Drug Metabolism Reviews
ISSN: 0360-2532 (Print) 1097-9883 (Online) Journal homepage: http://www.tandfonline.com/loi/idmr20
Drug Disposition and Liver Disease G. R. Wilkinson & S. Schenker To cite this article: G. R. Wilkinson & S. Schenker (1975) Drug Disposition and Liver Disease, Drug Metabolism Reviews, 4:2, 139-175, DOI: 10.3109/03602537508993754 To link to this article: http://dx.doi.org/10.3109/03602537508993754
Published online: 22 Sep 2008.
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Date: 06 May 2016, At: 11:04
DRUG METABOLISM REVIEWS, 4(2), 139-175 (1975)
Downloaded by [Australian National University] at 11:04 06 May 2016
Drug Disposition and liver Disease G. R. WILKINSON and S. SCHENKER Departments of Pharmacology and Medicine Vanderbilt University Medical School Nashville, Tennessee 37232
.. . .. .. . . . . . . . . , . . . . .. . . . . . . . STUDY DESIGN.. A. Clinical Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Pharmacokinetic Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . STUDIES OF DRUG DISPOSITION. . . . . . . . . . . . . . . . . . . . . . . . . A. Hepatitis and Cirrhosis, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Cholestasis.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . C. DrugInduced Hepatic Dysfunction . . . . . . . . . . . . . . . . . . . . . . . PREDICTION OF CHANGES IN DRUG DISPOSITION . . . . . . . . . A. Biochemical Function Tests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. In vitro Drug Metabolizing Activity . . . . . . . . . . . . . . . . . . . . . . .
I. INTRODUCTION. . . . 11.
,
140 141 144
154 155 164 164 165 IV. 167 168 C. ModelD............................................ 169 V. CLINICAL SIGNIFICANCE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 111.
,
VI. CONCLUSIONS.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
172
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
172
I. INTRODUCTION
An important goal in therapeutics is the design of a suitable drug dosage regimen providing the desired clinical effect without undue toxicity. A major difficulty in achieving this goal is a large interpatient variability in the response to a standard dose of many drugs,
139 Copyright 0 1976 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may he reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording. or by any information storage and retrieval system, without permission in writing from the publisher.
Downloaded by [Australian National University] at 11:04 06 May 2016
140
WILKINSON AND SCHENKER
It is generally considered that these variations in response a r e due to individual differences in the rate and extent of the processes of drug absorption, distribution, metabolism, and excretion. Consequently, there has been an increased interest in recent years to individualize drug therapy based upon pharmacokinetic consideration [l-41. It is now well recognized that genetic constitution, age, prior exposure to environmental pollutants, and drugs that are concomitantly administered may all significantly alter the disposition and elimination of a particular drug. A priori, it may also be expected that various disease states m a y also influence such processes, particularly if organs involved in drug elimination are affected. Considerable experimental data and clinical experience exist concerning renal dysfunction and its effects upon drug disposition [5]. However, comparable information relative to the other major organ of drug elimination, the liver, is fragmentary and less extensive. The purpose of this review is to indicate some of the problems associated with the design and interpretation of studies performed to investigate the effects of liver disease on drug disposition and elimination, and which, therefore, contribute to this unsatisfactory situation. Additionally, the present state-of-knowledge of some important drugs that are, o r have been, used extensively for either the treatment o r diagnosis of patients with liver dysfunction will be summarized. 11. STUDY DESIGN Investigations of drug disposition and elimination in the presence of liver disease have obvious clinical implications, particularly when the liver is the major organ responsible for maintaining blood levels of a drug and, consequently, its intensity and duration of action. In the past it has been intuitively reasoned that, when hepatic elimination is an important route of drug removal, any dysfunction to this organ will automatically lead to a n impairment of the removal process. Support for this hypothesis, however, is limited to a few clinical case reports implying some effect of the pathologic condition and to a small group of drugs where some quantitative estimate of the elimination process has been attempted (Table 1). Disconcertingly, this data base shows little consistency; liver disease affects the elimination half-life of some drugs but not of others although all undergo extensive hepatic biotransformation. Furthermore, contradictions a r e apparent between various studies involving a number of drugs such as antipyrine, pentobarbital, phenylbutazone, and tolbutamide. Questions arise, therefore, concerning the appropriateness of the design and interpretation of some of the reported studies.
DRUG DISPOSITION AND LIVER DISEASE
141
TABLE 1 The Effect o f Parenchymal Liver Disease in Man on the Elimination Half-Life of Various Drugs
-__
Downloaded by [Australian National University] at 11:04 06 May 2016
Difference reported Acetaminophen Acetanilide Amylobarbi tal Antipyrine Carbenicillin Chloramphenicol Clindam ycin Diazepam Hex0 barbital Isoniazid Lidocaine Meperidine Meprobamate Pen to barbi tal Phenobarbital Phenylbu tazone Prednisone Rifamycin Tolbu tamide Theop h ylline
No difference reported
Arninopyrine An tipyrine Chloramphenicol Chlorpromazine Dicoumarol Diphenylhy dan toin Pen to barbi tal Phenyl bu tazone Salicylic Acid Tolbutamide
1321 321 33 1 34 1 321 35 1 36 1 32,37,38] 321 391
A . Clinical Considerations
Human liver disease consists of an assortment of inflammatory, degenerative, o r neoplastic insults to the hepatic parenchyma and biliary tree, in addition to disturbances in the perfusion of the organ. Most of these abnormalities are unique to man, and suitable animal models for human cirrhosis and viral hepatitis are either not available o r very difficult to establish. Thus the study of drug disposition in the context of liver disease is limited to patients with the attendant clinical and ethical constraints. It is this difficulty to select and cont r o l the investigative system that is probably the most important factor in the inconsistency and contradiction of the various published reports A s indicated previously, liver disease is not a single entity but a collection of various structural and functional disabilities. Damage to the organ varies widely from one patient to another with respect to parenchymal synthetic and metabolic function, biliary excretion, and hemoperfusion; all factors which have been shown to have separate and potentially additive o r competitive effects on drug disposi-
.
Downloaded by [Australian National University] at 11:04 06 May 2016
142
WILKINSON AND SCHENKER
tion. Furthermore, the clinical and laboratory criteria for diagnosing the state and rating the severity of any particular c l a s s of liver disease a r e relatively crude. The importance of adequate classification of the patient population is well exemplified by studies with antipyrine LlZ]. There is a significant increase in the mean serum halflife of this drug in patients with liver disease a s compared to a normal control group (Fig. 1). Substratification of the patients according to their clinical diagnosis demonstrates, however, that patients with obstructive jaundice and acute hepatitis have a much lesser degree of impairment than those with cirrhosis and chronic active hepatitis. Unfortunately, many reported studies have neglected to provide suitably complete information to allow adequate characterization of the liver disease state. NORMAL
ALL LIVER
CHRONIC ACUTE CIRRHOSIS ACTIVE H E P A T ~ T ~ s ~ ~ ~ ~ $ ~ ~ ' HEPATITIS
50
'c
40
3 0
- 30 I
w
-
LL
-I LL -I
20
a
=
10
. 1 4 P
ISSN: 0360-2532 (Print) 1097-9883 (Online) Journal homepage: http://www.tandfonline.com/loi/idmr20
Drug Disposition and Liver Disease G. R. Wilkinson & S. Schenker To cite this article: G. R. Wilkinson & S. Schenker (1975) Drug Disposition and Liver Disease, Drug Metabolism Reviews, 4:2, 139-175, DOI: 10.3109/03602537508993754 To link to this article: http://dx.doi.org/10.3109/03602537508993754
Published online: 22 Sep 2008.
Submit your article to this journal
Article views: 24
View related articles
Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=idmr20 Download by: [Australian National University]
Date: 06 May 2016, At: 11:04
DRUG METABOLISM REVIEWS, 4(2), 139-175 (1975)
Downloaded by [Australian National University] at 11:04 06 May 2016
Drug Disposition and liver Disease G. R. WILKINSON and S. SCHENKER Departments of Pharmacology and Medicine Vanderbilt University Medical School Nashville, Tennessee 37232
.. . .. .. . . . . . . . . , . . . . .. . . . . . . . STUDY DESIGN.. A. Clinical Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Pharmacokinetic Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . STUDIES OF DRUG DISPOSITION. . . . . . . . . . . . . . . . . . . . . . . . . A. Hepatitis and Cirrhosis, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Cholestasis.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . C. DrugInduced Hepatic Dysfunction . . . . . . . . . . . . . . . . . . . . . . . PREDICTION OF CHANGES IN DRUG DISPOSITION . . . . . . . . . A. Biochemical Function Tests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. In vitro Drug Metabolizing Activity . . . . . . . . . . . . . . . . . . . . . . .
I. INTRODUCTION. . . . 11.
,
140 141 144
154 155 164 164 165 IV. 167 168 C. ModelD............................................ 169 V. CLINICAL SIGNIFICANCE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 111.
,
VI. CONCLUSIONS.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
172
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
172
I. INTRODUCTION
An important goal in therapeutics is the design of a suitable drug dosage regimen providing the desired clinical effect without undue toxicity. A major difficulty in achieving this goal is a large interpatient variability in the response to a standard dose of many drugs,
139 Copyright 0 1976 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may he reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording. or by any information storage and retrieval system, without permission in writing from the publisher.
Downloaded by [Australian National University] at 11:04 06 May 2016
140
WILKINSON AND SCHENKER
It is generally considered that these variations in response a r e due to individual differences in the rate and extent of the processes of drug absorption, distribution, metabolism, and excretion. Consequently, there has been an increased interest in recent years to individualize drug therapy based upon pharmacokinetic consideration [l-41. It is now well recognized that genetic constitution, age, prior exposure to environmental pollutants, and drugs that are concomitantly administered may all significantly alter the disposition and elimination of a particular drug. A priori, it may also be expected that various disease states m a y also influence such processes, particularly if organs involved in drug elimination are affected. Considerable experimental data and clinical experience exist concerning renal dysfunction and its effects upon drug disposition [5]. However, comparable information relative to the other major organ of drug elimination, the liver, is fragmentary and less extensive. The purpose of this review is to indicate some of the problems associated with the design and interpretation of studies performed to investigate the effects of liver disease on drug disposition and elimination, and which, therefore, contribute to this unsatisfactory situation. Additionally, the present state-of-knowledge of some important drugs that are, o r have been, used extensively for either the treatment o r diagnosis of patients with liver dysfunction will be summarized. 11. STUDY DESIGN Investigations of drug disposition and elimination in the presence of liver disease have obvious clinical implications, particularly when the liver is the major organ responsible for maintaining blood levels of a drug and, consequently, its intensity and duration of action. In the past it has been intuitively reasoned that, when hepatic elimination is an important route of drug removal, any dysfunction to this organ will automatically lead to a n impairment of the removal process. Support for this hypothesis, however, is limited to a few clinical case reports implying some effect of the pathologic condition and to a small group of drugs where some quantitative estimate of the elimination process has been attempted (Table 1). Disconcertingly, this data base shows little consistency; liver disease affects the elimination half-life of some drugs but not of others although all undergo extensive hepatic biotransformation. Furthermore, contradictions a r e apparent between various studies involving a number of drugs such as antipyrine, pentobarbital, phenylbutazone, and tolbutamide. Questions arise, therefore, concerning the appropriateness of the design and interpretation of some of the reported studies.
DRUG DISPOSITION AND LIVER DISEASE
141
TABLE 1 The Effect o f Parenchymal Liver Disease in Man on the Elimination Half-Life of Various Drugs
-__
Downloaded by [Australian National University] at 11:04 06 May 2016
Difference reported Acetaminophen Acetanilide Amylobarbi tal Antipyrine Carbenicillin Chloramphenicol Clindam ycin Diazepam Hex0 barbital Isoniazid Lidocaine Meperidine Meprobamate Pen to barbi tal Phenobarbital Phenylbu tazone Prednisone Rifamycin Tolbu tamide Theop h ylline
No difference reported
Arninopyrine An tipyrine Chloramphenicol Chlorpromazine Dicoumarol Diphenylhy dan toin Pen to barbi tal Phenyl bu tazone Salicylic Acid Tolbutamide
1321 321 33 1 34 1 321 35 1 36 1 32,37,38] 321 391
A . Clinical Considerations
Human liver disease consists of an assortment of inflammatory, degenerative, o r neoplastic insults to the hepatic parenchyma and biliary tree, in addition to disturbances in the perfusion of the organ. Most of these abnormalities are unique to man, and suitable animal models for human cirrhosis and viral hepatitis are either not available o r very difficult to establish. Thus the study of drug disposition in the context of liver disease is limited to patients with the attendant clinical and ethical constraints. It is this difficulty to select and cont r o l the investigative system that is probably the most important factor in the inconsistency and contradiction of the various published reports A s indicated previously, liver disease is not a single entity but a collection of various structural and functional disabilities. Damage to the organ varies widely from one patient to another with respect to parenchymal synthetic and metabolic function, biliary excretion, and hemoperfusion; all factors which have been shown to have separate and potentially additive o r competitive effects on drug disposi-
.
Downloaded by [Australian National University] at 11:04 06 May 2016
142
WILKINSON AND SCHENKER
tion. Furthermore, the clinical and laboratory criteria for diagnosing the state and rating the severity of any particular c l a s s of liver disease a r e relatively crude. The importance of adequate classification of the patient population is well exemplified by studies with antipyrine LlZ]. There is a significant increase in the mean serum halflife of this drug in patients with liver disease a s compared to a normal control group (Fig. 1). Substratification of the patients according to their clinical diagnosis demonstrates, however, that patients with obstructive jaundice and acute hepatitis have a much lesser degree of impairment than those with cirrhosis and chronic active hepatitis. Unfortunately, many reported studies have neglected to provide suitably complete information to allow adequate characterization of the liver disease state. NORMAL
ALL LIVER
CHRONIC ACUTE CIRRHOSIS ACTIVE H E P A T ~ T ~ s ~ ~ ~ ~ $ ~ ~ ' HEPATITIS
50
'c
40
3 0
- 30 I
w
-
LL
-I LL -I
20
a
=
10
. 1 4 P
