Drug metabolism in extrahepatic diseases

Pharmac. Ther. Vol. 35, pp. 375 to 404, 1987

0163-7258/87 $0.00+0.50 Copyright © 1987 Pergamon Journals Ltd

Printed in Great Britain. All rights reserved

Specialist Subject Editor: M. J. BRODIE

D R U G METABOLISM IN EXTRAHEPATIC DISEASES G. C. FARRELL Department of Medicine, University of Sydney, Westmead Hospital, Westmead, Sydney, NSW 2145, Australia

1. INTRODUCTION: GENERAL CONSIDERATIONS 1.1. INTERACTING EFFECTS OF DISEASE, ETIOLOGIC FACTORS AND THERAPEUTIC AGENTS

Alterations of hepatic drug metabolism occur in thyroid disease, diabetes mellitus, renal failure, infections and inflammatory states, cancer, and cardiopulmonary failure. In these and many other conditions such as epilepsy, peptic ulcer and asthma, treatment with pharmacological agents may also change rates of drug elimination by either inducing or inhibiting hepatic drug metabolizing enzymes (Park and Breckenridge, 1981). These treatment-induced effects on drug metabolism, usually of greater magnitude than any disease effects, are beyond the scope of this chapter. Factors which are of etiologic relevance for some diseases can also alter drug metabolism. For example, cigarette smoking, an etiologic factor for lung cancer, chronic obstructive pulmonary disease and myocardial infarction, enhances the hepatic metabolism of antipyrine (Hart et aL, 1976) and theophylline (Jenne et al., 1976; Hunt et al., 1976). Such etiologic factors will not be discussed here except when they could be the reason for the changes in drug metabolism observed in a particular disease. Similarly, the nutritional consequences of disease might cause an alteration in drug metabolism (Kappas et al., 1976; Krishnaswamy and Naidu, 1977) and this factor should be considered in relation to putative disease-specific effects. 1.2. HEPATIC DRUG METABOLISM IN RELATION TO DRUG EFFECTS, BLOOD LEVELS AND ELIMINATION RATES

Disease states may affect the pharmacologic response to a given concentration of drug at its effective site. Moreover, changes in gastrointestinal absorption, first pass hepatic clearance, drug binding to blood constituents, volume of distribution and hepatic and extrahepatic routes of drug elimination will alter effective blood levels of a drug. Extrahepatic diseases may influence one or more of these pharmacokinetic variables but in this review only changes in hepatic drug metabolism will be considered. The liver is the most important site for systemic drug metabolism. The significance of changes in drug metabolism will vary according to the hepatic intrinsic clearance of the agent under consideration as well as the metabolic pathway responsible for its biotransformation and the ultimate routes of excretion. In this review, oxidative pathways of hepatic drug metabolism will be considered almost exclusively because they appear to be most important and have been studied in greatest detail. Changes in the activity of drug metabolizing enzymes of extrahepatic tissues might alter the susceptibility of those organs to drug-induced toxicity or to carcinogenesis but would not usually be expected to affect drug metabolic clearance rates. 1.3. USE OF ANIMAL MODELS A recurring theme of this review will concern the dearth of satisfactory studies of hepatic drug metabolism in patients with extrahepatic diseases. Human studies are the 375

376

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FIG. 1. Potential mediators of altered hepatic drug metabolism in various diseases. In normal subjects, rates of drug metabolism are genetically determined but can be modified by many humoral, hormonal, nutritional and environmental factors. This diagram depicts some of these factors in relation to extrabepatic disease states which can be associated with altered rates of systemic drug metabolism. T4, thyroxine; T3, triiodothyronine; PG, prostaglandins; GH, growth hormone; TNF, tumor necrosis factor; IL-I, interleukin 1.

only means of establishing the clinical relevance of observations in this field. However mechanisms for altered hepatic drug metabolism are usually easier to study in vitro, or by a combined in vitro/in vivo approach using animal models. Furthermore, the use of inbred strains reduces the problem of genetically-determined interindividual variability which complicates human studies of drug metabolism (Vessell, 1977). Animal studies also allow appropriate control of constitutional factors such as age and sex which are associated with differences in rates of drug metabolism, as well as regulation of environmental variables such as dietary composition (Kappas et al., 1976), and exposure to foreign compounds which alter drug metabolism (Conney and Burns, 1972). However these advantages of using laboratory animals as an experimental model can be more than offset by species differences in content and regulation of individual drug metabolizing enzymes. A striking example relates to the sex differences in rats in metabolism of ethylmorphine and hexobarbital (but not aniline or zoxazolamine) (Kato and Gillette, 1965). The four-fold faster metabolism of these compounds in male rats compared to females is determined by the presence of at least two cytochrome P-450 isozymes, P-450UT.Aand P-450pCN.E(Waxman et al., 1985). Sex-dependent P-450 isozymes are regulated by the hypothalamic-pituitary-gonadal axis and their levels in the liver change during development and senescence of the animals (Morgan et al., 1985; Kamataki et al., 1985). In humans, sexdependent differences in oxidative drug and steroid metabolism also occur but are less striking (Pfaffenberger and Horning, 1977; Roberts et al., 1979; Wilson, 1984). The sexdependent pathways of drug metabolism in rats appear to be particularly sensitive to pathophysiological states such as cirrhosis (Murray et al., 1987), portal by-pass (Farrell et al., 1986), diabetes mellitus (Kato and Gillette, 1965; Skett and Joels, 1985) and starvation (Kato, 1977). Hence some observations made in male rats, while of biological interest, may not be directly transferable to the human clinical counterpart. Animal studies should not, however, be dismissed as irrelevant. In human disease, there is considerable variability between changes in the metabolism of different agents; an example is the marked effect of thyroid disease on antipyrine but not phenytoin metabolism. This sort of observation has led some authors to conclude that "each drug must be evaluated by itself in different pathological conditions" (Hansen et al., 1978). This cumbersome approach has little appeal to the biochemical pharmacologist who would prefer

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to understand the regulatory mechanisms of individual drug metabolizing enzymes, thereby allowing prediction of relevant disease effects. The value of animal studies is that information is obtained regarding the regulation of particular drug metabolizing enzymes and how such regulation may be altered in pathophysiologic states. Carefully conducted basic studies into analogous enzymes in human liver and their modulation by genetic, hormonal, humoral, nutritional, environmental and other relevant factors should eventually allow qualitative predictions of the effects of disease on drug metabolism in humans. Insights into such mechanisms will be highlighted here. Some possible relationships between disease states and factors known to alter hepatic drug metabolism are presented schematically in Fig. 1.

2. D R U G METABOLISM IN FEBRILE ILLNESS, STATES OF INFLAMMATION

AND ALTERED IMMUNITY 2.1. INTRODUCTION Rates of hepatic drug metabolism may be impaired in fever induced by etiocholanolone, influenza vaccination and viral illness as well as in experimental inflammation, adjuvantinduced arthritis, and after Bacillus-Calmette-Guerin (BCG) or Corynebacterium p a r v u m inoculation. These conditions will be considered together because of the possibility that mediators of inflammation and other host responses to chemical or infectious agents may affect hepatic drug metabolism. This concept is gaining credence with recent studies demonstrating effects of interferons on oxidative drug metabolism in animals and in human subjects (Section 2.6). The effects of fever and febrile illnesses on drug metabolism in man, together with potential clinical relevance, are summarized in Table 1.

2.2. PYROGEN-INDUCEDFEVER In 1972, Song et al. demonstrated that fever, induced in human volunteers by injection of endotoxin, altered salicylamide metabolism resulting in impaired formation of salicylamide glucuronide and enhanced formation of salicylamide sulfate and gentisamide glucuronide. Fever also impaired bromosulfophthalein (BSP) clearance but not that of indocyanine green; the latter is an indicator of hepatic blood flow (Blaschke et al., 1973). These findings suggest that impaired hepatic conjugation of BSP (or impaired secretion into bile) occurs in febrile states. Elin and colleagues (1975) measured antipyrine metabolic clearance in volunteers injected with the steroid pyrogen etiocholanolone. Among individuals who developed fever, antipyrine half-life was prolonged (29%) and metabolic clearance rate was reduced (16%). In those who did not develop fever, etiocholanolone had no effect on antipyrine clearance. Moreover, when clearance of a larger dose of antipyrine was studied, fever was suppressed and antipyrine elimination was unaltered (antipyrine does not exhibit dosedependent kinetics over the range of doses used). Antipyrine is metabolized by hepatic mixed function oxidation (Vessell, 1979) involving at least two separate cytochrome P-450 isozymes (Danhof et al., 1982). Antipyrine has a wide therapeutic range and does not have a place in current therapy, so that this study does not have direct clinical relevance. Moreover, oxidative metabolic pathways for other drugs may be catalyzed by different hepatic cytochrome P-450 isozymes (Jacqz et al., 1986). On the other hand, there is some evidence that quinine metabolism is reduced during acute malaria and steroid-induced fever (Trenholme et al., 1976). Quinine is also metabolized by hepatic oxidative pathways and the changes in disposition during fever led these authors to recommend a modification in quinine dosage during initial treatment of acute falciparum malaria. JPT 35/3~H

Forsyth et al., 1982 Chang et al., 1978; Kraemer et aL, 1982 Levine and Jones, 1983 Jacknowitz, 1984; Blumenkopf and Lockhart, 1983 Renton et al., 1980

Acute viral respiratory illness

Gray et al., 1983 Lipton et al., 1978 Williams and Farrell, 1986 Williams et al., 1987

BCG inoculation

Fever-interferon

*Studies showing absence of this effect have also been reported (see text).

impaired aminopyrine metabolism impaired antipyrine metabolism impaired theophylline metabolism

Kramer and McClain, 1981 Kramer et al., 1984

Influenza immunization

impaired theophylline metabolism*

rise in phenytoin levels warfarin sensitivity

impaired antipyrine clearance impaired theophylline elimination

impaired salicylamide glucuronidation enhanced salicylamide sulfation and formation gentisamide glucuronide impaired antipyrine clearance impaired quinine metabolism

impaired theophylline and chlordiazepoxide metabolism impaired aminopyrine metabolism warfarin sensitivity* ? no effect on metabolism impaired theophylline metabolism

Influenza immunization Meredith et al., 1985

Elin et al., 1975 Trenholme et al., 1976

Fever-etiocholanolone Acute malaria Steroid-induced fever

Herpes zoster

Song et al., 1972

Observed effect

TABLE 1. Effects o f Fever on Drug Metabolism in M a n Reference

Fever-endotoxin

Disorder or pyrogen

consider when using chemoimmunotherapy nil potential toxicity, theophylline and other agents

nil warfarin toxicity

possible changes in steady state blood levels

nil modify dosage schedule in falciparum malaria nil theophylline toxicity observed phenytoin toxicity hemorrhage

nil

Clinical relevance

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2.3. EXPERIMENTAL INFLAMMATIONAND INFLAMMATORYARTHRITIS

Morton and Chatfield (1970) observed that hepatic drug metabolism was impaired in rats with adjuvant-induced arthritis. This and related models of inflammatory arthritis have provided an interesting system in which to study the alterations of hepatic drug metabolism which occur in extrahepatic disease. Injection of acute irritants such as turpentine and both arthritic and nonarthritic adjuvants (preparations from delipidated Mycobacterium tuberculosis (human) or BCG cell walls) led to marked impairment of hexobarbital and aminopyrine metabolism (Beck and Whitehouse, 1973, 1974). Carrageenan had a profound effect on hepatic drug metabolism and even mild irritants such as kaolin had some effects (Beck and Whitehouse, 1974). Arthritis produced in rats by Mycoplasma arthritidus was also associated with a reduced activity of aminopyrine Ndemethylase (Cawthorne et al., 1976). Drugs which prevented the development of arthritis (e.g. cyclophosphamide, azauridine triacetate) or suppressed the inflammation (e.g. indomethacin) did not prevent the suppression of drug metabolism (Beck and Whitehouse, 1974). However, 6-mercaptopurine and dexamethasone prevented adjuvant arthritis-related depression of drug metabolism. Cawthorne et al. (1976) demonstrated by pair-feeding experiments that restricted food intake did not account for the impairment of drug metabolism in rats with adjuvant-induced arthritis. In attempting to elucidate the mechanism for adjuvant-induced arthritis Eiseman et al. (1982) reported that honeybee (Apis mellifera) venom suppressed, but did not abolish, the primary and secondary inflammatory responses to adjuvant injection in rats. However, both bee venom and adjuvant depressed hepatic levels of cytochrome P-450 and associated ethylmorphine N-demethylase and arylhydrocarbon hydroxylase activities. Both treatments also caused a marked enhancement of hepatic microsomal heme oxygenase activity while enzymes of heme synthesis were not altered. These findings are analogous to those observed with endotoxin (which, like adjuvant, is a complex lipopolysaccharide) (Bissell and Hammaker, 1976) as well as some interferon-inducers (see Section 2.6) and may result from destruction of the heme moiety of cytochrome P-450. Ishizuki et al. (1983) have also demonstrated that mixed function oxidase activity is reduced in hepatocytes isolated from rats with adjuvant-induced arthritis. In these cells there was a simultaneous increase in protein synthesis suggesting a possible relationship between the lowered drug metabolizing activity and production of the acute phase proteins after an inflammatory stimulus. All of these alterations in hepatic drug metabolism could be accounted for by stimulation of the immune system in adjuvant arthritis. It is clearly important to examine whether inflammatory arthritis in humans is associated with impaired metabolism of therapeutic agents such as phenylbutazone.

2.4. VIRAL INFECTIONS Both antipyrine (Forsyth et al., 1982) and theophylline metabolism (Chang et al., 1978; Kraemer et al., 1982) may be impaired during acute viral respiratory illness. The extent of impairment in theophylline elimination was sufficient to produce theophylline toxicity, including seizures in some instances (Kraemer et al., 1982). Recent case reports have highlighted the significance of these changes in drug metabolism, emphasizing that the greatest concern should be for agents with a narrow therapeutic range whose clearance is dependent on hepatic cytochrome P-450-dependent oxidative drug metabolism. Serum phenytoin levels rose from 16 to 51 g/ml during the course of a simple viral infection in one patient (Levine and Jones, 1983). An acute subdural hematoma developed in another patient with herpes zoster infection who was concurrently receiving warfarin therapy (Jacknowitz, 1984; Blumenkopf and Lockhart, 1983).

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2.5. IMMUNIZATIONAND VACCINATION Influenza immunization and BCG vaccination have been associated with clinically significant impairment of hepatic drug metabolism. In patients and healthy volunteers, influenza immunization impaired the elimination of theophylline (Renton et al., 1980), and aminopyrine as assessed by the [~4C]aminopyrine breath test (Kramer and McClain, 1981). The reduction in aminopyrine metabolism was variable in the first 2 days after immunization, but by day 7 there was a reduction of 45% in the elimination of aminopyrine and some abnormality remained in the majority of subjects 3 weeks after inoculation. The extent of impaired aminopyrine metabolism was comparable to that seen in severe alcoholic liver disease, one of the liver disorders usually associated with the most profound abnormalities of hepatic drug metabolism (Farrell et al., 1978). Warfarin side-effects have also been reported in patients receiving influenza immunization, although the mechanism may not be related to warfarin metabolism (Kramer et al., 1984). While studies are required to establish the effects on influenza vaccination on steady-state blood levels of agents such as warfarin, phenytoin and tricyclic antidepressants, clinicians should be aware of the possibility that influenza vaccination or intercurrent viral illness may impair the metabolism of such drugs and lead to toxic side-effects. Not all investigators have found an effect of influenza vaccine on theophylline clearance (Bukowskyj et al., 1984; Winstanley et al., 1985) or warfarin anticoagulation (Lipsky et al., 1984). Differences may reflect varying responses to different preparations of vaccine. Meredith et al. (1985) confirmed the findings of Renton et al. (1980) in relation to theophylline metabolism: 1 day after influenza immunization, theophylline clearance was reduced by 34% with a corresponding 27% increase in theophylline half-life. However, theophylline metabolism returned to prevaccination levels by day 7 after vaccination. Moreover, there may be variable effects of influenza vaccination on individual pathways of hepatic oxidative drug metabolism since chlordiazepoxide disposition was not altered (Meredith et al., 1985). Chlordiazepoxide is a drug that has low hepatic intrinsic clearance and is metabolized by oxidative pathways. The clearance of lorazepam, a benzodiazepine metabolized by glucuronidation, was not altered after influenza immunization (Meredith et al., 1985). In rats, injection of Bordetella pertussis vaccine increased phentoin half-life by about four-fold, decreased hepatic microsomal cytochrome P-450 levels and reduced in vitro oxidation of phenytoin by 36% (Renton, 1979). BCG treatment also reduced the activity of rat liver drug metabolizing enzymes (Farquhar et al., 1976). Similarly, Corynebacterium p a r v u m decreased hepatic and lung drug metabolizing enzyme activity in mice (Soyka et al., 1976) and rats (Farquhar et al., 1983). BCG inoculation also suppressed theophylline and aminopyrine metabolism in humans (Gray et al., 1983; Lipton et al., 1978). These changes in hepatic drug metabolism should be considered in patients receiving combined chemo-immunotherapy for malignant disease (Lipton et al., 1978). This subject has recently been reviewed elsewhere (Descotes, 1985).

2.6. EFFECTS OF INTERFERON AND INTERFERON INDUCERS ON HEPATIC OXIDATIVE DRUG METABOLISM

It has been suggested that the effects of viral infection, inflammation and vaccination on drug metabolism may be mediated by interferon (Descotes, 1985). In 1976, Renton and Mannering observed that tilorone, an interferon-inducing agent, depressed hepatic oxidative drug metabolism in rats. Since then it has been demonstrated that a variety of structurally-unrelated compounds, including the synthetic nucleotide poly-riboinosinic polyribocytidylic acid [poly-(rI.rC)], Freund's adjuvant, endotoxin and Bordetella pertussis vaccine have similar effects; all these compounds are interferon-inducers (Mannering et al., 1980). The mechanism of the poly-(rI.rC) and tilorone effect seems to involve enhanced heme turnover (el Azhary and Mannering, 1979; el Azhary et al., 1980), and is

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thus analogous to endotoxin (Bissell and Hammaker, 1976) and adjuvant-induced arthritis (Eiseman et al., 1982). However, other workers have suggested that these agents suppress cytochrome P-450 (P-450) isozyme synthesis (Zerkle et al., 1980). It should be noted that all the above agents, as well as pyrogenic and inflammatory conditions, are associated with interferon release. Sonnenfeld et al. (1980) demonstrated that depression of P-450-dependent metabolism in tuberculin-challenged BCG-sensitised mice was associated with production of ~-interferon. Moreover, the degree of enzymatic depression correlated with the interferon titer. From studies in mice, there is now abundant evidence that interferon affects hepatic oxidative drug metabolizing enzymes (Sonnenfeld et al., 1980; Singh and Renton, 1981, 1982; Parkinson et al., 1982; Moore et al., 1983). Interferons with potent antiviral efficacy are more likely to lower P-450 levels. Species differences have also been observed and autologous interferons seem more likely to suppress P-450 than heterologous ones (Singh and Renton, 1982; Parkinson et al., 1982; Moore et al., 1983). In the first hour after injection of interferon into mice there was no effect on in vivo drug metabolism (Taylor et al., 1985). Moreover, interferon did not impair theophylline clearance when added to an isolated perfused rat liver (Williams et al., 1987). When interferon was added to microsomal fractions in vitro, it did not inhibit mixed function oxidase activity (Parkinson et al., 1982). These findings are consistent with the assertion that interferon has an indirect effect on drug metabolizing enzymes. In support of this contention, antipyrine metabolism was impaired 24 hr after interferon injection and hepatic mixed function oxidase activity (assessed in vitro) remained suppressed despite the disappearance of interferon from the circulation (Taylor et al., 1985). Hence interferon appears to produce a sustained effect on hepatic levels of P-450, and also other microsomal proteins such as cytochrome b5 and NADPH-cytochrome c reductase which may be involved in drug metabolism (Parkinson et al., 1982). The indirect effect of interferon could be via release of a second mediator from macrophages, such as interleukin-1 (Peterson and Renton, 1984; Descotes, 1985) or by induction of hepatic xanthine oxidase which, in turn, produces free radical destruction of cytochrome P-450 (Ghezzi et al., 1984; Deloria et al., 1985; Koizumi et al., 1986). It has recently been demonstrated that interferon impairs hepatic drug metabolism in humans. Williams and Farrell (1986) showed that intramuscular injection of purified recombinant human leukocyte interferon ~tA inhibited antipyrine metabolism by a median 16% (range 5-47%). More striking changes were observed with theophylline metabolism: the metabolic clearance rate was decreased by 76% and half-life was increased by 146% (Williams et al., 1987). Further studies with other interferons and other drugs are now required to assess the frequency and magnitude of interferon-induced inhibition of hepatic drug metabolism. Finally, bacterial endotoxin has been shown to lower hepatic cytochrome P-450 levels and to reduce the activity of related drug metabolizing enzymes in rats (Gorodischer et al., 1976; Sonawane et al., 1982). It is uncertain whether this effect is mediated via interferon or interleukin release (Dinarello, 1984) or is a direct one as suggested by Bissell and Hammaker (1976). Clearly there is a need for information concerning the pharmacokinetics of drugs metabolized principally by the liver during the course of endotoxemia in humans.

3. RENAL DISEASE 3.1. INTRODUCTION The main effect of renal dysfunction on the disposition of drugs is to impair the elimination of agents excreted predominantly by the kidneys (Reidenberg, 1977; Bennett et al., 1977). A second effect is to increase the risk of toxic side-effects of some drugs, possibly as the result of impaired renal excretion of drug metabolites produced by hepatic metabolism (Drayer, 1977).

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G.C. FARRELL

Combined hepatic and renal failure may greatly impair the elimination of certain compounds such as chloramphenicol (Kunin e t al., 1959), phenobarbital (Breen e t al., 1973) and metronidazole (Ioannides e t al., 1981; Farrell e t al., 1984). A major reason for this synergistic effect is the loss of two alternative pathways of drug excretion. However, it should also be noted that the hepatorenal syndrome (that is, renal failure which complicates hepatic insufficiency) is found only in patients with severely impaired hepatic metabolic function. In one study of metronidazole disposition in patients with liver disease, hepatocellular failure appeared to be a more important determinant of reduced metronidazole clearance than the associated renal dysfunction (Farrell e t al., 1984). Although there is abundant evidence that renal failure is associated with impaired drug metabolism in animal experimental models, this does not appear to occur in patients. On the contrary, the possibility that renal failure enhances hepatic drug metabolism has been suggested (Balant e t al., 1°~a~ Ju.~

t.

3.2. DRUG METABOLISMIN EXPERIMENTALRENAL FAILURE In rats submitted to subtotal nephrectomy, hexobarbital sleeping time was prolonged (Richards e t al., 1953) and hepatic cytochrome P-450 content and aminopyrine Ndemethylase and acetanilide hydroxylase activity were decreased (Leber and Schiitterle, 1972). Using the same model, Mezey e t al. (1975) found decreased hepatic content of cytochrome P-450 but no change in aminopyrine N-demethylase and aniline hydroxylase activities. These findings were extended by Terner e t al. (1978) and Patterson and Cohn (1984) who found a 25-50% reduction in hepatic microsomal cytochrome P-450 content and related mixed function oxidase activities in acute and chronic uremia produced by subtotal nephrectomy. The activities of other drug metabolizing enzymes, including Sdemethylase, esterase, UDP-glucuronyl transferase and monoamine oxidase and the microsomal proteins, cytochrome b5 and N A D P H - c y t o c h r o m e c reductase, were not altered. Van Peer and Belpaire (1977) produced renal failure in rats by urethral ligation or by intravenous injection of uranyl nitrate. Both methods resulted in a reduction of aminopyfine N-demethylase activity in liver homogenates, but no decrease in total cytochrome P450 level or aniline hydroxylase activity.

TABLE2. Studies o f Drug Metabolism in Patients With Renal Failure Changes in disposition or Drug Reference metabolism Clinical relevance Pentobarbital Reidenberget al., 1976 none Phenacetin Prescott, 1969 none -Quinidine Kessler et al., 1974 none Lidocaine Thompson et al., 1973; none Collingsworth et al., 1975 Tolbutamide Reidenberg,1977 none -Phenytoin Letteri et al., 1971; increased elimination, probably none Odar-Cederl6f and Borga, 1974 raisedserum free drug probablynone fraction Phenylbutazone Heldand Enderle, 1976 probably none Propranolol Thompsonet al., 1972 ? metabolism enhanced probablynone Antipyrine Lichter et al., 1973 increased metabolism none Aminopyrine Scherreret al., 1978 increased metabolism none impaired metabolism Procainamide Reidenberg,1977 (hydrolysis) reduce dosage impaired metabolism Isoniazid Reidenberg, 1977 (acetylation) uncertain

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3.3. HEPATIC DRUG METABOLISMIN PATIENTSWITH RENAL FAILURE Unlike rats with uremia, impairment of hepatic drug metabolism is not usually found in patients with renal failure (Table 2) (Van Peer and Belpaire, 1977; Reidenberg, 1977). The metabolism of pentobarbital (Reidenberg et al., 1976), phenacetin (Prescott, 1969) quinidine (Kessler et al., 1974), lidocaine (Thomson et al., 1973; Collinsworth et al., 1975) and tolbutamide (Reidenberg, 1977) appears to be normal in these patients. However, some authors have reported that elimination half-lives of agents such as phenytoin (Letted et al., 1971; Odar-Cederl6f and Borga, 1974), phenylbutazone (Held and Enderle, 1976) and propranolol (Thompson et al., 1972) are shortened in patients with chronic renal failure. Each of these drugs is tightly bound to plasma proteins and increases in the serum free drug fraction of phenytoin (Letteri et al., 1971; Reynolds et al., 1976) and phenylbutazone (Held and Enderle, 1976) have been observed in renal failure. It is also possible that hepatic drug oxidizing enzymes are induced during uremia. Lichter et al. (1973) found enhanced antipyrine elimination rates in eight nondialyzed uremic patients compared with controls but this difference was not apparent in patients on a hemodialysis program. Similar findings were reported by Scherrer et al. (1978) using the [~gC]aminopyrine breath test and plasma aminopyrine disappearance rate; elimination rates were approximately doubled in patients with chronic renal failure, especially when renal failure was associated with analgesic abuse. A problem with these clinical studies is the possible interaction of other variables which could alter rates of hepatic drug metabolism, especially the concurrent administration of other drugs. If uremia itself is associated with induction of hepatic drug metabolizing enzymes, the responsible agent(s) remain unclear although a possible role for dietary inducers such as naturally-occurring indoles (the excretion of which may be decreased in renal disease) has been proposed (Reidenberg, 1977). In contrast to the above drugs which are metabolized by microsomal oxidation, elimination of agents subjected to reductive (e.g. cortisol) and hydrolytic pathways of drug metabolism(e.g, procainamide) may be impaired in patients with renal failure. However, conjugation reactions are usually normal with the possible exception of some acetylation reactions (e.g. isoniazid) (Reidenberg, 1977). 4. DIABETES MELLITUS 4.1. INTRODUCTION Diabetes mellitus is a metabolic disorder which is caused either by destruction of the pancreatic beta cells (Type I, insulin dependent diabetes) or by ineffectiveness of insulin action (Type II, non-insulin dependent diabetes). The disorder is characterized by hyperglycemia, ketonemia, abnormalities of lipid metabolism and degenerative disorders of small and large blood vessels. When produced in laboratory animals, diabetes is associated with both impairment and enhancement of drug metabolism, depending on the sex of the animal and the agent studied. These effects are best explained by altered regulation of individual cytochrome PTABLE3. Studies of Drug Metabolism in Patients With Diabetes Mellitus Drug Reference Type of disease Effect enhanced metabolism Antipyrine Daintithet al., 1984 type1: insulin treatment normal metabolism type 2: diet alone type 2: tolbutamide treatment normal metabolism normal metabolism Antipyrine Pirttiahoet al., 1984 type2 with fatty liver normal elimination Tolbutamide Vedaet al., 1963 type 2 half-liife raised hepatic Salmela et al., 1980 type 2 cytochromeP-450 level

384

G.C. FARRELL

450 isoforms. Diabetes mellitus is a common chronic medical illness with many sequelae that may require drug therapy. Despite this consideration, there are few studies addressing the question of whether clinically relevant changes in drug metabolism occur in diabetic patients (Table 3).

4.2. CHANGESOF DRUG METABOLISMIN EXPERIMENTALDIABETES Dixon et al. (1961, 1963) observed altered oxidative drug metabolism in male rats given alloxan, a toxic agent which, among other effects, destroys pancreatic beta cells and thereby results in diabetes. Hexobarbital sleeping time was prolonged while the metabolism of hexobarbital, codeine and chlorpromazine in hepatic microsomal fractions was decreased and that of aniline was increased. Analogous findings have been found by others, using alloxan or other diabetogens in rats (Ackerman and Leibman, 1977; Reinke et al., 1978, 1979; Faas and Carter, 1980; AI-Turk et al., 1981a,b). In male rats with streptozotocin-induced diabetes, hepatic aryl hydrocarbon hydroxylase activity was decreased (Reinke et al., 1978) but ethoxycoumarin O-deethylase activity was increased (AI-Turk et al., 1981a). In diabetic female rats, both these enzymes were stimulated (AITurk et al., 1981a; Reinke et al., 1979) and hepatic content of cytochrome P-450 was increased (Reinke et al., 1979). In male rats, Reinke et al. (1978) noted that aminopyrine N-demethylase activity was decreased while aniline hydroxylase activity and cytochrome P-450 levels were increased. Faas and Carter (1980) also observed that cytochrome P-450 was increased (by 65%) in streptozotocin-diabetic female rats, but they found normal levels of this protein in diabetic male rats. Ethylmorphine N-demethylase and aminopyfine N-demethylase activities were decreased in males but increased in females. In alloxan-diabetic mice and rabbits, aniline hydroxylase activity was found to be increased in both sexes (Kato, 1977). Aminopyrine N-demethylase, hexobarbital hydroxylase and aryl hydrocarbon hydroxylase activities of liver microsomes, as well as cytochrome P-450 levels were also increased in diabetic mice (Kato, 1977; Rouer and Leroux, 1980). More recently, Cook et al. (1984) have studied drug metabolism in guinea pigs with spontaneous diabetes mellitus associated with elevated plasma insulin levels. The guinea pig also exhibits a clear sex difference in hepatic oxidative drug metabolism and in diabetic animals aminopyrine N-demethylase activity was reduced in males but not in females.

TABLE4. Possible Mediators of Altered Hepatic Drug Metabolism in Diabetes Mellitus

Factor Insulin

Effects in animal studies • reversesimpairmentof sex-dependent MFOs, e.g. hexobarbital hydroxylase, ethylmorphineN-demethylase drug metabolismnormal in type 2 diabetes mellitusmodels Glucagon • depresses total P-450 but stimulates some MFOs Hyperglycemia • lowers total P-450 impairs MFO activity impairs antipyrineclearance Hyperketonemia• stimulates anilinehydroxylase,PCNMAN-demethylase Androgen • regulator of male-dependent P-450 isozymes Growth • regulator of sex-dependent P-450 isozymes hormone P-450, cytochromeP-450; MFO, mixed functionoxidase; PCNMA, p-chloromethyl-N-methylaniline.

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4.3. CHANGES IN CYTOCHROME P-450 ISOFORMS IN DIABETIC RATS

Past and Cook (1982a,b, 1983) have demonstrated that a constitutive cytochrome P-450 isoform is increased in alloxan-induced diabetic male rat liver. They have separated two hemoprotein fractions from diabetic male rat liver microsomes, one of which has high aniline hydroxylase and low ethylmorphine N-demethylase activities in a reconstituted enzyme system. This 'diabetes-dependent' cytochrome P-450 accounted for the increase in total cytochrome P-450 levels in diabetic rat liver and also for some of the selective changes in mixed function oxidase activity. Whether the 'diabetes-dependent' P-450 isozyme is a form unique to the diabetic state remains to be ascertained. In addition to this selective increase in the 'diabetes-dependent' isozyme, Rouer et al. (1985) demonstrated in mice that a protein which reacted with antibodies to rat cytochrome P-450UT.A was increased by 50% after glucagon infusion and by 20% in streptozotocin-diabetes. In the same animal model, xenobiotic-inducible forms of P-450 which reacted with antibodies to rat P'4501SF.C and P-450pa.a respectively, remained unchanged. It thus appears that there are changes in the sex-dependent P-450 isozymes in diabetes, including reduced P-450UT.A levels in male rats (Skett, 1986; Rouer et al., 1986). Rotter et al. (1985, 1986) have suggested that there is also an increase in a form resembling a phenobarbital-inducible cytochrome P-450 isozyme in streptozotocin-diabetic mice and rats. Finally, the stimulated activity of aniline hydroxylase in males and females of several species may be due to increased levels of other cytochrome P-450 isozymes. 4.4. WHAT ARE THE MEDIATORS OF ALTERED HEPATIC DRUG METABOLISM IN EXERIMENTAL DIABETES MELLITUS?

The factors which could mediate changes in hepatic drug metabolism in diabetes are listed in Table 4. None of the chemicals used to produce diabetes in laboratory animals is thought to be directly responsible for the changes in drug metabolism (Reinke et al., 1978). Administration of insulin to diabetic rats or mice reversed changes in hexobarbital hydroxylase activity (Dixon et aL, 1963) as well as ethylmorphine N-demethylase, aminopyrine N-demethylase and aryl hydrocarbon hydroxylase activities (Reinke et al., 1978; Faas and Carter, 1980; Rouer and Leroux, 1980). Moreover, changes in drug metabolism were absent or minimal in rat or mouse models of insulin-resistant diabetes (Ackerman and Leibman, 1977; Rouer and Leroux, 1980). Hence insulin deficiency is one major factor in mediating changes in drug metabolism in diabetic rats. Other features of the diabetic state which might have effects on hepatic drug metabolism are hyperglucagonemia (Rouer et al., 1985), hyperglycemia (Strother et al., 1971; Campbell, 1977; Hartshorn et al., 1979) and hyperketonemia. From an interesting comparison of drug metabolism in mice with genetic (hyperinsulinemic) and streptozotocin-induced (hypoinsulinemic) diabetes, Knodell et al. (1984) suggested that both hyperglycemia and insulin separately influence cytochrome P-450 turnover and mixed function oxidase activity. One striking feature about altered drug metabolism in diabetic rats is its sex-dependence. While aniline hydroxylase and p-chloro-N-methylaniline N-demethylase activities are increased in both sexes, hexobarbital hydroxylase, ethylmorphine N-demethylase, aminopyrine N-demethylase and aryl hydrocarbon hydroxylase are decreased in male and increased in female rats. The latter group of substrates are those with greater activity in male than in female rats (Kato and Gillette, 1965; Kato, 1977). The higher activity in male rats depends on the presence of sex-dependent cytochrome P-450 isoforms including P450UT.Aand P'450pCN.E (Waxman et al., 1985). The hepatic levels of these hemoproteins are controlled by both androgens and by hypothalamic-pituitary regulation (Waxman et al., 1985; Morgan et al., 1985; Kamataki et al., 1985). The latter is determined by androgenimprinting in the perinatal period and is most likely mediated by the pattern of growth hormone release (MacGeoch et al., 1985). Kato and Gillette (1965) noted that it was the sex-dependent pathways of oxidative drug metabolism that were reduced in diabetic male

386

G.C. FARRELL

rats and suggested that this was due to impaired action of androgens on these enzymes. Serum testosterone levels are reduced in male diabetic rats and in some (but not all) studies are increased in female diabetic rats (Howland and Zebrowski, 1976; Baxter et al., 1981; Warren et al., 1983). However, in streptozotocin-diabetic male rats the changes in serum testosterone levels did not correlate with changes in drug metabolism (Skett et al., 1984). Insulin may also play a role in maintaining the sex differences in hepatic drug and steroid metabolism (Skett, 1986). However, growth hormone levels are also altered in diabetes mellitus (Harrison and Robinson, 1980), the pattern of growth hormone secretion is affected by insulin, and growth hormone release is the major regulator of sex-dependent forms of cytochrome P450 (Tannenbaum, 1981; Gustafsson et al., 1983; Skett, 1986). It has thus been suggested that growth hormone may be the mediator of the sex-dependent effects of diabetes on hepatic drug metabolism in the rat (Skett et al., 1984). 4.5. CLINICAL RELEVANCE OF ALTERED DRUG METABOLISM IN DIABETES

In view of the high prevalence of diabetes mellitus in the community and its common association with other medical disorders, it is surprising that there are few published studies of drug metabolism in patients with this disease (Table 3). Daintith et al. (1976) measured antipyrine clearance in 28 diabetic patients on various treatment regimens. Insulin treatment was associated with a significant (40%) enhancement of antipyrine clearance compared with controls. However, antipyrine elimination was normal in patients being treated with diet alone or with the oral hypoglycemic agent tolbutamide. Moreover, antipyrine clearance was normal in a group of patients with Type II diabetes mellitus who were selected because of the presence of fatty liver (Pirttiaho et al., 1984). Tolbutamide half-life was also normal in diabetic patients (Ueda et al., 1963). Cytochrome P-450 levels actually appeared to be increased in liver biopsy samples for a small number of patients (Salmela et al., 1980). The results of these studies are thus consistent with the experimental data in animals and suggest that non-insulin dependent diabetes is not associated with altered hepatic drug metabolism. However, the possibility that insulin treatment may enhance drug metabolism has not been evaluated in man. Studies of drug elimination rates in patients with insulinopenic diabetes determined before and after insulin therapy would be of interest. 5. HEPATIC DRUG METABOLISM IN EXTRAHEPATIC MALIGNANCY 5.1. EFFECTS OF IMPLANTED TUMORS ON DRUG METABOLISM IN EXPERIMENTAL ANIMALS

It was first observed in 1941 that implanted tumors have effects on hepatic metabolism in rats (Greenstein et al., 1941). Twenty years later, Kato and colleagues (1963) reported that implantation of Walker carcinosarcoma 256 tumors into rats resulted in impaired oxidative drug metabolism. Similar findings have now been observed in rats of both sexes (Rogers et al., 1967; Hickie and Kalant, 1967; Wilson, 1971), in mice (Rosso et al., 1971), guinea pigs (Litterst et al., 1977) and rabbits (Weiner and Olson, 1980). Changes in hepatic drug metabolism occur with a variety of tumor types implanted into different anatomic sites. Reduced levels of hepatic microsomal cytochrome P-450 as well as cytochrome b 5 and NADPH-cytochrome c reductase occur in malignancy. Suppression of drug metabolism has usually been progressive with time after tumor implantation and correlates roughly with tumor bulk (Rogers et al., 1967; Hickie and Kalant, 1967; Matsuura et al., 1984). Moreover, removal of tumor implants reverses the abnormalities of drug metabolism. These findings have given rise to the concept of a circulating 'toxohormone' which suppresses hepatic drug metabolism (Hickie and Kalant, 1967; Rosso et al., 1971; Boulos et al., 1972; Bartos6k et al., 1972, 1975). There are conflicting data as to whether 'toxohormone' secretion is more likely with necrotic tumors (Kato et al., 1963;

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387

Rogers et al., 1967; Boulos et al., 1972). There has also been a suggestion that this humoral effect of malignancy is associated with raised hepatic content of cyclic-adenosylmonophosphate (Olson and Weiner, 1980). The forms of cytochrome P-450 altered in tumor-bearing animals have not been ascertained. In some tumors, particularly shortly after implantation and especially in growth hormone-secreting pituitary mammotropic tumors (Wilson, 1968a,b, 1969a,b; Villeneuve et al., 1979), male-sex-dependent pathways of mixed function oxidase activity are reduced most strikingly. However, with larger tumor burdens, effects on pathways of drug metabolism appear less specific. More recently, increased turnover of hepatic and cytochrome P450 heme has been observed in tumor-bearing animals (Bonkowsky et al., 1973; Weiner and Olson, 1980; Beck et al., 1982; Schacter and Kurtz, 1982, 1984; Matsuura et al., 1984). It has been suggested that the primary defect in cytochrome P-450 formation in this situation is impaired apoprotein synthesis (Beck et ai., 1982; Schacter and Kurtz, 1984) but these studies have not been undertaken with reliable methods for P-450 isozyme quantitation. Moreover, the observed suppression of cS-aminolevulinic acid synthetase and stimulation of heme oxygenase (Beck et al., 1982; Schacter and Kurtz, 1982) are suggestive of expansion of the regulatory heme pool, such as that which occurs when heme is displaced from its prosthetic binding site on cytochrome P-450 (Bissell and Hammaker, 1976; FarreU and Zaluzny, 1985). There are thus parallels between the changes observed in hepatic cytochrome P-450 in inflammation (section 2.6) and in extrahepatic malignancy. 5.2. HUMAN STUDIES The abnormal pathways of drug metabolism in tumor-bearing experimental animals involve those of several commonly used drugs, including cyclophosphamide (Bartos~k et al., 1975), a cancer chemotherapeutic agent. Despite this, there are few studies of drug metabolism in patients with nonhepatic malignancy (Table 5). The available studies suffer from the difficulty of obtaining satisfactory control groups and the problem of compounding variables such as etiologically-relevant environmental factors, nutritional and other consequences of the disease. Sotaniemi et al. (1973) measured antipyrine elimination in 12 men with carcinoma of the prostate before and 10 days after castration and commencement of diethylstilbestrol treatment. There was a variable change in antipyrine halflife (from - 37 to + 140%) with an overall reduction of 11%. If prostatic cancer has a real effect on hepatic antipyrine metabolism it is a minor one, because values for antipyrine half-life remained within the normal range, even when metastases were present. Antipyrine metabolism appeared to be enhanced in 14 patients with newly-diagnosed carcinoma of the bronchus compared with healthy controls (Ambre et al., 1977). However, the smoking habits of cancer and control groups may not have been identical and it is now known that cigarette smoking is associated with enhancement of antipyrine metabolism of the same magnitude as that observed in this study (Hart et al., 1976). Tschanz et al. (1977) found no significant alterations in antipyrine elimination among patients with lung cancer who were matched for smoking and drug history. Danhof (1980) also found no change in antipyrine metabolic clearance rate among ten patients with lung cancer compared with nonsmoking controls, although a minor (nonsignificant) decrease of antipyrine half-life was observed. The impression that extrahepatic malignancy does not alter oxidative drug metabolism in humans is supported by the results of a study of the [14C]aminopyrine breath test in 153 patients with malignant tumors (Hepner et al., 1976). Among 78 patients without hepatic metastases, only 6% had impaired hepatic aminopyrine metabolism. In contrast, among 75 patients with hepatic metastases, aminopyrine elimination was reduced below the normal range in 83%. This study therefore seemed to indicate that hepatic oxidative drug metabolism is impaired in most patients with hepatic metastases but is usually normal in patients without this complication. It is important that further studies be conducted in which drugs of greater clinical relevance are examined. Such studies should ensure that the patients investigated exhibit a range of tumor type, site and size.

Drug

Aminopyrine (breath test)

Antipyrine

carcinoma bronchus carcinoma bronchus

Tschanz et al., 1977

Danhof, 1980 varied, extrahepatic

carcinoma bronchus

Ambre et al., 1977

Hepner et al., 1975

prostatic + metastases

Type of malignancy

Sotaniemi et al., 1973

Reference

no effect or enhancement 94% of patients had normal values

no effect

from 37% decrease in half-life to 140% increase enhanced

Effect

presence of hepatic metastases associated with abnormal values

impossible to separate effects of concurrent castration and stilbestrol therapy ? effect of cigarette smoking, concurrent drugs controlled for cigarette smoking controlled for cigarette smoking

Comment

TABLE 5. Studies o f Drug Metabolism in Patients with Extrahepatic Malignancy

t-

"lq >

~o oo

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389

6. T H Y R O I D DISEASE 6.1. INTRODUCTION It has long been recognized that both hyperthyroidism and hypothyroidism may be associated with altered sensitivity to drugs (Lund and Benedict, 1929; Boas, 1931; Carrier and Buday, 1961; Conney and Garren, 1961; Schrogie and Solomon, 1967; Coville and Teldford, 1970). Several physiological variables may be altered in states of thyroid dysfunction, including renal function, plasma protein binding, hepatic intermediary metabolism, hepatic blood flow and tissue sensitivity to drug effects especially in the brain, liver and muscle (Table 6). This subject has been reviewed in detail (Shenfield, 1981) and only those aspects pertinent to hepatic drug metabolism will be considered here. Thyroid hormone stimulates many oxidative reactions in the body (Hellman et al., 1961). It is thus not surprising that hyperthyroidism may be associated with enhanced oxidative drug metabolism, but there is considerable variability between agents, and some pathways of drug metabolism are not affected. Impairment of drug metabolism in hypothyroidism is also unpredictable. This variability of response, together with the possibility of other metabolic effects, such as the increased catabolism of clotting factors which enhances individual sensitivity to warfarin therapy (Schrogie and Soloman, 1967), makes extrapolation from one compound to another unreliable. Animal studies indicate that several changes which affect drug metabolism may occur in states of thyroid dysfunction. Altered NADPH-cytochrome c reductase activity is one of the more constant changes and appears to be more important here than in other pathophysiologic states. The effects of thyroxine on hepatic drug metabolizing enzymes are dose-dependent and, in rats, differ between males and females. In general, hypothyroidism results in impaired oxidative drug metabolism with reduced levels of hepatic cytochrome P-450 and NADPH-cytochrome c reductase activity. Small ('physiological') doses of triiodothyronine (T3) stimulate mixed function oxidase activity that has been lowered by thyroidectomy or hypophysectomy. Cytochrome P-450 levels are reduced and NADPH-cytochrome c reductase activity is increased in male rats that have been dosed TABLE 6 Physiological Variables Which May Be Associated With Altered Drug Disposition in Patients With Thyroid Dysfunction

Variable Renal function Plasma protein binding Hepatic intermediary metabolism Hepatic blood flow Tissue sensitivity

Hepatic drug metabolism Nutritional state

Possible effects altered renal clearance altered free drug fraction increased NADPH increased NADPH-cytochromec reductase altered hepatic clearance cerebral sensitivityto amphetamine, caffeine,morphine accelerated catabolismclotting factors altered hepatic clearance effects on drug metabolism

TABLE 7 Indices of Hepatic Drug Metabolism in Rats With Hyperthyroidism

Factor Total cytochromeP-450 NADPH-cytochromeP-450 reductase Sex-dependent MFOs (hexobarbital hydroxylase, aminopyrineN-demethylase) Non sex-dependentMFOs (aniline hydroxylase, zoxazolaminehydroxylase)

Male rats decreased increased

Femalerats increased increased

decreased

increased

unchanged or increased

increased

390

G . C . FARRELL

with thyroxine. In female rats, pharmacological doses of thyroxine (experimental hyperthyroidism) stimulate the oxidative metabolism of several drugs. However, in male rats, and also in mice of either sex, the effects of experimental hyperthyroidism are reminiscent of diabetes with impaired hexobarbital and aminopyrine metabolism, and stimulated aniline hydroxylase activity. Hence, hyperthyroidism in male rats impairs sex-dependent drug metabolism but stimulates sex-independent pathways. 6.2. HYPERTHYROIDISMIN LABORATORYANIMALS Administration of thyroxine to male rats reduced hepatic morphine N-demethylation (Cochin and Sokoloff, 1960) and prolonged hexobarbital sleeping time because of decreased hepatic metabolism of hexobarbital (Conney and Garren, 1961). Pair-fed control rats exhibited identical changes in hexobarbital hydroxylation, a finding which implicated a role for caloric intake in the maintenance of mixed function oxidase activity. In contrast to hexobarbital, the duration of zoxazolamine action was decreased after thyroxine administration and this effect was demonstrated to be due to acceleration of zoxazolamine metabolism (Conney and Garren, 1961). Dietary deprivation did not stimulate zoxazolamine metabolism. The most important factors contributing to enhanced zoxazolamine metabolism were increased liver size and increased supply of N A D P H resulting from enhanced activity of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. Thyroxine administration also stimulated NADPH-cytochrome c reductase (Tata et al., 1963; Phillips and Langdon, 1956; Kato and Takahashi, 1968; Rumbaugh et al., 1978), a key component of hepatic mixed function oxidases. The contrasting effects of experimental hyperthyroidism on the oxidation of different drugs have been investigated by Kato and colleagues (Kato and Gillette, 1965; Kato and Takahashi, 1968; Kato et al., 1970; Kato, 1977). Sex-dependent pathways of oxidative drug metabolism (e.g. aminopyrine N-demethylase, hexobarbital hydroxylase) were suppressed in male rats given thyroxine, whereas sex-independent pathways were unchanged (e.g. zoxazolamine hydroxylation) or stimulated (e.g. aniline hydroxylation). In female rats, thyroxine increased the microsomal metabolism of aminopyrine, aniline and zoxazolamine. However, whereas NADPH-cytochrome c reductase activity was enhanced in both sexes, cytochrome P-450 levels were reduced in males but unaltered in female rats. These sex-dependent effects are summarized in Table 7. Coville and Teldford (1970) also found that hexobarbital sleeping time was prolonged in hyperthyroid male rats and shortened in hyperthyroid female rats. In mice, thyroxine administration prolonged hexobarbital sleeping times in both sexes. In addition to the changes in drug metabolism, thyrotoxic animals also exhibited increased cerebral sensitivity to amphetamine, caffeine and morphine (Coville and Teldford, 1970). It has also been shown that thyroxine administration is associated with inhibition of the metabolism of bishydroxycoumarin, meperidine and pentobarbital in mice (Prange et al., 1966; Schrogie and Solomon, 1967). In contrast, dogs appear less susceptible to these effects of hyperthyroidism; neither antipyrine nor propranolol elimination were altered after thyroxine administration (Ishizaki and Tawara, 1980). 6.3. HYPOTHYROIDISM IN LABORATORY ANIMALS In thyroidectomized rats of both sexes, the hepatic metabolism of pentobarbital, aminopyrine, hexobarbital, aniline and p-nitrobenzoic acid, and NADPH-cytochrome c reductase activity were all decreased whereas levels of cytochromes b5 and P-450 were unchanged (Prange et al., 1966; Kato and Takahashi, 1968). In female thyroidectomized rats, values for all these indices were restored by thyroxine supplementation. However in male rats, thyroxine further suppressed aminopyrine N-demethylase and hexobarbital hydroxylase activities while cytochrome P-450 levels remained low (Kato and Takahashi, 1968). In view of the apparent sex-dependence of thyroxine effects on oxidative drug metabolism it is of interest that both thyroxine administration and thyroidectomy reduced

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391

TABLE 8 Studies o f Drug Metabolism in Patients With Thyrotoxicosis Drug Antipyrine

Study

Effect enhancement of metabolism (about 40%)

Phenytoin Propranolol

Crooks et al., 1973 Eichelbaum et al., 1 9 7 4 Vessell et al., 1975 Saenger et al., 1976 Hansen et al., 1978 Bell et al., 1977

Warfarin

Schrogie and Solomon, 1967

increased anticoagulation not due to altered elimination enhanced elimination enhanced elimination normal elimination

Solomon and Schrogie, 1967 Methimazole Propylthiouracil

Crooks et al., 1973 Vessell et al., 1975 Vessell et al., 1975 Kampmann and Skovsted, 1975

no change no change

Comment

high clearance compound

assay lacked specificity conflicting

data, methodology problems

testosterone hydroxylation and stimulated testosterone 5~ reduction in male rats (Kato et al., 1970). The altered pattern of testosterone metabolism was similar to that seen in normal female rats and thus indicated that feminization of hepatic steroid metabolism occurs in hypothyroidism. Hypothyroidism has also been produced in animals by administration of the antithyroid agent propylthiouracil. In weanling rats, propylthiouracil-induced hypothyroidism was associated with decreased NADPH-cytochrome c reductase and aniline hydroxylase activities but normal cytochrome P-450 level and aminopyrine N-demethylase activity (Aranda et al., 1973). Propylthiouracil-induced hypothyroidism was associated with prolonged pentobarbital sleeping time and zoxazolamine paralysis time in adult male rats (Raheja et al., 1985). Cytochrome P-450 levels were not altered but NADPH-cytochrome c reductase and aniline hydroxylase activities were reduced. In contrast, in mice, propylthiouracil treatment accelerated elimination of pentobarbital, thereby decreasing its hypnotic effect (Prange et al., 1966). Hypophysectomy in rats of either sex also lowers activity of oxidative drug metabolizing enzymes in the liver (Rumbaugh et al., 1978). Small (physiological) doses of thyroxine partially restore the activities of ethylmorphine N-demethylase, aryl hydrocarbon hydroxylase and aniline hydroxylase but larger doses reverse these effects as well as suppressing cytochrome P-450 levels and inducing NADPH-cytochrome c reductase. It can be concluded that physiological amounts of thyroxine uniformly stimulate hepatic drug metabolism in both male and female rats, but pharmacologic doses impair the activity of sex-dependent pathways of metabolism and enhance sex-independent pathways. Pituitarydependent factors appear to modulate the response of hepatic drug metabolizing enzymes to thyroxine (Kato, 1977).

6.4. CHANGES IN HEPATIC DRUG METABOLISM IN PATIENTS WITH HYPERTHYROIDISM

Peterson (1958) demonstrated that thyrotoxicosis was associated with enhanced cortisol clearance and suggested that this was due to stimulated hepatic steroid metabolism. It has now been demonstrated repeatedly that hyperthyroidism is associated with enhanced antipyrine metabolism (Table 8) (Crooks et al., 1973; Eichelbaum et al., 1974; Vessell et al., 1975; Seanger et al., 1976). The resultant reduction in antipyrine half-life is approximately 40% and it is reversed by treatment of the hyperthyroidism. It has also been observed that hepatic endoplasmic reticulum is hypertrophied in patients with hyperthyroidism (Klion et al., 1971), and this finding is also consistent with induction of drug metabolizing enzymes. While these findings might suggest a generalized increase in oxidative drug metabolism in hyperthyroidism, this does not appear to be the case (Table 8). Hansen et al. (1978) found no change in phenytoin disposition in patients with thyroid dysfunction. Similarly,

392

G. C.

FARRELL

TABLE9 Effects of Blood Gas Abnormalities on Drug Metabolism and Disposition Abnormality Effects Comments Acute hypoxia impairedantipyrine metabolism Cumming,1976 impaired theophyllinemetabolism Letarteand du Souich, 1984 ? reduced hepatic blood flow du Souich, 1978 ? decreased protein binding du Souich, 1978 Chronic hypoxia enhanced antipyrine clearance Agnihotri et al., 1978 increased hepatic P-450 Ou et al., 1980 increased hepatic MFOs Merritt and Medina, 1968; Medina and Merritt, 1970 enhanced tolbutamide elimination Sotaniemi et al., 1971a,b Hypercarbia raised serum theophyllinelevels Letarte and du Souich, 1984 Metabolic acidosis no effect theophyllinekinetics Letarte and (rabbits) du Souich, 1984 increased theophyllineclearance Kolbeck et al., 1978; (dogs) Clozel et al., 1981 altered theophyllinekinetics Vallner et al., 1979; (patients); increased volume of Resar et al., 1979; distribution Cusack et al., 1986 thyroid status does not appear to affect elimination of the high clearance compound propranolol (Bell et al., 1977). Moreover, although patients with hyperthyroidism may be more sensitive to the anticoagulant effects of warfarin, the elimination of this drug is unaltered in thyrotoxicosis (Schrogie and Solomon, 1967). The potentiation of warfarin anticoagulation in hyperthyroidism may be due to enhanced binding of warfarin to its receptor (Solomon and Schrogie, 1967) or to direct effects of thyroxine on clotting factor turnover (Shenfield, 1981). In addition to the warfarin paradox, the renal elimination of agents that are not metabolized by the liver may be altered in thyroid dysfunction because of changes in glomerular filtration rate. For example, blood levels of digoxin are lower in thyrotoxicosis and higher in hypothyroidism (Doherty and Perkins, 1966; Croxson and Ibbertson, 1975). An important but unresolved question concerning drug metabolism in patients with hyperthyroidism is whether there is enhanced clearance of antithyroid agents. Crooks et al. (1973) and Vessell et al. (1975) reported that methimazole half-life was shortened among patients with hyperthyroidism. However, the assay procedure employed did not separate the parent compound from the principle metabolite, which has a much longer elimination half-life (Skellern et al., 1980). There are large interindividual differences in methimazole kinetics, especially when this agent is administered as the precursor drug carbimazole. Furthermore, the absorption of carbimazole may be altered in thyrotoxicosis (Skellern et al., 1980). It thus remains unclear as to whether elimination of methimazole is enhanced in this disorder (Shenfield, 1981). There are also conflicting reports of enhanced (Vessell et al., 1975) and normal (Kampmann and Skovsted, 1975) propylthiouracil elimination in hyperthyroidism and this question should be re-examined with more specific methods.

6.5. CHANGESIN HEPATIC DRUG METABOLISMIN HYPOTHYROIDISM

Impairment of hepatic antipyrine (Crooks et al., 1973; Vessell et al., 1975; Eichelbaum et al., 1975) and cortisol metabolism (Peterson, 1958) occurs in patients with hypothyroidism but it is unclear whether this apparent reduction in oxidative metabolism also applies to other compounds. The prolongation of antipyrine half-life is a major one with a 50-200% increase over control; thyroxine treatment reverses this abnormality. Renal elimination of digoxin (Croxson and Ibbertson, 1975) and practolol (Bell et al., 1977) is reduced in hypothyroidism. Clearly, drugs should be administered with caution to such patients and further studies are needed.

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6.6. EFFECTS OF THYROID DYSFUNCTION ON HEPATOTOXICITY Experimental hyperthyroidism enhances the toxicity of carbon tetrachloride, 1,1dichloroethylene, chloroform, halothane and acetaminophen (paracetamol) but not bromobenzene (Calvert and Brody, 1961; Wood et al., 1980; Smith et al., 1983). Suggested explanations for this effect include enhanced hepatic biotransformation of compounds to reactive intermediates such as radicals or active oxygen species, depletion of hepatic levels of reduced glutathione which usually acts as a protective nucleophile, and regional hypoxia in the central zone of the hepatic lobule. It is not known whether patients with hyperthyroidism are at increased risk of liver damage from agents such as acetaminophen and halothane but the possibility should be borne in mind. Conversely, hypothyroidism protects against carbon tetrachloride (Calvert and Brody, 1961) and acetaminophen toxicity in animals. The mechanism of propylthiouracil protection of acetaminophen toxicity is, however, independent of its hypothyroid effect (Raheja et al., 1982; Yamada and Kaplowitz, 1980; Yamada et al., 1981). 7. CARDIOPULMONARY DYSFUNCTION 7.1. INTRODUCTION Abnormalities of hepatic drug metabolism occur in some patients with respiratory and/or cardiac failure. These two pathophysiologic states will be considered together because of the likelihood that tissue hypoxia is a critical determinant of impaired oxidative drug metabolism (Table 9). As with other disorders, cardiopulmonary disease produces changes in plasma drug concentrations due to altered drug absorption, distribution or elimination. Drug metabolism is the principal determinant of hepatic intrinsic clearance as reflected by the hepatic extraction ratio. However, for high clearance compounds, hepatic blood flow becomes the limiting factor which determines total hepatic clearance; hepatic blood flow falls in relation to reduced cardiac output. The combination of arterial hypoxemia and reduced cardiac output appears especially likely to impair hepatic drug clearance and this may be associated with the toxic accumulation of several therapeutic agents. In assessing the results of drug elimination studies in patients with cardiopulmonary disease, it is often difficult to identify the separate effects of liver perfusion and hepatic drug metabolism. 7.2. CARDIAC FAILURE

Cardiac failure may result in a reduced volume of distribution for lidocaine (lignocaine) (Thomson et al., 1973) and procainamide (Koch-Weser and Klein, 1971). The fall in cardiac output may lead to slower excretion of drugs by the kidneys because of reduced renal blood flow. In turn, hepatic blood flow is lowered in cardiac failure, directly in proportion to the fall in cardiac index (Stenson et al., 1971). It follows that elimination rates of agents with a high hepatic intrinsic clearance, such as propranolol, meperidine (pethidine), pentazocine, amitriptyline and lidocaine are most likely to be reduced in cardiac failure. The disposition and metabolism of lidocaine, an antiarrhythmic drug with an hepatic extraction ratio of 0.7, have been studied in patients with cardiac failure (Table 10). Stenson et al. (1971) found an inverse relationship between the estimated hepatic blood flow and the steady state arterial blood levels obtained during a lidocaine infusion. Hence, in cardiac failure, therapeutic blood levels are obtained with a slower infusion of lidocaine. Conversely, normal infusion rates or frequently repeated doses of lidocaine readily produce toxic blood levels. Thomson et al. (1973) have constructed a nomogram from which to estimate the infusion rate required to produce therapeutic lidocaine blood levels in the presence of a known cardiac output. In a patient with cardiogenic shock, Prescott et al. (1976) observed that the metabolism of lidocaine virtually ceased. Clearly, repeated JPT 35/~-I

Prescott et al., 1976 Prescott et al., 1976

antipyrine lidocaine

lidocaine

theophylline

Cardiogenic shock

Cardiac failure

Cardiac failure, especially acute pulmonary edema and cor pulmonale

Zwillich et al., 1975; Piafsky et al., 1977; Jenne et al., 1977; Vicuna et al., 1979; Powell et al., 1978; Ogilvie, 1978; Westerfield et al., 1981

Stenson et al., 1971; Thompson et al., 1973

Prescott et al., 1976

Study

impaired elimination

impaired elimination grossly impaired elimination impaired elimination

impaired elimination

Effect

impaired metabolism virtual cessation of lidocaine metabolism decreased hepatic blood flow in proportion to cardiac index impaired metabolism

decreased hepatic blood flow + impaired metabolism

Mechanism

TAaLE 10. Drug Disposition and Metabolism in Patients With Cardiac Disorders

Drug

lidocaine

Myocardial infarction (uncomplicated)

Disorder

Clinical relevance

avoid repeated doses or infusion therapeutic blood levels with slower infusion rates risk of toxicity, use normal loading dose but reduce infusion rate or frequency of repeated doses, monitor blood levels

therapeutic blood levels obtained with slower infusion rates

tr"

at~

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doses or infusion of lidocaine should be avoided in this situation. In patients with uncomplicated acute myocardial infarction, the lidocaine elimination half-life was 4.3 hr compared with 1.4 hr in healthy controls (Prescott et al., 1976). The presence of concomitant cardiac failure was associated with a further prolongation of lidocaine half-life to 10.2 hr. Reduced hepatic blood flow is undoubtedly a major determinant of impaired lidocaine elimination in cardiac failure. However, in patients with acute myocardial infarction and overt cardiac failure, antipyrine elimination was also decreased (by about 50%); the elimination half-life reverted to normal values during convalescence (Prescott et al., 1976). The reduction in hepatic blood flow should not itself account for decreased hepatic clearance of antipyrine because this compound has low hepatic intrinsic clearance with an hepatic extraction ratio of 0.03. Rather, the findings indicate that, in addition to the changes in hepatic blood flow, hepatic drug oxidation is impaired in cardiac failure. This presumably results from factors such as regional tissue hypoxia and interruption of intermediary metabolism which is required for NADPH generation (oxygen and NADPH are both required for mixed function oxidation, the process loosely termed 'drug oxidation' in this review). Theophylline metabolism is also impaired during cardiac failure (Zwillich et al., 1975; Piafsky et al., 1977; Jenne et al., 1977; Vicuna et al., 1979). Like antipyrine, theophylline is slowly but extensively metabolized by hepatic mixed function oxidases so that theophylline elimination is essentially independent of hepatic blood flow. Zwillich et al. (1975) identified severe cardiac or pulmonary disease (or both) as important underlying factors among eight patients who developed grand mal seizures as a result of toxic theophyUine blood levels during aminophylline treatment. Several authors have noted that intersubject variability of theophylline elimination half-life is greatly increased (up to 20-fold) in patients with cardiac failure. Impaired theophylline metabolism is especially likely during acute pulmonary oedema and during cardiac failure complicating chronic obstructive pulmonary disease (that is, in cor pulmonale) (Piafsky et al., 1977; Jenne et al., 1977; Powell et al., 1978; Ogilvie, 1978; Vicuna et al., 1979; Westerfield et al., 1981). In these situations, the volume of theophylline distribution does not appear to be altered (Piafsky et al., 1977; Powell et al., 1978) so that the usual loading dose of 5.6 mg/kg body weight can be administered safely. However, plasma concentrations and toxicity would be unpredictable after repeated bolus doses or constant infusion so that reduced infusion rates and frequent monitoring of blood levels are recommended for the use of theophylline in these patients (Vicuna et al., 1979; Westerfield et al., 1981). This subject has been reviewed elsewhere (Ogilvie, 1978). 7.3. RESPIRATORY DISEASE Cigarette smoking enhances antipyrine (Hart et al., 1976) and theophylline metabolism (Jenne et al., 1975; Hunt et al., 1976). Hence, as an etiologic factor relevant to common heart and lung disorders, smoking contributes to the variability in rates of theophylline metabolism in patients with cardiopulmonary disease (Powell et al., 1978). Uncomplicated asthma or chronic obstructive pulmonary disease are not associated with clinically important abnormalities of drug metabolism (Simons et al., 1978; Ogilvie, 1978). In one study, Powell et al. (1978) found a 10-20% increase in theophylline clearance following recovery among patients hospitalized for uncomplicated asthma or chronic bronchitis. Acute pneumonia, however, was associated with a 36% reduction in antipyrine clearance that could not be ascribed to hypoxemia (Sonne et al., 1985). Moreover, in patients with asthma or chronic bronchitis complicated by pneumonia or cardiac failure there may be a 50-75% reduction in theophylline clearance; this is reversible upon recovery (Jacobs and Senior, 1974; Hendeles et al., 1977; Powell et al., 1978; Vicuna et al., 1979). Changes in theophylline metabolism during the course of an acute illness provide an additional problem in the use of this agent. Reduced maintenance doses of theophylline and therapeutic drug monitoring are recommended for patients with complicated airways disease (Powell et al., 1978).

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7.4. EFFECTS OF HYPOXEMIA ON DRUG METABOLISM Hypoxemia appears to be the factor most likely to cause impaired oxidative drug metabolism in cardiopulmonary disease (Table 9) (Jones, 1981). In some studies, in which acute hypoxemia did not appear to be associated with altered drug metabolism, a confounding effect of concomitant drug administration seems possible (Simons et al., 1978), and this appears even more likely in the published studies of chronic hypoxemia (Sotaniemi et al., 1971a,b; Cusack et al., 1986). Cumming (1976) observed that patients with lung disease whose PaO2 was less than 55 mm Hg had a prolonged antipyrine half-life (18.4 hr) compared with those whose PaO2 was greater than 55 mm Hg (8.4 hr). In contrast, Agnihotri et al. (1978) found enhanced antipyrine clearance in eight patients with chronic pulmonary disease. It has been shown that the liver in intact rats or when perfused e x vivo is more sensitive to the effects of lowered oxygen tension than are microsomal preparations studied in vitro (Cumming and Mannering, 1970; Roth and Rubin, 1976; Jones et al., 1984). Acute hypoxemia decreased theophylline biotransformation in rabbits (Letarte and du Souich, 1984). It should also be borne in mind that acute hypoxemia may alter hepatic blood flow; a P~O2 of 8% leads to a 60% reduction of splanchnic blood flow (du Souich et al., 1978). Tissue hypoxia also contributes to acidosis which some authors believe has a separate and important effect on theophylline disposition (section 7.5). Moreover, hypoxemia may decrease protein binding resulting in an increase in the free drug fraction, and it may also affect renal excretion of drugs (du Souich et al., 1978). In contrast to acute hypoxia, which is associated with impaired hepatic drug metabolism, chronic hypoxia may actually stimulate oxidative drug metabolizing enzymes (Table 9) (Agnihotri et al., 1978; du Souich et al., 1978). In mice and rats, chronic hypoxia equivalent to living at an altitude of 6000 m stimulated hexobarbital, zoxazolamine and pentobarbital metabolism (Merritt and Medina, 1968; Medina and Merritt, 1970) as well as increasing hepatic levels of cytochrome P-450 (Ou et al., 1980). The mechanism for these changes is unclear but it is not related to enhanced heme turnover (Ou et al., 1980). In patients, Sotaniemi et al. (1971a) reported a 33% shortening of tolbutamide half-life in patients with chronic asthma (who were taking a variety of unspecified medications), all of whom were noted to be hypoxemic. In patients with chronic hypoxemia due to chronic obstructive pulmonary disease or pulmonary fibrosis, tolbutamide clearance was increased to 180% of control values (Sotaniemi et al.,1971b) while antipyrine clearance was increased by 50% (Agnihotri et al., 1978). Moreover, Cusack et al. (1986) observed that correction of hypoxemia (by home oxygen treatment) in patients with chronic hypoxic lung disease failed to enhance theophylline clearance. The reason for 'adaptation' of drug metabolism in chronic hypoxia is obscure. Whether this process would necessitate an alteration of the doses required for some drugs to achieve therapeutic blood levels has not been ascertained. 7.5. EFFECTS OF HYPERCAPNIA AND ACID-BASE DISTURBANCES ON DRUG METABOLISM

Letarte and du Souich (1984) found that metabolic acidosis did not have an independent effect on theophylline kinetics in rabbits, although hypercapnia and hypoxemia both were independently associated with raised serum theophylline concentrations (Table 9). In this study, theophylline protein binding was not altered by pH, carbon d;oxide or oxygen concentrations. In dogs, respiratory acidosis slightly increased theophylline clearance, although the volume of distribution was not altered (Kolbeck et al., 1978; Clozel et al., 1981). In contrast, Vallner et al. (1979) and Resar et al. (1979) both considered that acidosis contributed to the variability of theophylline kinetics in patients with acute exacerbations of chronic obstructive pulmonary disease and that an increased volume of distribution was a major factor in producing these changes. Cusack et al. (1986) found that the volume of theophylline distribution increased by 25% with a change in arterial pH from

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7.45 to 7.35. This is an important finding since it implies a need to increase loading doses in acidotic patients in order to obtain therapeutic blood levels of theophylline. None of these studies, however, has provided any direct evidence for a specific effect of pH on theophylline metabolism. While it is difficult to draw conclusions from the available data (Table 9), it seems unlikely that hypercapnia and pH changes have important effects on hepatic drug metabolism that are separate from concomitant hypoxia, although changes in other pharmacokinetic variables may be mediated by acidosis. Acknowledgemems--Research in the author's laboratory is supported by the Australian National Health and

Medical Research Council and the Bortolussi Trust Fund of the Westmead Hospital. I am grateful to Dr. Michael Murray for stimulating discussions and for constructive criticism of an earlier draft of this review and to Diane West who skilfully and patiently typed the manuscript.

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