrine clearance 2.19
vs 4.48 L/h, respectively) were given increasing
single oral doses of nefazodone (50, 100 and 200mg).
Increasing doses resulted in supraproportional in-
creases in AUC (388, 1180 and 2890 μg/L • h, re-
spectively, in patients with cirrhosis vs 195, 705 and
2130 μg/L • h, respectively, in controls). This is
indicative of nonlinear pharmacokinetics. In this
study, too, there was a large interindividual vari-
ability of pharmacokinetic parameters.
In conclusion, the findings of these studies in-
dicate that lower than usual dosages of nefazodone
should be considered in patients with hepatic im-
pairment, starting with 50mg twice daily with the
drug response monitored.
6.2.3 Moclobemide
Moclobemide is a reversible and selective in-
hibitor of the enzyme monoamine oxidase subtype
A (MAO-A).[93] It is subject to substantial hepatic
first-pass metabolism. The oral bioavailability of
moclobemide is about 55% with a single 100mg dose,
but is higher after repeated doses (about 85%),
probably because the drug metabolism is a satura-
ble process. Moclobemide is almost completely
metabolised by hepatic CYP2C19. The binding to
plasma proteins (mainly albumin) is about 50%.
The kinetics of moclobemide are altered in pa-
tients with cirrhosis. Twelve cirrhotic patients with
a drastically reduced liver function,[94] assessed
with antipyrine and ICG clearance, were given a
single oral 100mg dose or intravenous 90mg dose
of moclobemide. They had a lower CL and in-
creases in bioavailability, maximum concentration
and t1⁄2 (CL 14.6 vs 37.3 L/h in healthy individuals,
F 84 vs 56%, Cmax 1607 vs 582 μg/L and t1⁄2 3.87 vs
1.67h). The parameters reported above show a sub-
stantial interindividual variation, reflecting a wide
range of age in the group of patients with cirrhosis.
In the presence of hepatic impairment the dos-
age of moclobemide should be reduced to half or
one-third of the usual dosage, or the administration
interval should be prolonged, to avoid excessive
accumulation of the drug after repeated administra-
tion.
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Rodighiero
6.3 Tiagabine
Tiagabine, a new drug effective in the manage-
ment of patients with refractory partial epilepsy,
prevents γ-aminobutyric acid (GABA) uptake by
inhibiting one of the GABA transporters (GAT-1)
responsible for the uptake of the neurotransmitter
into neurons and glial cells after synaptic release,
thus increasing synaptic GABA concentrations and
reducing neuronal excitability.[95]
Tiagabine has an oral absolute bioavailability of
about 90% and is extensively metabolised by he-
patic CYP3A. About 96% of the drug is bound to
plasma proteins.
The elimination of tiagabine is reduced in pa-
tients with liver impairment.[96] Patients with mild
and moderate impairment of hepatic function (4
class A, 3 class B Child-Pugh classification) who
were given oral tiagabine 4mg twice daily for 5
days showed a decreased drug elimination caused
by liver function impairment, as shown by the sig-
nificantly lower elimination rate constants, in-
creased AUC and longer t1⁄2 (AUC 632 μg/L • h in
mild impairment, 674 μg/L • h in moderate impair-
ment and 395 μg/L • h in healthy individuals; t1⁄2
11.7, 15.9 and 6.5h, respectively). The patients
with moderate hepatic impairment had a higher
fraction of unbound drug (5.13 vs 3.59% in healthy
individuals) which was consistent with a reduced
level of albumin (2.8 g/dl). Patients with hepatic
disease had a higher incidence of adverse effect,
mostly neurological. The drug should be given
with caution to epileptic patients with impaired
liver function. Patients should be closely moni-
tored because of potential increased incidence of
neurological adverse effects. Reduced dosages or a
longer interval, or both, may be needed. Even
though the number of patients studied was small, it
can be said that if liver impairment causes a de-
crease in plasma proteins the fraction of unbound
tiagabine will increase and therefore increase the
effect of the drug, thus making it dangerous to ad-
ministration tiagabine to patients with severe he-
patic impairment because of the very high inci-
dence of neurological adverse effects.
Clin Pharmacokinet 1999 Nov; 37 (5)
Effects of Liver Disease on Pharmacokinetics
7. Antiemetics
Antiemetic drugs are widely used to treat nau-
sea and vomiting from a variety of causes, but es-
pecially in patients undergoing cancer chemother-
apy. Little work has been done on the influence of
liver disease on the kinetics of these drugs.
7.1 Metoclopramide
Metoclopramide is subject to a first-pass effect,
but there are wide interindividual variations; the
oral bioavailability ranges from 32 to 97%.[97] It is
about 40% bound to plasma proteins and metabo-
lised to sulphate and glucuronide conjugates, 20%
being excreted unchanged in the urine.
In 8 patients with severe alcoholic cirrhosis and
marked hepatic impairment (Child-Pugh class C)
given single intravenous and oral doses of meto-
clopramide 20mg a 50% decrease in CL was ob-
served.[98] This decrease resulted in a correspond-
ing prolongation of t1⁄2 (15 vs 7h in healthy
volunteers) and similar increases in AUC after both
intravenous and oral administration (AUCIV 1689
vs 749 μg/L • h, AUCoral 1559 vs 689 μg/L • h).
Changes in metoclopramide kinetics were also
found in another study.[99] 18 cirrhotic patients
with varices, characterised with antipyrine and
ICG clearance, were studied after administration
of single intravenous and oral doses of metoclopra-
mide 0.25 mg/kg. The presence of hepatic blood
shunting determined an increase in bioavailability
and consequently a higher AUC (F 82 vs 60% in
controls and AUC 242 vs 180 μg/L • h). Dosage
adjustments are advisable in patients with cirrho-
sis, especially in the case of prolonged therapy; a
50% reduction of the dosage is recommended.
In these 2 studies,[98,99] the authors did not re-
port the renal function of patients with cirrhosis.
This parameter is important because 20% of meto-
clopramide is excreted unchanged in the urine. Pa-
tients with renal impairment have a reduced elim-
ination of the drug. Thus, when severe hepatic
impairment and reduced kidney function coexist,
the use of metoclopramide is probably best
avoided.
© Adis International Limited. All rights reserved.
415
7.2 Serotonin Antagonists
Serotonin antagonists are a new class of anti-
emetics which are selective antagonists of 5HT3
receptors. Ondansetron and tropisetron are repre-
sentatives of this class of drug.
7.2.1 Ondansetron
Ondansetron has an oral bioavailability of about
60% because of first-pass metabolism.[100] It is 70
to 76% protein bound and extensively metabolised
by hepatic CYP2D6, 1A2 and 3A.[7] Its kinetics are
affected by liver disease, depending on the degree
of hepatic impairment. This has been shown in 2
studies in patients with varying degrees of hepatic
impairment (mild, moderate and severe according
to Child-Pugh classification).
19 patients with chronic liver disease (type of
disease not specified) and hepatic impairment (6
class A, 6 class B, 7 class C) were given a single
intravenous dose of ondansetron 8mg.[101] The pa-
tients with mild to moderate hepatic impairment
had similar pharmacokinetic changes: a reduction
in CLp, an increase in AUC and a prolongation of
t1⁄2 (CLp 12.7 to 17.9 vs 28.7 L/h in healthy individ-
uals, AUC 633 to 646 vs 279 μg/L • h, t1⁄2 9.1 to 9.2
vs 3.6h); the changes were much more marked in
patients with severe hepatic impairment (CLp 5.76
L/h, AUC 1383 μg/L • h, t1⁄2 of 20.6h).
Similar results have been obtained in another
study[102] of 12 patients with chronic liver disease
(type of disease not specified) and varying degrees
of hepatic impairment (4 class A, 4 class B, 4 class
C) after single intravenous and oral doses of
ondansetron 8mg. In patients with severe impair-
ment the bioavailability was almost complete
(98%) with a decreased CL/F (14.1 L/h/kg), in-
creased Cmax (56 μg/L) and prolonged t1⁄2 (20h).
These changes were less pronounced in patients
with mild to moderate impairment (F 78 to 80% vs
60% in matched controls, CL/F 20.2 to 21.4 vs 44.6
L/h/kg, Cmax 39 to 40 vs 28 μg/L, t1⁄2 10 to 13 vs
6h).
On the basis of these results, when hepatic im-
pairment is moderate to severe, a dosage adjust-
ment is recommended for ondansetron: a once
Clin Pharmacokinet 1999 Nov; 37 (5)
416
daily dosage of less than 8mg would appear appro-
priate.
7.2.2 Tropisetron
Tropisetron is subject to dose-dependent first-
pass metabolism because its kinetics are nonlin-
ear;[103,104] thus, the bioavailability is 52% for the
20mg dose and 66% for the 100mg dose. Protein
binding of tropisetron is 59 to 71%. Tropisetron is
metabolised by hepatic CYP2D6 and, because of the
polymorphism of this system, there are poor and
extensive metabolisers. In patients with liver cir-
rhosis the metabolic clearance (dose not reported)
was 50% lower than that of healthy volunteers who
were extensive metabolisers. Accumulation of the
drug in such patients was considered unlikely at the
recommended dosage of 5 mg/day.[104]
8. Antiulcers
8.1 Proton Pump Inhibitors
Omeprazole is a substituted benzimidazole
which reduces gastric acid secretion by inhibition
of the H+,K+ ATPase in gastric parietal cells.[105]
Lansoprazole and pantoprazole, compounds which
are structurally similar to omeprazole, reduce acid
gastric secretion by the same mechanism.[106,107]
Lansoprazole has an oral bioavailability of about
85%, pantoprazole about 77%, omeprazole about
60% and all 3 drugs have a low to medium extrac-
tion ratio. These drugs are completely metabolised
by hepatic CYP2C19. Plasma protein binding is
high for all 3 drugs (>95%).
8.1.1 Lansoprazole
The effects of cirrhosis on lansoprazole kinetics
are considerable.[108] The results obtained in 16 pa-
tients with compensated or decompensated cirrho-
sis and ascites after a single oral dose of lanso-
prazole 30mg were similar. The severity of liver
disease was established on the basis of routine lab-
oratory tests, sulfobromophthalein (SBP) clearance
and the presence of ascites. The impairment of liver
function resulted in a considerable decrease in
lansoprazole CL/F (0.04 to 0.07 vs 0.26 L/h/kg in
healthy individuals) and a several-fold higher AUC
(11.7 to 10.7 vs 2.67 mg/L • h) and t1⁄2 (6.1 to 7.2 vs
© Adis International Limited. All rights reserved.
Rodighiero
1.4h).[108] There was no substantial difference be-
tween patients with compensated and uncompen-
sated cirrhosis.
Similar results were obtained in another
study[109] after repeated oral administration of
lansoprazole 30 mg/day for 9 days to 12 patients
with cirrhosis (3 class A, 1 class B, 8 class C Child-
Pugh classification). There was no significant dif-
ference in pharmacokinetics between the first and
last dose, indicating that the severity of cirrhosis
had little effect on accumulation of the drug.
It is recommended that a lansoprazole dosage of
30 mg/day should not be exceeded in patients with
impaired liver function.
8.1.2 Pantoprazole
The elimination of pantoprazole is also consid-
erably impaired in patients with cirrhosis. Twelve
patients with cirrhosis (Child class A and B) were
given an intravenous dose of pantoprazole 30mg
once daily for at least 5 days and 40mg orally once
daily for at least 7 days.[110] At steady state the pa-
tients had a greatly increased AUC (33.8 mg/L • h)
and t1⁄2 (7.8h) caused by the reduced CL (0.0161
L/h/kg). No accumulation of the drug was observed.
Similar results have been obtained in 12 patients
with cirrhosis with severe liver impairment given
pantoprazole 40mg orally for 7 days and 30mg in-
travenously for 5 days.[111]
8.1.3 Omeprazole
Cirrhosis causes marked changes in the pharma-
cokinetics of omeprazole. Eight patients with liver
cirrhosis (3 class A, 4 class B, 1 class C Child clas-
sification) given a single dose of omeprazole 20mg
intravenously or 40mg orally had a 9-fold decrease
in CL as compared with healthy volunteers, an al-
most 2-fold increase in bioavailability, a 7-fold in-
crease in AUC and a 4-fold prolongation of t1⁄2.[112]
However, the patients were older (40 to 80 years)
than the healthy volunteers (19 to 31 years). Thus,
part of the changes observed in the patients may be
caused by age, as a more than 2-fold decrease in
the clearance of omeprazole was found in elderly
healthy volunteers.[113]
Similar results were obtained in another study[114]
in 8 patients with alcoholic cirrhosis (severity of
Clin Pharmacokinet 1999 Nov; 37 (5)
Effects of Liver Disease on Pharmacokinetics
disease not specified) after administration of a single
oral dose of omeprazole 20mg. No accumulation of
the drug was reported in 2 separate studies[115,116]
after repeated administration to patients with cir-
rhosis because the t1⁄2, even though prolonged in
patients with cirrhosis (about 3h), is still very short
in relation to the administration interval (24h).
The substantial decreases in clearance of om-
eprazole, lansoprazole and pantoprazole observed
in patients with impaired liver function are similar
for all 3 drugs; this is expected because they are
metabolised by the same CYP isoform. As a clinical
consequence of reduced elimination, patients with
hepatic impairment would need lower dosages
than those normally used because the degree of
inhibition of gastric acid secretion is dose related.
Proton pump inhibitors could be used in prefer-
ence to cimetidine and ranitidine in patients with
liver disease because of the CNS adverse effects
experienced in these patients after administration
of cimetidine and ranitidine. Several cases of men-
tal confusion have been reported after cimetidine
administration.[117] There is enhanced penetration
of cimetidine into the CNS in this patient group;
the amount of cimetidine crossing the blood-brain
barrier is almost doubled compared with that in
healthy individuals.[118] Neuropsychiatric compli-
cations in patients with liver dysfunction have been
reported in association with ranitidine (confusion,
disorientation, hallucinations and delirium), but
with a lower incidence than with cimetidine.[119]
Ranitidine may cross the blood-brain barrier, but
to a lesser extent than cimetidine.
9. Antimicrobials and Antiretrovirals
9.1 Grepafloxacin
Grepafloxacin is a new broad spectrum fluoro-
quinolone antibacterial. It has an absolute oral bio-
availability of about 72% and protein binding of
about 50%. Grepafloxacin is primarily metabolised
by hepatic CYP1A2.[120] The kinetics are nonlinear,
probably because of saturation of metabolism.
Impairment of liver function influences grepa-
floxacin kinetics. 22 patients with mild and mod-
© Adis International Limited. All rights reserved.
417
erate hepatic impairment caused by different types
of liver disease (10 class A and 12 class B Child-
Pugh) received grepafloxacin 400mg orally for 7
days. They had reduced CL/F [23.16 (mild impair-
ment) and 14.94 (moderate impairment) vs 35.82
L/h in healthy controls] with an increased AUC (20
and 28 vs 13 mg/L • h, respectively) and prolonga-
tion of t1⁄2 (13 and 19 vs 12h, respectively), these
changes being more pronounced in patients with
moderate than in mild impairment.[121]
A dosage of grepafloxacin 400mg once daily is
considered appropriate for patients with mild he-
patic impairment, whereas grepafloxacin should not
be used in patients with moderate or severe impair-
ment. One drawback of this study was that the
group of patients had heterogeneous types of liver
disease.
9.2 Ornidazole
Ornidazole is a nitroimidazole derivative with
activity against protozoa and bacteria.[122] It is a
low clearance drug with plasma protein binding of
8 to 13% and is primarily metabolised by the liver.
Hepatic impairment affects the kinetics of this
drug. Ten patients with severe alcoholic liver cir-
rhosis and ascites were given a single intravenous
dose of ornidazole 500mg. The severity of the dis-
ease was assessed according to routine laboratory
tests. The patients had a significant reduction in
CLp (2.09 vs 3.04 L/h in healthy volunteers) lead-
ing to a prolonged t1⁄2 (21.9 vs 14.1h, respec-
tively).[123] Results in agreement with those reported
in the previous study were obtained in 3 groups of
patients with different hepatic diseases (acute viral
hepatitis, alcoholic cirrhosis and extrahepatic cho-
lestasis) after a single intravenous dose of or-
nidazole 500mg.[124] No significant difference was
observed between pharmacokinetic parameters
(CLp and t1⁄2) in these 3 groups of patients. What-
ever the type of hepatic disease may be, ornidazole
kinetics are markedly impaired.
To avoid excessive accumulation of ornidazole
after repeated administration in patients with he-
patic impairment, the dosage should be adjusted
Clin Pharmacokinet 1999 Nov; 37 (5)
418
appropriately and the administration interval
should be doubled.
9.3 Pefloxacin
Pefloxacin is a broad spectrum antibacterial of
the quinolone group. The oral bioavailability is
about 100% and protein binding is between 20 and
30%. Biotransformation of pefloxacin in the liver
is extensive (85 to 90%).[125]
Several studies on the pharmacokinetics of
pefloxacin in patients with hepatic impairment
have been published. The results of these studies
are in agreement and suggest hepatic impairment-
related pharmacokinetic modifications. In one
study,[126] 16 patients with alcoholic cirrhosis and,
mostly, with ascites were given a single intravenous
dose of pefloxacin 8 mg/kg; the severity of disease
was not specified (routine laboratory tests). They
showed a marked decrease in CLp (2.66 vs 8.19
L/h/1.73m2 in healthy individuals) as a result of
decreased hepatic metabolism and a significantly
longer t1⁄2 (35 vs 11h).
Two other studies[127,128] have reported similar
values in 25 patients with hepatocellular deficiency
caused by alcoholism (2 class A, 9 class B, 14 class
C Child-Pugh classification) and in 10 cirrhotic pa-
tients with ascites (routine laboratory tests). In ad-
dition, in both studies a marked accumulation of
the drug was observed after repeated administra-
tion. There was also penetration of pefloxacin into
the ascitic fluid with accumulation of the drug, the
concentration in the ascitic fluid being 72% of that
in plasma.
The pharmacokinetic parameters in these 3 studies
showed a great interindividual variability. In con-
sideration of the altered pharmacokinetics in pa-
tients with hepatic impairment, dosage adjustments
are advisable: a single daily dose of pefloxacin
400mg should suffice.
9.4 Stavudine
Stavudine is a pyrimidine nucleoside analogue
with potent activity against HIV and is used in the
treatment of patients with HIV infections. The oral
bioavailability is almost 100%.[129] Stavudine is
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Rodighiero
eliminated by both renal and nonrenal routes.
About 40% of a dose is excreted unchanged in the
urine, while the remaining is probably metabolised
via glucuronidation or other routes. The pharmaco-
kinetics of stavudine are not altered in patients with
liver disease.
In 5 cirrhotic patients with moderate to severe
hepatic impairment (Child-Pugh classification grade
B or C) given a single oral dose of stavudine 40mg,
the pharmacokinetic parameters were similar to
those found in age-matched controls.[130] However,
the number of patients in the study was very small
and further research is needed to clarify this is-
sue.
It is, however, necessary to evaluate the renal
function of patients with HIV infections because
the pharmacokinetics of stavudine are impaired
when renal function is reduced.[131]
9.5 Zidovudine
Zidovudine is a drug used for the treatment of
patients with the acquired immunodeficiency syn-
drome (AIDS).[132] It undergoes significant first-
pass metabolism with an average bioavailability of
63%, the binding to plasma proteins being about
25% (mainly to albumin). Zidovudine is primarily
metabolised via hepatic glucuronidation with a mi-
nor contribution of CYP3A; the main metabolite is
an inactive glucuronyl derivative (GZDV).
Patients with AIDS have a rather high incidence
of chronic hepatitis. Therefore, it is important to
know how liver disease influences the pharmaco-
kinetics of zidovudine. Several studies have shown
that hepatic impairment affects, sometimes mark-
edly, zidovudine disposition.
In 8 asymptomatic HIV-infected patients with
liver disease (chronic hepatitis) and mild hepatic
impairment (7 with a Child-Pugh score of 5 and 1
with a score of 7) after single intravenous 120mg
and oral 200mg doses of zidovudine, the CL/F of
the drug was reduced and less GZDV metabolite
formed.[133] The lower clearance (1.57 vs 2.28
L/h/kg in healthy individuals) resulted in an in-
creased AUC (1670 vs 1387 μg/L • h, respectively)
and bioavailability (75%), a prolongation of t1⁄2
Clin Pharmacokinet 1999 Nov; 37 (5)
Effects of Liver Disease on Pharmacokinetics
(2.04 vs 1h) and a reduced AUC ratio of GZDV to
zidovudine (GZDV/zidovudine 2.8 vs 4.6).
The pharmacokinetic changes are more marked
in HIV seronegative patients with liver cirrhosis of
varying degrees.[134] In these patients (3 grade A,
5 grade B and 6 grade C Child-Pugh score) after a
single oral dose of zidovudine 200mg, a 4-fold de-
crease in the CL/F of zidovudine compared with
healthy individuals was observed. As a conse-
quence of the reduced clearance, there was a 4-fold
increase in AUC, a more than 2-fold prolongation
of t1⁄2 and a 4-fold reduction in the AUC ratio of
GZDV to zidovudine. The patients were consid-
ered as whole group because there was a great inter-
individual variability of kinetic parameters among
the 3 groups of patients and no clear difference in
parameters could be established among the groups;
in addition, the number of patients was small. In
another study,[135] AIDS patients with liver disease
(type of disease not specified) had pharmacoki-
netic changes comparable to those observed in the
latter study.[134]
The findings of these studies suggest that in
AIDS patients with hepatic impairment, dosage ad-
justments of zidovudine may be necessary. I rec-
ommend dosage reduction or prolongation of the
dosage interval; the dosage could be halved or the
interval between doses doubled. If this is not done,
repeated administration may lead to an excessive
accumulation of the drug increasing the risk of tox-
icity. It is of note that the glucuronidation of
zidovudine is affected whatever the severity of
liver disease, even when impairment is mild.
10. Immunosuppressants
10.1 Cyclosporin
Cyclosporin is a lipophilic cyclic endecapeptide
with potent immunosuppressive properties used to
prevent the rejection of transplanted organs and the
treatment of autoimmune disorders.[136] Because
of the poor absorption of standard formulation
cyclosporin from the intestine, bioavailability is
about 30%, with the binding to plasma lipoproteins
being about 34%. To overcome this problem a new
© Adis International Limited. All rights reserved.
419
formulation has been developed:[137] it is a micro-
emulsion which results in a more extensive and
faster absorption. Even though some presystemic
metabolism occurs in the gastrointestinal mucosa,
the drug is mainly metabolised in the liver by
CYP3A.
Impaired liver function results in a decrease in
cyclosporin elimination. This has been shown in
several studies. Renal transplant patients with im-
pairment of liver function[138] had a reduction in
CLp (0.525 vs 0.786 L/h/kg in patients with normal
liver function) and a 30 to 50% increase in AUC.
The impaired hepatic function in 5 patients with
cirrhosis[139] after an infusion of cyclosporin 2
mg/kg over more than 2 hours resulted in a marked
decrease in CL (0.146 L/h/kg) and in a longer t1⁄2
(32h) as compared with patients with renal or bone
marrow transplants.
The kinetics of cyclosporin 3 mg/kg intrave-
nously were studied in 5 liver transplant recipients
prior to transplantation and 1 to 3 months post-
transplantation, when hepatic function was consid-
ered stable.[140] Comparing pre- and post-transplant,
there was an increase in CL (0.21 to 0.37 L/h/kg)
and a decrease in AUC (15 737 to 8811 μg/L • h)
as liver function stabilised, the post-transplant val-
ues being consistent with those in healthy volun-
teers.
Cyclosporin has a narrow therapeutic range
with a number of toxic effects, which are largely
concentration dependent. The risks of rejection and
toxicity vary inversely with increases or decreases
in cyclosporin concentrations. Dosage adjustments
are necessary according to the status of liver func-
tion.
10.2 Tacrolimus
Tacrolimus is a novel macrocyclic lactone with
potent immunosuppressive properties used for pro-
phylaxis of organ rejection after transplanta-
tion.[141] Approximately 25% of the oral dose is
available. This low bioavailability can be caused
by either poor oral absorption or gut metabolism.
Tacrolimus is, in fact, a low clearance drug (blood
clearance of about 6 L/h). The binding to plasma
Clin Pharmacokinet 1999 Nov; 37 (5)
420
proteins is between 72 and 77%. Tacrolimus is
completely metabolised by hepatic CYP3A to sev-
eral metabolites mainly excreted via the bile, which
have a lower immunosuppressive activity than the
parent drug.
Impairment of liver function affects the elimi-
nation of tacrolimus. After infusion of tacrolimus
0.15 mg/kg or an oral dose of 0.15 mg/kg, patients
with moderate to severe liver impairment had a re-
duced CL (one-third or less than normal), a many-
fold longer t1⁄2 (38.5h) and a higher oral bioavaila-
bility (36%), the changes depending on the severity
of liver dysfunction.[142] During the immediate
postoperative period following orthotopic liver
transplantation, 9 patients received a continuous
infusion of tacrolimus 0.15 mg/kg/day for 3 to 6
days.[143] There was a high variability in the phar-
macokinetic parameters, which was attributed to
the variability in the functional status of the liver
in patients after transplantation.
Elevated plasma concentrations of tacrolimus
have been found in transplanted patients with im-
paired liver function[144,145] and were associated
with a higher incidence of nephrotoxicity (renal
failure).[145,146] In patients with liver dysfunction,
high concentrations of tacrolimus metabolites have
been observed, indicating impaired biliary excre-
tion of metabolites.[147]
Tacrolimus is a drug with a narrow therapeutic
index. To avoid overdose and the resulting toxicity,
close monitoring of patients with impaired liver
function and appropriate dosage adjustments, with
both oral and intravenous formulations, is neces-
sary.
11. Miscellaneous Agents
11.1 Naltrexone
Naltrexone is a potent competitive antagonist of
opioids at the receptor level and is used for the
treatment of patients with heroin addiction to pre-
vent relapse.[148] Its oral bioavailability ranges be-
tween 5 and 60% because of its extensive first-pass
metabolism in the liver; the plasma protein binding
is about 20%. It is mainly biotransformed by the
© Adis International Limited. All rights reserved.
Rodighiero
liver via reduction and glucuronidation, the main
metabolite being the active 6β-naltrexol.
Heroin addicts are likely candidates for chronic
liver disease. Thus, it is important to assess the ef-
fects of liver impairment on the pharmacokinetics
of naltrexone. A single oral dose of naltrexone
100mg was given to 11 patients with cirrhosis (6
with decompensated cirrhosis, Child-Pugh class C,
and 5 with compensated cirrhosis, Child-Pugh
class A and B).[149] Patients with decompensated
cirrhosis had a marked increase in the systemic
availability of naltrexone as shown by a greatly
increased AUC (1610 vs 200 μg/L • 24h in controls)
and an impaired conversion of naltrexone to 6β-
naltrexol; patients with compensated cirrhosis had
similar changes but to a lesser extent. The pharma-
cokinetic alterations paralleled the degree of liver
disease severity.
Adjustments of naltrexone dosage are advisable
in patients with liver dysfunction. It is probably
better to avoid the use of naltrexone in patients with
severe liver impairment because of these marked
alterations in pharmacokinetics.
11.2 Tolcapone
Tolcapone is a potent, specific reversible inhib-
itor of catechol-O-methyltransferase (COMT), an
enzyme that metabolises levodopa. It is used for the
management of patients with Parkinson’s disease.
The oral bioavailability is about 68% and the protein
binding is approximately 87 to 88%.[150] Tolcapone
is a drug with a low extraction and is almost com-
pletely metabolised, largely via glucuronidation to
an inactive metabolite.
Tolcapone was given as single doses, 200mg
orally and 50mg intravenously, to 8 patients with
moderate noncirrhotic liver disease (type of dis-
ease not specified), 8 patients with moderate liver
cirrhosis (Child-Pugh class A) and 8 healthy indi-
viduals.[150] Although total tolcapone bioavaila-
bility, CL and volume of distribution were similar
in the 3 groups, the kinetics of unbound tolcapone
were modified in the 2 groups of patients, particu-
larly in patients with moderate cirrhosis. The patients
had an increased unbound fraction of drug because
Clin Pharmacokinet 1999 Nov; 37 (5)
Effects of Liver Disease on Pharmacokinetics
of a decrease in albumin levels (unbound fraction
0.20% in the patients with cirrhosis, 0.14% in non-
cirrhotic disease, 0.12% in controls). The CL/F and
the volume of distribution at steady-state (Vss) of un-
bound drug were markedly decreased (CL/F 3830
L/h in patients with cirrhosis, 5528 L/h in patients
with noncirrhotic liver disease and 6874 L/h in
controls; Vss 4787, 6050 and 7371L, respectively).
Thus, it can be expected that the average con-
centration of unbound tolcapone would be twice as
high in patients with cirrhosis than in those with
healthy liver function. Therefore, the dosage of the
drug can be reduced by 50% in patients with mod-
erate cirrhosis. Further studies are needed to assess
the kinetics of tolcapone in patients with severe
hepatic impairment. A drawback of this study is the
heterogeneity of liver diseases considered.
11.3 Toremifene
Toremifene is a nonsteroidal estrogen antago-
nist used in the treatment of patients with breast
cancer.[148] It exerts antitumour activity by specific
and competitive inhibition of the binding of estro-
gen to its receptor. Toremifene has a bioavailability
of about 100% and it is >99% bound to plasma
proteins, mainly albumin. It is extensively metabo-
lised in the liver by CYP3A. Thus, liver function
should be considered when evaluating the pharmaco-
kinetics of toremifene in clinical practice.
Ten patients with impaired liver function (de-
gree not specified) due to alcoholic liver disease
had a significantly decreased drug elimination af-
ter a single oral dose of toremifene 120mg as
shown by the reduced CL/F (3.7 vs 5.1 L/h in
healthy individuals), increased AUC (44.5 vs 28.4
mg/L • h) and prolonged t1⁄2 (10.9 vs 6.2 days).[149]
Caution is advised when toremifene is adminis-
tered to patients with liver impairment; a lower
dosage is recommended.
12. Clinical Implications
12.1 Altered Pharmacokinetics
The studies reported above have shown that
liver disease impairs the kinetics of many drugs.
© Adis International Limited. All rights reserved.
421
There are different types of liver disease but most
studies have examined the disposition of drugs in
patients with liver cirrhosis, especially alcoholic
cirrhosis and, less frequently, chronic hepatitis.
This is probably because cirrhosis and chronic hep-
atitis are among the more widespread types of liver
pathology. The data have shown that the pharmaco-
kinetics can be altered even in patients with mild
liver impairment. Data on hepatic drug elimination
in patients with primitive or metastatic cancer are
scanty,[4] but the pharmacokinetics do not appear
to be affected when the only liver pathology is can-
cer without complications.
Changes in pharmacokinetics depend on the se-
verity of liver disease. However, many of the stud-
ies compared patients with different degrees of
liver impairment, in others the degree of severity
was not reported and in some studies patients with
different types of liver disease were grouped to-
gether. Thus, it is not easy to generalise from indi-
vidual studies. In addition, the number of participants
included in several studies was small. There was a
tendency to use small samples in these studies, and
thus caution should be used in drawing conclu-
sions.
Usually, the kinetics of drugs are evaluated in
patients having only liver disease. However, these
drugs are used to treat other diseases, such as car-
diovascular illnesses, psychiatric disorders and so
on. These diseases can themselves cause patho-
physiological changes in the body, which can af-
fect the kinetics of the drug administered because
the drug is not working in a normal environment.
It would be more appropriate, for instance, to study
the kinetics of an antidepressant agent in patients
with liver disease and depression using a control
group of patients with depression. The results
would be more consistent.
Very often, in studies evaluating the influence
of liver disease on pharmacokinetics the total drug
clearance is measured and drug binding to plasma
proteins is not considered. Liver disease can de-
crease plasma proteins, with a consequent increase
in unbound drug for high extraction ratio drugs. A
significant decrease in the clearance of unbound
Clin Pharmacokinet 1999 Nov; 37 (5)
422
drug, with little or no change in total drug clear-
ance, was observed when the unbound drug con-
centration was taken into consideration.[150,151] The
recommendation to lower the dosage should, there-
fore, be based on the clearance of the unbound drug
rather than on total clearance. To measure only total
drug clearance could be deceiving.
Most of the studies reported are single dose
studies. In clinical practice, patients are commonly
treated for a prolonged period of time. Upon repeated
administration the drug accumulates until it reaches
a steady-state concentration; the length of time to
steady state varies depending on the half-life of the
drug. When drug clearance is reduced, and bio-
availability and half-life are increased by liver dis-
ease, the drug accumulates at a higher rate and
reaches a higher steady-state concentration in a
longer time as compared with healthy individuals.
Thus, excessive accumulation of the drug can occur
after several doses, increasing the risk of toxicity
and exaggerating the pharmacological effect if a
normal dosage of the drug is used.
According to the available data, the kinetics of
many drugs are altered enough in patients with
liver disease to require dosage adjustment. This can
be accomplished by reducing the dosage but main-
taining a normal administration interval, or by
lengthening the interval with a normal dose, or
changing both the dose and the interval. The prob-
lem is to quantify these changes.
It is obvious that the degree of hepatic impairment
should be evaluated to adjust the dosage, but the
problem is how. Unlike creatinine clearance for the
kidney, at present there is no clinical laboratory test
which gives a quantitative measure of liver function
and the degree of its impairment. In addition, there
is no clear correlation between routine liver func-
tion tests and the capacity of the liver to metabolise
drugs. Usually, changes in pharmacokinetic param-
eters do not correlate well with the indicators of
liver function impairment. Liver biopsy is commonly
used in patients with chronic hepatitis and cirrhosis
to evaluate the severity of disease; however, histo-
logical findings can be misleading, especially if ad-
© Adis International Limited. All rights reserved.
Rodighiero
equate tissue is not obtained to exclude sampling
errors.
Dynamic tests of liver function have long been
used. Such tests include measuring the plasma
clearance of antipyrine, ICG, galactose and SBP.
However, these tests are cumbersome for clinical
purposes and may not accurately reflect changes in
liver histological status and the severity of liver
disease. The SBP test has been largely abandoned
in clinical use because severe systemic reactions,
possibly fatal, can occur.[152] Another method
widely used is the Child-Turcotte and the Child-
Pugh classification.[11,12] These classifications are
semiquantitative tests of liver function, but do not
provide an accurate evaluation of hepatic impair-
ment.[153,154] They are somewhat empirical and the
evaluation of the scores in clinical practice can be
subjective. More recently, because of the greater
understanding of pharmacokinetics, probe drugs
have been used as quantitative tests of liver func-
tion and the degree of liver impairment, especially
in relation to CYPs.[155] These drugs are probes for
specific enzymes, whereas antipyrine, ICG, galac-
tose and SBP are considered general metabolic
probes. In addition to the ethical problems and safety
of probe drugs, the metabolism of probe drugs is
affected by genetic and environmental factors (to-
bacco smoking, alcohol consumption, concomitant
drugs and genetic polymorphism). These factors
should be taken into consideration to avoid mis-
leading results when a drug is used as a probe.
In conclusion, at present there is no single sat-
isfactory test which gives a quantitative measure of
liver function and impairment. In the clinical set-
ting more than one single test is needed to evaluate
the severity of liver disease.
Besides the use of clinical tests, some criteria
can provide a rational basis for determining dosage
adjustment. It is important to make a careful eval-
uation of the clinical situation of the patient to as-
certain what type of pathophysiological changes
has caused liver disease (hepatic failure, reduced
liver blood flow or portosystemic shunting). A fun-
damental factor is the type of drug administered
(drug with a low or high hepatic extraction, protein
Clin Pharmacokinet 1999 Nov; 37 (5)
Effects of Liver Disease on Pharmacokinetics
binding), because the effect of liver disease de-
pends on the type of drug. Drugs with a low hepatic
extraction are not sensitive to liver blood flow
changes but to variations of the activity of drug-
metabolising enzymes, whereas drugs with a high
hepatic extraction are sensitive to liver blood flow
changes. In any case, a close observation of the
patient’s response to the drug is mandatory; there
is an interindividual variability in the response.
Plasma drug concentrations, mainly unbound
drug, should be monitored whenever it is possible
and useful. An adequate knowledge is needed of
the kinetic changes caused by liver disease for the
particular drug. The pharmacokinetic parameters
of the drugs discussed in this review are reported
in table I for ease of reference. In general, I would
advise caution in the administration of drugs me-
tabolised by the liver to patients with hepatic im-
pairment. I recommend that the drug should be
started at lower dosages and that the dosage should
be adjusted to the patient’s clinical response, with
the help of plasma drug concentration monitoring
when applicable.
12.2 Altered Pharmacodynamics
Finally, it is important to consider that liver dis-
ease not only affects the pharmacokinetics but also
the pharmacodynamics of drugs. Hepatic patients
have a greater sensitivity to a number of drugs,
especially drugs acting on the CNS, resulting in an
altered response.[156] Therefore, in adjusting drug
dosage in these patients both pharmacokinetic and
pharmacodynamic changes should be taken into
consideration. Some drugs reported in this review
have abnormal pharmacodynamics in hepatic dis-
ease; only these will be examined in detail.
Patients with cirrhosis usually have a resistance
to loop diuretics, a diminished response because of
pharmacodynamic alterations.[157] This has been
observed with torasemide. In healthy individuals
the relationship between the urinary excretion of
torasemide and the natriuretic response is charac-
terised by a sigmoidal curve,[157] but in cirrhotic
patients with ascites the curve is shifted downward
and to the right.[67] Thus, the diuretic response in
© Adis International Limited. All rights reserved.
423
these patients is lower than normal. The mecha-
nism of this pharmacodynamic abnormality is not
clear.[66] Probably, in these patients the reabsorp-
tion of sodium in the proximal tubule is increased,
leaving a smaller amount of sodium to the loop of
Henle, which is the site of action of torasemide.
Thus, the saluretic effect of torasemide is dimin-
ished.
There is evidence that patients with cirrhosis are
more sensitive to triazolam than healthy individu-
als; they have an increased cerebral sensitivity to
this drug.[78] Psychometric tests of CNS performance
(flicker sensitivity, digit symbol substitution test
and pursuit rotor) were given to patients with cir-
rhosis and healthy individuals before triazolam ad-
ministration and again when plasma concentra-
tions of unbound drug were the same in the 2
groups (i.e. 2.25h after administration). Prior to ad-
ministration the performance in the tests was sim-
ilar in both groups and it was not influenced by
cirrhosis per se. At 2.25h after administration the
patients with cirrhosis had a significant higher
average impairment in the performance of tests
(30% greater than the controls). This impairment
can be considered evidence of the brain’s hyper-
sensitivity to triazolam in patients with cirrhosis
and is not caused by altered pharmacokinetics. The
mechanism underlying this hypersensitivity re-
mains to be explained.
CNS effects represent an important adverse ef-
fect of the quinolones.[158] They include headache,
dizziness, agitation, sleep disorders and, rarely,
convulsions. These effects have been correlated
with the binding of quinolones to GABA receptors
in the brain, thus inhibiting GABA and increasing
the excitability of CNS. Cases of grand mal sei-
zures have been reported in patients with severe
cirrhosis who received pefloxacin at the usual dos-
age of 400mg twice daily.[159] The increased pene-
tration of pefloxacin into the CNS because of the
increased permeability of the blood-brain barrier
in patients with cirrhosis could favour the develop-
ment of grand mal seizures. When liver cirrhosis is
severe it is probably better to avoid the use of
pefloxacin. Increased penetration into the CNS in
Clin Pharmacokinet 1999 Nov; 37 (5)
 Table I. Pharmacokinetic parameters of drugs in patients with hepatic disease. Values for healthy individuals are in parentheses. Values for clearance are all corrected for 70kg
424
bodyweight and are systemic clearances (CL) unless otherwise indicated. Values for the apparent volume of distribution are corrected for 70kg bodyweight
Drug Disease n fm (%) fu (%) F (%) CL (L/h/70kg) CLu (L/h/70kg) Vss (L/70kg) t1 ⁄2 β (h) References

Cardiovascular agents
Angiotensin converting enzyme inhibitors
Quinalapril The conversion of these prodrugs to the active form is reduced in patients with cirrhosis 32-35
Cilazapril
Enalapril
Angiotensin II receptor antagonists
Irbesartan C, both mild and moderate 10 (10) >99 10a 22
Losartan C >90 <10 ↓50% 37

© Adis International Limited. All rights reserved.

Calcium antagonists
Felodipine C 9 (23) >99 <1 178b (580) 392 (721) 16.3 (11) 41
Gallopamil C 6 93 7 60 109 11 44
Nicardipine C 9 (8) >99 1-2 13.7 (1.6) 45
Nifedipine C 7 (7) 99 2-4 90.5 (51.1) 13.9 (35.3) 7 (1.85) 46
Nimodipine C 6 (5) >99 2 217b (519) 48
Nisoldipine C 8 (8) >90 <1 14.7 (3.7) 29.6b (50.8) 16.6 (9.7) 49
Nitrendipine C 11 >90 2 51.16c 51
CH 5 (6) 50.4c (77.36c)
54 41.2d
48 (40) 44.1d (82.7d)
Ketanserin C 26 (10) 99 5 17.5 (33.9) 10.1 (14.3) 54
Antiarrhythmics
Flecainide C 6 (6) 75 60-70 16.0 (38.2) 49 (9.5) 56
Mexiletine C 6 (6) 85-92 30 9.66 (34.7) 28.7 (9.9) 59
Propafenone C 11 >90 4 Higher Lower 61
Hypolipidaemics
Fluvastatin C 11 (11) 98 1 ↓28%b ↓31% 63
Pravastatin C 53 50 Lower 65

Diuretics
Torasemide C + ascites 12 (12) 80 <1 96 2.27 (2.52) CLR 0.55 (0.38) 24 (11.7) 8.1 (3.6) 67

Psychoactive and anticonvulsant agents

Benzodiazepines
Alprazolam C 17 (17) >90 17-21 2.35b (5.12) 19.7 (11.4) 70
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Clin Pharmacokinet 1999 Nov; 37 (5)

 Midazolam C - moderate 10 (9) >90 5 24.1 (38.2) 2.8 (2.25) 74
C - severe 7 (8) 22.7 (54.1) 3.09 (1.6) 75
C - severe 7 (7) 76 (38) 14.0 (23.6) 7.36 (3.80) 76
Triazolam C 8 (7) >90 11 21.0b (28.1) 77
C - severe 8 (18) CL/Fu 62.2 (100.4) 78
Flumazenil C 8 (8) >99 50-60 65 (27) 42 (72) 64 (68) 81
Antidepressants
Fluvoxamine C 13 96 33 54.6b 24.7 84
Fluoxetine C 13 (12) 95-97 5 17.6b (40.3) 6.6 (2.2) days 86
Norfluoxetine C 13 (12) 5.9 (8.4) 12 (6.4) days 86
Paroxetine C 12 (6) 98-99 5 83 (36) 89

© Adis International Limited. All rights reserved.

Nefazodone C 12 >90 <1 Decreased 91
C 12 Decreased 92
Effects of Liver disease on Pharmacokinetics

Moclobemide C 12 (14) >99 50 84 (56) 14.6 (37.7) 75.7 (84.1) 94

Anticonvulsants
Tiagabine C - mild 7 97 4 11.7 96
C - moderate 6 15.9
(6) (6.5)

Antiemetics
Metoclopramide C - severe 8 (8) 80 60 84 (79) 11.2 (23.8) 3.1 (3.4) 15.4 (7.2) 98
C - severe 18 (12) 82 (60) 99
Ondansetron CLD - mild 19 >95 24-30 12.6 224 9.1 101
CLD - moderate 17.6 230 9.2
CLD - severe 5.38 179 20.6
(6) (28.6) (153) (3.6)
CLD - mild 12 80 1411b 10 102
CLD - moderate 78 1495b 13
CLD - severe 98 987b 20
(12) (60) (3121)b (6)
Tropisetron C - mild to moderate 10 (10)a 52-66 29-41 104

Antiulcers
Proton pump inhibitors
Lansoprazole C - compensated 8 >95 <5 2.77b 24.5 6.1 108
C - uncompensated 8 0.67b 38.5 7.2
(18) (18.2) 31.0 1.4
Continued over page
425

Clin Pharmacokinet 1999 Nov; 37 (5)

 Table I. Contd
426
Drug Disease n fm (%) fu (%) F (%) CL (L/h/70kg) CLu (L/h/70kg) Vss (L/70kg) t1 ⁄2 β (h) References

Pantoprazole C 12 >95 <5 Lower Higher 110

Omeprazole C - mild 3 >95 <5 2.96 112
C - moderate 4 0.72
C - severe 1 98 4.0
(18) (56) (35.6)
C 8 (8) 5.84b (47.9b) 2.85 (0.73) 114

Antimicrobials and antiretrovirals

Grepafloxacin HI - mild 10 90-94 50 23.1b 13 121
HI - moderate 10 14.9b 19

© Adis International Limited. All rights reserved.

(12) (35.8b) (12)
Ornidazole C - severe 10 (10) >90 87-92 2.06 (3.02) 21.9 (14.1) 123
Pefloxacin C 16 (12) 85-90 70-80 186 (571) 35.1 (11.0) 126
Stavudine C 5 60a 130
Zidovudine CH 8 (6) 80-86 75 1.55b (2.27b) 2.04 (1.0) 133

Immunosuppressants
Cyclosporin HI >90 66 36.8 (55.0) 138
Pre-transplantation 14.7 140
Post-transplantation 25.9
Tacrolimus HI - moderate to severe 5 >99 23-28 36 38.5 142

Miscellaneous drugs
Tolcapone C 8 >80 12-13 70 7.27 3826 1.2 150
NCLD 8 (8) 72 7.48 5527 1.2
(8) (68) (8.27) (6871) (1.1)
Toremifene ALD 10 (10) High <1 3.70 (5.08) 10.9 (6.2) 149

a No significant differences compared to healthy individuals.

b Apparent clearance (CL/F).
c Single intravenous dose.
d Oral for 7 days.
ALD = alcoholic liver disease; C = cirrhosis; CH = chronic hepatitis; CLD = chronic liver disease; CLR = renal clearance; CLu = clearance of unbound drug; F = oral bioavailability;
fm = fraction metabolised; fu = fraction of unbound drug in plasma; HI = hepatic impairment; IV = intravenous; n = number of patients and (healthy individuals); NCLD = noncirrhotic
liver disease; t1⁄2β = elimination half-life; Vss = volume of distribution at steady state; ↓ = decrease.
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Clin Pharmacokinet 1999 Nov; 37 (5)

Effects of Liver Disease on Pharmacokinetics
hepatic disease has also been reported for cimeti-
dine and ranitidine, again with the occurrence of
mental disturbances.[117,119]
13. Conclusions
The pharmacokinetics of many types of drugs
metabolised by the liver are modified in patients
with hepatic disease. Liver disease can affect the
pharmacokinetics by: (i) reducing the activity of
drug metabolising enzymes; (ii) reducing the syn-
thesis of plasma proteins; or (iii) changing liver
blood flow. The pharmacokinetic modifications
depend on the characteristics of the drug (low or
high hepatic extraction, protein binding) and the
severity of liver disease. The problem is to quantify
the degree of severity because, at present, there is
no single satisfactory test which gives a quantita-
tive measure of liver function and degree of im-
pairment. A promising development is the study of
CYP isoforms, which is a rapidly expanding area
in pharmacology and is concerned with the identi-
fication and characterisation of individual CYP
isoforms. Several drugs metabolised by specific
CYP isoforms have been used as probes for quan-
titative tests of liver function and degree of hepatic
impairment.
Because the kinetics of many drugs are altered
by liver disease to an extent that requires dosage
adjustment, guidelines providing a rational basis
for the required changes have been suggested.
However, it should be noted that liver disease af-
fects not only pharmacokinetics but also pharma-
codynamics.
In order to improve our knowledge of the kinet-
ics of drugs in patients with liver disease, the follow-
ing aspects should be considered when designing
studies in this patient population.
• The degree of liver impairment should be spec-
ified in the study.
• Patients with heterogeneous liver diseases
should not be grouped together. However, pa-
tients with varying degrees of hepatic impair-
ment should be included as separate groups.
• An adequate number of patients should be in-
cluded to enable any differences to be identified.
© Adis International Limited. All rights reserved.
427
• Repeated administration of the drug under in-
vestigation should be studied, as this would be
more clinically relevant than the use of a single
dose.
• The clearance of the unbound drug rather than
total drug clearance should be measured, be-
cause unbound drug concentrations may be in-
creased by liver impairment.
• When the drug being studied is used to treat a
concomitant disease (e.g. depression) then the
kinetics of the antidepressant agent should be
assessed in patients with liver disease and de-
pression using a control group of patients with
depression. This should be done as the concur-
rent disease may cause pathophysiological
changes in the body, which can affect the phar-
macokinetics.
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Correspondence and reprints: Dr Vanni Rodighiero,
Dipartimento di Farmacologia, Università di Padova,
Largo E. Meneghetti 2, 35131 Padova, Italy.
Clin Pharmacokinet 1999 Nov; 37 (5)