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Pharmac. Ther. Vol. 48, pp. 71-94, 1990 0163-7258/90 $0.00 + 0.50 Printed in Great Britain. All rights reserved © 1990 Pergamon Press plc

Associate Editor: M. J. BRODIE

ENZYME INDUCTION AND INHIBITION

M. BARRY* a n d J. FEELY

Department of Pharmacology and Therapeutics, Trinity College Medical School, St James's Hospital, Dublin 8, Ireland

Abstract--The rate and extent of drug metabolism significantly influences drug effect. Enzyme induction by increasing the metabolism of drugs may result in important drug interactions. Other implications of enzyme induction include alterations in the metabolism of endogenous substrates, vitamins and activity of extrahepatic enzyme systems. Similarly a wide range of drugs may produce clinically significant drug interactions following enzyme inhibition. Assessment of enzyme induction and inhibition in man involves diverse methods including the use of model drugs.

C O N T E N T S

I. Introduction 71 2. Enzyme Induction, Underlying Mechanism 73 3. Assessment of Enzyme Induction and Inhibition in Man 74

3.1. Model drug substrates 74 3.2. Antipyrine 74 3.3. Breath test analysis 75 3.4. Endogenous substrates 75

3.4.1. ~, Glutamyltransferase 75 3,4.2. Urinary D glucaric acid 76 3.4.3. Urinary 6 fl hydroxycortisol 76 3.4.4. Plasma bilirubin 77

4. Enzyme Inducers 77 4. l. Rifampicin 77 4.2. Phenobarbitone 78 4.3. Phenytoin 78 4.4. Carbamazepine 79 4.5. Cigarette smoking 79 4.6. Ethanol 79 4.7. Diet and nutrition 80

5. Implications of Enzyme Induction 80 6. Induction of Extrahepatic Drug Metabolizing Enzymes 82 7. Enzyme Inhibition, Underlying Mechanism 83 8. Enzyme Inhibitors 84

8. I. Cimetidine and other ulcer healing drugs 84 8.2. Cardiovascular drugs including calcium antagonists and fl-blockers 85 8.3. Chemotherapeutic agents 86 8.4. Anti-inflammatory and analgesic drugs 86 8.5. Neuroleptics 87 8.6. Oral contraceptives 87 8.7. Valproic acid 87 8.8. Disulfiram 87 8.9. Allopurinol 87 8.10. Monoamine oxidase inhibitors 87

9. Conclusion 88 References 88

1. I N T R O D U C T I O N dependent on the drug concentration available at the receptor site (Ariens, 1979). While several factors

The pharmacological effect of a drug results f rom its including absorption, distribution, protein binding interaction with its receptor and is therefore critically and elimination may influence drug concentrat ion at

the receptor site, by and large the rate of drug *Present address: Department of Pharmacology and elimination is a principal determinant for many

Therapeutics, University of Liverpool, New Medical Build- drugs. Thus factors influencing drug metabolism may ing, Ashton Street, P.O. Box 147, Liverpool L69 3BX, U.K. be expected to significantly alter drug effect.

'71

72 M. BARRY and J. FEELY

Organ function end diteese

Liver Gastrointestinal Renal Cardiovascular Endocrine

% / Disease

: + i " 1 'dd+ ( ' , / Infections Sex % s Malignancy Pregnancy • Genetic constitution Enzyme inducers rhythmCircadian / % Enzyme inhibitors

Environment / lifestyle / /

Occupation Exercise / Diet Cigarettes

FI~. 1. Overlapping variables that influence rate and extent of drug metabolism in liver.

A large number of drugs, toxins and endogenous metabolizing enzyme systems including age, sex, substances are lipid soluble and would be expected to dietary constituents, smoking and drugs (Fig. 1). The accumulate in the body disrupting cellular activity if metabolizing activity of the enzymes may be in- elimination did not take place. A fundamental role of creased following administration of certain xeno- drug metabolism is the conversion of these lipophilic biotics. When this results from the selective increase compounds into more water soluble metabolites in the concentration of enzyme the term enzyme which are readily excreted thus limiting drug action induction is used to describe the process (Goldberg, and potential toxicity (Woolf and Jordan, 1987). 1980). Likewise the activity of the hepatic drug

It is generally accepted that the liver is the principal metabolizing enzymes may be decreased following site of drug metabolizing activity. However the con- drug administration. This usually involves a direct tribution of extra hepatic sites, e.g. kidney, to drug effect on the enzyme rather than a change in enzyme metabolism is becoming increasingly recognized biosynthesis and is termed enzyme inhibition. (Vainio and Hietanen, 1980). The enzymes concerned The consequences of enzyme induction and inhi- with drug metabolism are located primarily in the bition will be determined by the relative activity of the hepatic endoplasmic reticulum (Mannering, 1981). parent drug and the formed metabolite. Usually the The conversion of lipophilic compounds to more metabolite will be less active than the original corn- polar metabolites proceeds via two metabolic conver- pound and therefore enzyme induction will result in sions. The first conversion or phase one reactions a reduction in the pharmacological effect due to the include oxidation, reduction and hydroxylation reac- increased drug metabolism. Enzyme inhibition would tions (Woolf and Jordan, 1987). The metabolic inter- result in an increased concentration of parent drug mediates produced may then undergo phase two or at the receptor site and hence an increase in drug conjugation reactions. This involves the conjugation action. Also the metabolite formed during the bio- of the metabolite with glucuronic, sulfuric and transformation may be chemically reactive, e.g. cyclo- mercapturic acids and amino acids (Caldwell, 1982). phosphamide to aldophosphamide, prednisone to The most influencial enzymes involved in the bio- prednisolone and hence enzyme induction may result transformations are the hepatic microsomal P-450 in increased toxicity due to the increased production mixed function oxidases. They catalyze phase one of the toxic intermediate (Bolt et al., 1975). reactions with the insertion of molecular oxygen into One of the major factors leading to the realization drug molecules via the cytochrome P-450 enzyme- of the significance of enzyme induction and inhibition substrate complex. This enables transformations such in man is the common practice of polypharmacy. The as N, S and O deaikylation, aliphatic and aromatic resultant drug interactions observed have produced hydroxylations to be carried out. many relevant examples of the processes of induction

The enzymes catalyzing these reactions are and inhibition. In this clinical setting interactions versatile and nonspecific while the rate of activity involving drugs with a narrow therapeutic index, e.g. may be under strong genetic influences. Numerous oral anticoagulants, antiepileptics etc. will be of external and physiological factors may affect drug greater importance as moderate changes in drug

Enzyme induction and inhibition 73

metabolism could result in significant changes in isoenzyme resulting in increased synthesis of the pharmacological activity, isoenzyme (Jones et al., 1986).

The effects of enzyme induction and enzyme inhi- Proliferation of smooth endoplasmic reticulum bition are reversible on withdrawal of the inducing or may be regarded as a morphological expression of inhibiting compound although the rate of onset and enzyme induction. An increase in the smooth endo- offset of these processes may differ (MacDonald and plasmic reticulum content of animal and human Robinson, 1968). hepatocytes has been observed following treatment

with the enzyme inducing agent rifampicin (Jezequel et al., 1971).

The number of compounds known to stimulate the 2. ENZYME INDUCTION, UNDERLYING activity of drug metabolizing enzymes is large and

MECHANISM includes compounds of most pharmacologically ac- In recent years the mono-oxygenase system has tive groups. The apparent nonspecificity of inducers

been solubilized and various components purified, suggests some common characteristics. In fact many The system includes NADPH cytochrome P-450 re- enzyme inducing agents are lipid soluble at physio- ductase, phospholipid and a number of cytochrome logical pH and possess relatively long elimination P-450 isoenzymes (Goldstein, 1984) which are present half-lives. The ability to bind to cytochrome P-450 is in the uninduced state and possess overlapping another common characteristic. The ability of some specificities. Exposure to a variety of foreign corn- water soluble barbiturate derivatives to stimulate pounds may preferentially increase the hepatic con- drug metabolizing enzymes represents an exception tent of specific forms of cytochrome P-450. Therefore to the general rule. The importance of achieving high the process of enzyme induction involves the adaptive hepatic concentrations of the inducing agent is also increase in the content of specific enzyme in response appreciated (Gelehrter, 1972). to the enzyme inducing agent. At least four distinct The ability of enzyme incuding agents to increase classes of enzyme inducing agents are known to exist the rate of phase one reactions is recognized. How- (Adesnik et al., 1981). They induce distinct subsets of ever administration of these agents may also increase P-450 isozymes, a fact that suggests the isozymes are the activity of phase two enzymes, such as glucuronyl under separate regulatory control. The classes of transferase as demonstrated by the ability of oral enzyme inducing agents include: contraceptive steroids to increase glycine and glu-

curonide conjugation pathways (Miners et al., 1986). (i) phenobarbitone and a wide variety of struc- The time course of induction will vary with differ-

turally unrelated compounds; ent inducing agents. Increased transcription of P-450 (ii) polycyclic aromatic hydrocarbons such as 3- mRNA has been detected in the rat nucleus as early

methylcholanthrene; as 1 hr after administration of phenobarbitone. The (iii) steroids including pregnenalone 16 ct carboni- maximum induction with phenobarbitone may be

trile; apparent in animals after 48-72 hr (Eriksson, 1973). (iv) ethanol. However induction following 3 methylcholanthrene

may reach a maximum at 24 hr. Less potent inducers The hypolipidemic agent clofibrate may represent a of hepatic drug metabolism may take a much longer fifth class of enzyme inducing agent. The proposed time course of induction, e.g. antipyrine. The time mechanism of enzyme induction involves the deacti- course of induction is a reflection of the enzyme vation of the active repressor, a product of the turnover for the particular inducing agent. In man a regulatory gene component. The absence of the re- turnover rate ranging from 1 to 6 days was found pressor at the operator gene facilitates the binding of resulting from the interaction between carba- the particular RNA polymerase to the promotor mazepine and clonazepam (Lai et al., 1978). This may gene. This in turn facilitates the expression of the also reflect the considerable intersubject variation in structural gene and the production of mRNA enzyme induction. A number of studies suggest that resulting in increased protein (enzyme) synthesis subjects who are initially slow metabolizers of drugs (Hardwick et al., 1983). have a greater potential for induction than subjects

Complementary DNA, RNA hybridization studies with initial high rates of metabolism (Vesell and Page, indicate that phenobarbitone induces nucleotide 1969). However it is now recognized that intersubject mRNA which codes for the translation of the pheno- variance in steady state drug concentrations may be barbitone induced P-450 in vitro. An increase in as wide following induction as before induction mRNA by thirty-fold was observed with phenobarbi- (Branch and Shand, 1979). tone increasing the transcription of the drug induced From the many experiments in animals and man P - 4 5 0 g e n e ( W a n g e t a L , 1983). Despite the fact that it is apparent that enzyme induction is a dose- phenobarbitone appears to regulate cytochrome P- dependent phenomenon (Breckenridge et al., 1973). 450 by increasing transcription of mRNA, for pheno- Induction is easily evoked under appropriate con- barbitone induced cytochrome P-450s there is to date ditions in animal experiments with numerous com- no evidence for interaction of the drug with a specific pounds in a high dose range. Because the high receptor. In contrast there is good evidence that concentrations required for induction are rarely 3-methylcholanthrene and other polycyclic aromatic achieved without toxic side effects in man, pharmaco- hydrocarbons interact with a specific cytoplasmic logical drug interactions from induction are only seen receptor (Ah receptor) which may enter the nucleus, with a small number of compounds. These include the The drug receptor complex then interacts with the antiepileptic agents e.g. phenobarbital, phenytoin regulatory gene of the specific cytochrome P-450 and carbamazepine and the antituberculous agent


TABLE 1. Some Enzyme Inducers 3.1. MODEL DRUG SUBSTRATES

Barbiturates Marijuana smoke For a drug to be a useful substrate for assessing Carbamazepine Meprobamate hepatic drug metabolizing enzyme activity, its clear- Cigarette smoke Phenytoin Dichloralphenazone Primidone (phenobarbitone) ance from plasma or the rate of appearance of a Ethanol (chronic) Rifampicin metabolite should be directly related to the activity of Glutethimide Sulfinpyrazone the enzyme(s) responsible for its metabolism. Other Griseofulvin desirable properties required for marker drugs

include simple, e.g. one or two compartmental, pharmocokinetics, with elimination entirely depen-

rifampicin (McInnes and Brodie, 1988). Given this dent on hepatic metabolism but metabolism independent of liver blood flow or plasma protein binding. limitation it is possible in man to compare drugs as

enzyme inducers by the construction of dose- All routes of metabolism and enzymes involved response curves. The effect of phenobarbitone on should be known. For drugs administered orally the warfarin and antipyrine metabolism has been found absorption should be rapid and complete otherwise to be dose dependent as is the effect of rifampicin on the substance is best given parenterally (Wilkinson antipyrine and cortisol hydroxylation. In clinical and Shand, 1975). practice most inducing agents administered in therapeutic doses will produce maximum effect within 3.2. ANTIPYRINE fourteen days. It is also recognized that many potent inducing agents may actually inhibit drug metabolism Antipyrine has proved the most popular marker during the first few hours following administration drug for assessing drug metabolism in man. It fulfils prior to the onset of induction although this may not the above requirements for the ideal marker drug be detectable in man. Although numerous chemical with almost complete hepatic metabolism, less than and pharmacological compounds are capable of en- 10% plasma protein binding and less than 5% ex- zyme induction (Table 1), of greatest interest are creted unchanged in the urine. Its single compartment those that produce clinically apparent drug inter- kinetics together with its relative ease of measurement

in either plasma or saliva by gas liquid chromatog- actions resulting from the induction process. Import- ant examples of these drugs are discussed later, raphy, radioimmunoassay or high performance liquid Numerous methods have been described for the chromatography also render it a suitable marker drug detection of enzyme induction and inhibition. The (Stevenson, 1977). Vesell has shown a high degree of methods are common to both and summarized here. reproducibility of antipyrine disposition in individ-

uals studied on up to 8 different occasions, enabling subjects to act as their own controls (Vesell, 1979). This is suited to the study of the effect of various

3. ASSESSMENT OF ENZYME INDUCTION environmental conditions on drug metabolism. Anti- AND INHIBITION IN MAN pyrine clearance which relates the concentration of

the drug to the rate of elimination should be used as The assessment of enzyme induction in man may be conducted by both in vi tro and in vivo studies, it is a better indicator of drug elimination than Direct measurement of enzyme activities, e.g. 7 antipyrine half life as assessed from the plasma ethoxy phenacetin O de-ethylase from liver biopsy drug concentration decay curve (Branch and Shand, samples before and after administration of the induc- 1979). Antipyrine clearance has been shown to in- ing/inhibiting compound is an obvious method, crease and half life decrease following administration However the sample may not be representative of the of a wide range of inducing agents including liver as a whole and there is not always a strong pesticides and drugs. Similarly enzyme inhibiting correlation with in vivo assessment. Furthermore agents increase antipyrine elimination half life ethical and practical considerations restrict the use of (Tables 2 and 3). this method (Sesardic et al. , 1988). Therefore more indirect methods are required. Changes in the pharmacokinetics of a marker drug like antipyrine or TABLE 2. Substances which Decrease Antipyrine Ha l f Life changes in metabolite form~ttion of the drug under in Man study are commonly used to assess drug metabolizing activity (Vesell, 1979). In assessment of enzyme in- Drug Reference duction an alternative approach is to monitor Phenobarbitone Vesell and Page, 1969 changes in the disposition of an endogenous sub- Organochlorine compounds Kolmodin et al., 1969 stance such as plasma glutamyl transpeptidase and Ethanol Vesell et al., 1971b bilirubin or urinary excretion of o-glucaric acid and Spironolactone Huffman et al., 1973

Tricyclic antidepressants O'Malley et al., 1973a 6 fl hydroxycortisol (Hildebrandt et al., 1975; Heir- Chlorimipramine O'Malley et al., 1973b wegh and Blanckaert, 1981; Hunter et al., 1974; Park, Phenytoin Petruch et al., 1974 1981). The advantage of this approach is the exclu- Quinine Berlin et al., 1975 sion of possible effect of marker drugs on the metab- Testosterone Johnsen et al., 1976 olizing enzymes. It is the changes in the endogenous Rifampicin Miguet et aL, 1977 compounds rather than their absolute levels which Ascorbic acid Houston, 1977 are important. While the specificity and sensitivity of Glutethimide Jackson et al., 1978 this approach may be limited in certain circumstances Antipyrine Ohnhaus and Park, 1979 it may prove most informative. Carbamazepine Moreland et al., 1981


TABLE 3. Substances which Increase Antipyrine H a l f Life 3.3. BREATH TEST ANALYSIS in Man

Assessment of drug metabolism by breath analysis Drug Reference affords an alternative method of assessing possible Allopurinol Vesell et aL, 1970 enzyme inducers and inhibitors in man. The substrate Levodopa Vesell et al., 1971a most commonly used is aminopyrine although Norethynodrel and Mestranol Carter et al., 1974 caffeine and diazepam have been employed also. The Disulfiram Vesell et al., 1975 substrate is labeled with a 14C which undergoes Aminopyrine Vesell et al., 1976 hepatic demethylation and the resultant radiolabeled Delta 9 tetrahydrocannabinol Benowitz and Jones, 1977 Cimetidine Serlin et al., 1979 carbon dioxide is excreted in the breath. In the Propranolol Bax et al., 1981 aminopyrine breath test the percentage of adminis- Metoprolol Bax et al., 1983 tered radiolabeled 14C aminopyrine excreted as ~4CO2

2 hr after the oral dose (Hepner and Vesell, 1974) is used as the index of hepatic demethylation. Studies in animals demonstrate a correlation between exhaled

While antipyrine clearance has been widely used 14CO2 following administration of ~4C aminopyrine to document environmental and drug induced change and the mass of hepatic microsomal mixed function in hepatic drug metabolizing oxidative activity, monoxygenase system (Lauterburg and Bircher, changes in clearance are not usually predictable of 1976). The aminopyrine breath test has also been the extent of alteration in the clearance of other shown to be a useful test for enzyme induction in drugs under the same influence. Another disadvan- patients taking anticonvulsant drugs indicating that it tage of antipyrine as a model drug is its ability to act is sensitive to changes in cytochrome P-450 (Hepner as a mild enzyme inducer; it therefore may stimulate et al., 1977). N demethylation is the major biotrans- its own metabolism and the metabolism of other formation for aminopyrine in man. In recent studies drugs such as warfarin and diazepam (Bax et al., the aminopyrine breath test has been used to demon- 1981; Ohnhaus and Park, 1979; Breckenridge et al., strate the inhibitory effect of amiodarone and cotri- 1971). This effect is however only apparent after moxazole on hepatic drug metabolism (Barry et al., pretreatment for at least 7 days (Ohnhaus et al., 1986; Duenas-Laita et al., 1986). 1979b).

Measurement of the kinetics of antipyrine metab- 3.4. ENDOGENOUS SUBSTRATES olites has also been used for assessing the activity of drug metabolizing enzymes. Several studies have indi- Noninvasive methods for the assessment of drug cated that the three major metabolites of antipyrine metabolizing capacity of the liver do not require the representing three separate enzymatic processes are administration of a test drug such as antipyrine. produced by different forms of cytochrome P-450 in Changes in the disposition of endogenous com- man (Danhof et al., 1982). Drugs and disease states pounds or altered activity of a readily accessible have been shown to exhibit either a nonselective or enzyme may provide a useful noninvasive method of selective effect on antipyrine metabolism. Barbitu- assessing enzyme induction in man. A variety of rates, sulfinpyrazine and hyperthyroidism have been substances have been proposed. shown to nonselectively increase the rate of antipyrine oxidation (Saenger et al., 1976). Selective 3.4.1. 7 Glu tamy l t rans f e rase induction by rifampicin results in increased formation of the norantipyrine metabolite. On the other hand This enzyme is found in many tissues such as phenytoin and carbamazepine selectively induce the kidney, liver, pancreas and testes (Orulowski, 1963). formation of 4 hydroxy antipyrine and 3 hydroxy- It catalyzes the transfer of 7 glutamylpeptides (7 GT) methyl antipyrine. Testicular cancer seemed to be from glutathione to other peptides or amino acids. associated with more pronounced induction of 3 Initially thought to be primarily located in the endo- hydroxymethyl antipyrine (Schellens and Breimer, plasmic reticulum highest concentrations are found in 1987). The measurement of the activities of the plasma membranes of cells. The function of this separate metabolite pathways may be more reliable enzyme is not related to drug metabolism. Neverthe- for correlation studies than the overall rate of less raised plasma concentrations have been found in metabolism. It has been found that the rate of patients receiving enzyme inducing agents such as formation of 4 hydroxy antipyrine was very strongly anticonvulsants and hypnotics (Hildebrandt et al., correlated with theophylline clearance (Teunissen 1975; Table 4). et al., 1985). Following these observations the plasma level of

The lack of predictive value of antipyrine kinetics the enzyme was proposed as an indicator of enzyme in estimating how the liver will handle other drugs induction. However, drugs not regarded as enzyme has prompted the study of other potential marker inducers also resulted in increased ), GT levels, e.g. drugs. Other drugs used as model substrates include benzodiazepines and imipramine. Furthermore the diazepam, hexobarbitone, phenylbutazone, phena- recognized enzyme inducer rifampicin while increas- cetin, quinine, propranolol, tolbutamide and warf- ing antipyrine clearance and urinary 6 fl hydroxy- arin. The latter three have the added attraction of cortisol (other indices of enzyme induction) did not allowing one to follow concomitant changes in consistently result in significant increases in 7 GT dynamics (heart rate, blood sugar, PTT) in addition levels. Studies of phenobarbitone induction in rabbits to kinetics but all again have limited predictive showed an increase in ~ GT concentrations in parallel value, with hepatic cytochrome P-450 content but only after


TABLE 4. Substances which Increase Plasma ? GT TABt~ 5. Some Substances which Increase Urinary Concentration in Man Excretion o f D Glucaric Acid in Man

Drug Reference Drug Reference

Anticonvulsants Rosalki et al., 1971 Aminopryrine Aarts, 1965 Ethanol Rosalki and Rau, 1972 Phenylbutazone Aarts, 1965 Nitrazepam Whitfield et al., 1973 Barbiturates Hunter et al., 1971a Phenobarbitone Hildebrandt et al., 1975 DDT Hunter et al., 1971b Antipyrine Ohnhaus and Park, 1979 Spironolactone Huffman et al., 1973 Rifampicin Back et al., 1979 Antipyrine Davis et al., 1974 Imipramine Tazi et al., 1980b Phenobarbitone Lantham et al., 1975

Carbamazepine Lai et al., 1978 Rifampicin Ohnhaus and Park, 1979

eighteen days of treatment (Tazi et al., 1980a). Paral- lel in vi tro studies showed the longer phenobarbitone was administered the more readily ), GT was solubil- P-450 content and urinary D glucaric acid following ized from hepatic plasma membranes. The plasma y phenobarbitone treatment (Hunter et al., 1973). Simi- GT concentration is therefore dependent on at least lady in man phenobarbitone has been shown to two factors: (i) induction of hepatic ? GT and (ii) increase D glucaric acid by seven-fold (Roots et al., disturbances of hepatic plasma membranes. As these 1977). Increases in D-glucaric acid excretion have two functions are not necessarily associated the as- been shown to correlate with the clearance of the sessment of enzyme induction by plasma levels of 7 marker drug antipyrine though not with ~ GT levels. GT must be regarded as unreliable. The effect of No relation has been found between excretion of o concomitant disease processes on ? GT levels must glucaric acid and basal levels of metabolism. The also be considered as raised levels are commonly dose-dependent effect of enzyme inducers is further found in patients with liver damage, high alcohol suggested by the dose dependency in production of o intake and pancreatitis (Kryszewski et al., 1973). glucaric acid with little or no change in the pro-

duction following low dose phenobarbital (30 mg) 3.4.2. Urinary D Glucaric A c i d and a seven-fold increase with higher doses of pheno-

barbitone (300-500mg/day) (Roots et al., 1977). D glucaric acid, first identified in mammalian urine However low dose phenobarbitone 30 mg does pro-

in 1963, is an end product of carbohydrate duce a significant increase in drug oxidation rates metabolism via the glucuronic acid pathway which is (Perucca et al., 1981; Price et al., 1986). Therefore a metabolic route, branching from glycogenolysis induction of hepatic drug metabolizing enzymes may (Fig. 2)(Marsh, 1963). be dissociated from increases in D glucaric acid

Since the original report by Aarts that treatment excretion. This lack of sensitivity renders D glucaric with phenobarbitone or antipyrine caused an increase acid excreted less useful in detecting enzyme induc- in urinary D glucaric acid, many workers have advo- tion. The mechanism whereby enzyme induction re- cated the use of this parameter in assessing enzyme suits in increased D glucaric acid production is not inducing agents (Aarts, 1965). Urinary D glucaric acid entirely clear. It may possibly be due to a feedback production reflects phenobarbitone type induction mechanism involving NADPH production in the mainly, and by virtue of a parallel effect on enzyme pentose phosphate pathway, NADPH being required activities of the glucaric acid pathway and the cyto- for the reduction of cytochrome P-450. Alternatively chrome P-450 system glucaric acid provides an in- D glucaric acid may be an index of phase two drug direct parameter of changes in cytochrome P-450 metabolism. As many mammals convert D glucuronic activity, Many drugs known to be enzyme inducers in acid to ascorbic acid it is only in animals incapable man, stimulate D glucaric acid excretion in urine of this conversion, e,g, primates and guinea pigs, that (Table 5). increases in D glucaric acid may be used as an index

Experimental data from animal studies found a of increased enzyme activity. Despite the reservations significant correlation between hepatic cytochrome o glucaric acid has proved a useful tool for the

detection of enzyme induction.

Uridine diphosphoglucose 3.4.3. Urinary 6 fl H y d r o x y c o r t i s o l

(UDP glucose) 6 fl OH cortisol is a minor metabolite (2-6%) of

cortisol formed primarily in the endoplasmic reticu- UDP glucuronic acid lum of hepatocytes by the mixed function oxidases

and is excreted unconjugated in the urine (Frantz et al., 1961). As cortisol hydroxylation is directly depen-

D gl ucuronic acid dent upon the activity of the hepatic mixed function oxidase system the excretion of 6/~ OH cortisol may be expected to reflect changes in hepatic drug metab-

D glucuronolactone olizing enzyme activity (Ohnhaus and Park, 1979). In fact changes in urinary 6 fl OH cortisol excretion have

D glucaric acid been found to be a useful and sensitive index of microsomal enzyme induction in man (Park, 1981). A

Fro. 2. Formation of D glucaric acid. wide range of drugs and environmental chemicals


TABLE 6. Substances Increasing the Urinary Excretion excretion (Park, 1981). Enzyme inhibitors including of6f l Hydroxycortisol in Man cimetidine and isoniazid may reduce 6 fl hydroxy

Drug Reference cortisol excretion but the changes are small and cannot be used to accurately monitor enzyme inhi-

op DDD Bledsoe et al., 196g bition in man (Brodie et al., 1981). Phenobarbitone Burnstein and Klaiber, 1965 Phenylbutazone Kuntzman et al., 1966 DDT Poland et al., 1970 3.4.4. Plasma Bilirubin Pentobarbitone Berman and Green, 1971 Spironolactone Huffman et al., 1973 Bilirubin is taken up by hepatocytes where it is Antipyrine Davis et al., 1974 conjugated with glucuronic acid and excreted into Carbamazepine Roots et al., 1979 bile. The estimation of plasma bilirubin has been Rifampicin Davis et al., 1974 studied in relation to drug metabolism. Patients

administered phenobarbitone, rifampicin and phenytoin were found to have significantly lower serum

have been found to increase 6 fl OH cortisol excretion unconjugated bilirubin than control subjects. A sig- (Table 6). nificant correlation between plasma unconjugated

The extent of 6 fl OH cortisol production depends bilirubin and antipyrine half life was found (Scott on the daily cortisol formation whose variation may et al., 1979). However plasma bilirubin has been be compensated for by referring 6 fl OH cortisol considered an unreliable index of enzyme induction values to the excretion rates of 17 hydroxy cortico- because plasma concentrations are affected by diet steroids. Hence many workers now use the 6 fl OH and numerous diseases and show diurnal variation cortisol/l 7 hydroxycorticosteroid ratio in the assess- (Hunter and Chasseaud, 1976). ment of enzyme inducing agents. Recent studies have Finally it must be stressed that no endogenous been greatly facilitated by the development of sensi- compound or probe drug can yet replace the tive and specific radioimmunoassay and high per- measurement of the actual drug with which the formance liquid chromatography assays for 6 fl OH patient is being treated. However, they do provide cortisol (Roots et al., 1979). The increase in 6 fl OH useful tools for better understanding the various cortisol excretion produced by enzyme induction has aspects underlying enzyme induction and inhibition been shown to reflect an increase in 6 fl OH cortisol in man and may be useful in screening tests. production without a change in cortisol production (Burnstein et al., 1967). A selectivity in the form(s) of cytochrome P-450 catalyzing cortisol 6 fl hydroxylation is suggested from animal studies demonstrating 4. ENZYME INDUCERS cortisol 6 fl hydroxylase activity, a function of cyto- 4.1. RlFAMPICIrq chrome P-450 rather than cytochrome P-448 mixed function oxidase activity. This is supported by the One of the most potent enzyme inducing agents observation that cigarette smoking does not influence known to man is the antituberculous agent ri- 6 fl OH cortisol excretion. Also poor metabolizers of fampicin. Since its introduction to clinical practice spartine and debrisoquine in man have normal 6 fl there have been many reports of associated drug OH cortisol excretion rates (Park et al., 1 9 8 2 ) . interactions largely as a consequence of its inducing

Measurement of 6 fl OH cortisol is particularly properties. Rifampicin has been shown to increase the useful for monitoring the time course of enzyme smooth endoplasmic reticulum of human and guinea- induction. In comparative induction studies anti- i pig hepatocytes (Galehrter, 1972). The increase was pyrine clearance and 6 fl OH cortisol, both direct noted after two days and reached a maximum by five measurements of hepatic mono-oxygenase activity, days. The cytochrome P-450 content of human liver showed a significant correlation but no such corre- has also been shown to increase following rifampicin lation existed for plasma 7 GT or D glucaric acid (Bolt et al., 1975). Furthermore in common with excretion (Ohnhaus and Park, 1979). other agents autoinduction is a property ofrifampicin

Unfortunately urinary 6 fl OH cortisol cannot be and the serum concentration of rifampicin falls on used to predict interindividual differences in the repeated administration to human volunteer subjects 'basal' rate of drug metabolism in man as studies (Acocella et al., 1978). The corresponding increase in have demonstrated a lack of correlation between the rate of formation of the major metabolite antipyrine clearance and 6 fl OH cortisol excretion in deacetylrifampicin supported the concept of induc- healthy volunteers. This may be due to the many tion as a cause of the fall in rifampicin levels. factors known to influence both 6 fl OH cortisol Rifampicin produces maximum changes in the ac- production and antipyrine clearance including sex, tivity of the hepatic drug metabolizing enzymes thyroid function, liver disease, hypertension and within 9-12 days (Park and Breckenridge, 1981). adrenal status. It is also probable that the adrenal Many studies have demonstrated induction by ri- production of 6 fl OH cortisol shows considerable fampicin to be dose dependent (Ohnhaus et al., 1987). interindividual variation. While measurements of 6 fl The induction of drug metabolizing enzymes fol- OH cortisol excretion cannot be used to predict lowing rifampicin treatment was of the order of 'basal' drug metabolism rates in man they may be 60-70% as assessed by the increase in antipyrine employed serially as a simple noninvasive method for clearance in healthy human volunteers. Interestingly detecting enzyme induction and as such are probably the induction of antipyrine clearance in patients with a better index of microsomal enzyme induction pulmonary tuberculosis following rifampicin was of than either plasma ~ GT or urinary D glucaric acid the order of 30% (Teunissen et al., 1984)possibly due


to concomitant therapy. The oxidative routes of , o[ f " ' X / ~ _ / lo . . . . . "~x antipyrine metabolism are differentially induced by •

rifampicin lending further support to the concept of \ 20 i,/ multiple forms of cytochrome P-450, the different 5 o routes of antipyrine metabolism being catalyzed by ,o different forms of cytochrome P-450 (Saenger et al. , 1976). In all studies the clearance of norantipyrine is ! ~ 2.~ f O--o.~-~ ~ i m n e t / ~ . increased to the greatest extent. Furthermore subjects --,., ,. . , . /" with lower initial values of antipyrine clearance t.o "-. -"v" tended to be more inducible than those with higher o clearance (Teunissen e t al. , 1984). The observation ~ ~ -

o $ t~ 2~- 3;~ ~o ~# s6 6~ 72 that patients on long term anticoagulant treatment required an increase in their daily dose during con- Time (oar0 comitant rifampicin treatment was one of the first FIG. 3. Change in steady-state plasma warfarin concen- reported interactions of rifampicin. Further studies in tration and thrombotest produced by phenobarbitone healthy volunteers demonstrated a reduction in the (120mg/day for 30 days). prothrombin time and a corresponding decrease in the plasma half life of warfarin following rifampicin treatment(O'Reilly, 1974).Another clinically import- was seen. Unlike other enzyme inducing agents ant interaction with rifampicin involves the con- phenobarbitone was also found to increase liver comitant administration of the oral contraceptive blood flow (Pirttiaho et al. , 1982). The dose- pill. Mensti'ual disturbances and unplanned pregnan- dependent degree of enzyme induction in patients cies have been reported with this combination. The receiving phenobarbitone and other antiepileptic increased metabolism of both components of oral agents is well recognized (Perucca e t al. , 1984). contraceptives i.e. ethynylestradiol and norethi- Like rifampicin, phenobarbitone can stimulate a sterone is thought to be the underlying mechanism wide range of metabolic routes and one of the earlier (Back e t al. , 1979). The relative importance of the reported interactions with phenobarbitone also in- enhanced metabolism of estrogen and progestagen is volved oral anticoagulants. Breckenridge and Orme unknown. The range of metabolic pathways induced (1971) found that concurrent administration of by rifampicin is apparent from the wide range of phenobarbitone and warfarin resulted in changes in exogenous and endogenous compounds whose steady state plasma warfarin concentrations and anti- metabolism is increased following rifampicin treat- coagulant effect after six days, the maximum effect ment (Table 7). recorded between fourteen and twenty one days

Rifapentine, the cyclopentyl derivative of ri- (Fig. 3). Withdrawal of phenobarbitone in these fampicin, is also capable of enzyme induction patients may, in the absence of an appropriate re- (Durand e t al. , 1986). duction in warfarin dosage, result in fatal hemor-

rhage as drug metabolism reverts to normal resulting 4.2. PI-IENOBARBITONE in higher warfarin concentrations (MacDonald and

Robinson, 1968). The enzyme inducing properties of phenobarbitone The hazards of polypharmacy in the treatment of

have been widely studied in both animals and man. epileptic patients is well recognized and this clinical In animal studies phenobarbital was found to in- setting provides another example of a drug inter- crease the smooth endoplasmic reticulum of liver cells action involving phenobarbitone, in this case with with resultant hypertrophy and increase in liver cell phenytoin whose metabolism is increased (Kutt et al. , mass (Schulte-Hermann, 1974). In human studies 1969). Recent studies suggest that phenytoin inhibits administration of phenobarbitone resulted in in- phenobarbitone metabolism in epileptic patients creased smooth endoplasmic reticulum and cyto- (Kutt, 1984). However the interaction is not now chrome P-450 content. The activity of NADPH thought to be of great clinical significance. Similar to cytochrome P-450 reductase enzyme was also found rifampicin, pregnancies in women taking phenobarbi- to be increased. In addition an increase in liver size tone with oral contraceptives have been described.

Again the relative contribution of the induction of estrogen or progestogen components is unknown.

TABLE 7. Drug Interactions with Rifampicin Examples of drug interactions with phenobarbitone Drug Reference are shown in Table 8.

Enzyme induction by other barbiturates including Rifampicin A c o c e l l a e t a l . , 1 9 7 1 amylobarbitone, barbitone, butobarbital, quinal- Warfarin O'Reilly, 1974 barbital and vinbarbital has been demonstrated Digitoxin Peters et al., 1974 (Anthintz e t al. , 1968). A variation in the potency of Cortisol Edwards et aL, 1974 Hexobarbitone Zilly et al., 1975 induction of these agents is recognized and an inverse Dapsone Gelber et al., 1975 relationship between enzyme induction and plasma Ethynylestradiol Bolt et al., 1975 half life has been found. Norethisterone Back et al., 1979 Oral hypoglycemics Kenny and Strates, 198 l Antipyrine Bennett et al., 1982 4.3. PHENYTOIN Metoprolol Bennett et al., 1982 The anticonvulsant phenytoin has been found Rifapentine Durand et al., 1986 to induce the metabolism of other exogenous and


TABLE 8. Drug Interactions with Phenobarbitone Other drugs with enzyme inducing properties in- Drug Reference clude the hypnotic glutethimide and the anti-inflam-

matory agent phenylbutazone (Jackson et al., 1978; Phenytoin Cucinell et al., 1965 Lewis et al., 1974). Bishydroxycoumarin Cucinell et al., 1965 Some evidence of enzyme inducing properties for Cortisol Burnstein and Klaiber, 1965 Desmethylimipramine Hammer and Sjoqvist, 1967 meprobamate, spironolactone and diazepam have Testosterone Southern et al., 1969 been produced but the clinical significance of these is Antipyrine Vesell and Page, 1 9 6 9 undetermined. Chlorpromazine Forrest et al., 1970 Quinine Saggers et al., 1970 4.5. CIGARETTE SMOKING Diazepam Viala et al., 1971 Glyceryltrinitrate Bogaert et al., 1971 Cigarette smoking increases the metabolism of a Warfarin Breckenridge and Orme, 1971 number of drugs and chemicals in man (Jusko, 1978). Digitoxin Soloman and Abrams, 1972 The lower plasma concentrations of phenacetin in Oral contraceptives Hempel et al., 1973 Doxycycline Neuvonen and Pentilla, 1974 smokers was the first indication of the inductive Aminopyrine Shaw et al., 1985 properties of smoking in man (Pantuck et aL, 1974).

Hepatic drug metabolism as assessed by antipyrine clearance may be increased by 30% in heavy smokers

endogenous compounds. Antipyrine clearance may (Vestal et al., 1975). Polycyclic aromatic hydrocar- be increased by up to 90% in some subjects following bons (PAH) are a prominent component of cigarette phenytoin dosing (Shaw et al., 1985). Phenytoin has smoke and are known inducers of hepatic xenobiotic also been found to increase the hepatic cytochrome metabolism in experimental animals. It is thought P-450 content in epileptic patients, the cytochrome that these compounds are responsible for the enzyme P-450 content correlated linearly with antipyrine induction resulting from smoking in man. However clearance (Pirttiaho et al., 1978). Phenytoin appears differences in aryl hydrocarbon hydroxylase activity, to be a less potent inducer in man compared with which is induced by PAH, between smokers and phenobarbitone or rifampicin at doses used in clinical nonsmokers are nonexistent (Boobis et al., 1980). practice. Phenytoin blood levels remain stable for However the high affinity components of the O relatively long periods suggesting an absence of auto- deethylation of both phenacetin and 7 ethoxy- induction (Kutt, 1971). Study of the metabolism of resorufin are two to three times greater in liver phenytoin is complicated by its dose related satur- samples from smokers than in those from non- ation kinetics, smokers (Kahn et al., 1985; Pelkonen et al., 1986).

Phenytoin induces the metabolism of exogenous Recent studies suggest that the form of cytochrome compounds including anticoagulants, theophylline, P-450 catalyzing the O deethylation of phenacetin in digitoxin and carbamazepine (Hansen et al., 1971; man is orthologous to rat form d, and that this is Marquis et al., 1982; Patsalos et al., 1988). The inducible by hydrocarbons in cigarette smoke induction of endogenous compound metabolism in- (Sesardic et al., 1988). cluding corticosteroids and thyroxine may also result Studies of in vivo drug biotransformations have from phenytoin treatment (Jubiz et al., 1970; Larsen demonstrated increased metabolism of antipyrine, et aL, 1970). imipramine, nicotine, pentazocine and theophylline.

The metabolism of diazepam, nortryptilline, 4.4. CARBAMAZEPINE pethidine, phenytoin and warfarin was unchanged

(Park and Breckenridge, 1981). Carbamazepine is another example of an anticon- Smoking habit of individuals must be considered

vulsant drug with enzyme inducing properties. The when studying drug metabolism in humans. It is clearance of the model drug antipyrine was increased known that plasma propranolol steady state concen- by 60% in healthy volunteers following carba- trations are lower in smokers than in nonsmokers and mazepine treatment (Shaw et al., 1985). Similarly in in younger compared to elderly patients (Feely et al., epileptic patients carbamazepine administration re- 1981a). The latter effect may however be due to an suited in higher antipyrine clearance and increased age related change in drug metabolism influenced by urinary excretion of D glucaric acid. The enzyme smoking, the effect being greatest in the younger age induction is dose dependent and the relative potency group. for antipyrine clearance was 0.84 compared with Smoking may indeed influence therapeutic inter- phenobarbitone (Perucca et al., 1984). It has been vention as demonstrated by the recent U.K. MRC demonstrated that carbamazepine induces its own trial on the effect of treatment in mild hypertension. metabolism during maintenance therapy and con- Reduction in blood pressure following treatment with comitant treatment with phenobarbitone or pheny- propranolol was less marked in patients who smoked toin further induces its metabolism (Eichelbaum cigarettes (MRC Working Party, 1985). et al., 1985). In contrast carbamazepine inhibits the metabolism of concomitantly administered phenytoin 4.6. ETHANOL (Patsalos et al., 1988). Further evidence for the enzyme inducing properties of carbamazepine is Chronic alcoholism is a major cause of liver disease derived from studies with warfarin, doxycycline and leading to abnormal drug metabolism. However, clonazepam whose half lives were all decreased fol- ethanol itself and independently of liver disease also lowing treatment (Hansen et al., 1971; Penttila et al., influences the biotransformation of other drugs. The 1974; Lai et al., 1978). nature of this effect is largely determined by the

i ~ AQ¢I C

80 M. BAggY and J. FEELY

duration of ethanol exposure. Generally, acute bition of presystemic primary conjugation may be the ethanol administration depresses the rate of drug underlying mechanism (Liedholm and Melander, metabolism (Rubin et al., 1970). This inhibitory effect 1986). Food may also influence the bioavailability of on hepatic drug metabolizing enzyme activity may drugs by altering absorption (Melander, 1978). involve several possible mechanisms. Ethanol nor- The degradation of drugs by phase one and two mally metabolized by the cytoplasmic alcohol dehy- reactions is catalyzed by microsomal enzymes and the drogenase may also be metabolized by an inducible formation of metabolites requires the participation of microsomal enzyme. Ethanol may compete for the a wide range of substances provided by nutrition. The same microsomal system required to metabolize other ability of the nutritional state to influence drug drugs. Ethanol may also inhibit metabolism by in- metabolism and the activity of hepatic mono- hibiting the activity of NADPH cytochrome P-450 oxygenase enzymes is increasingly appreciated reductase, the rate limiting step in the oxidative (Anderson, 1988). A low protein diet in animals biotransformation of drugs. The disturbance of the produces diminished activities of NADPH dependent lipid bilayer membrane may also interfere with enzymes (Campbell and Hayes, 1974). In children metabolizing enzymes, with protein-calorie malnutrition the elimination of

Acute ethanol intake has been shown to result in chloramphenicol, antipyrine and sulfadiazine is im- higher plasma levels of many benzodiazepines inclu- paired (Eriksson et al., 1984). In adults a high protein ding diazepam, chlordiazepoxide and clobazam, low carbohydrate diet enhances the metabolism of Acute ethanol administration prolonged the elimin- antipyrine, theophylline and phenacetin (Kappas et ation half life of meprobamate, phenobarbitone, al., 1978b). A diet rich in carbohydrates causes a tolbutamide and antipyrine (Rubin et al., 1970). decrease in microsomal mixed function oxidase ac-

All the above studies focused on phase one bid- tivities. The third macronutrient, fat, does not seem transformations. However acute ethanol intake may to affect the metabolism of drugs, e.g. theophylline or also inhibit phase two reactions. The glucuronidation antipyrine (Anderson et al., 1979). Preparation of of disulfiram may be decreased and the glucuroni- food may also play a role in drug metabolism. The dation of p-nitrophenol by microsomes is impaired ingestion of charcoal broiled beef for four days was by ethanol (Rubin et al., 1970). found to significantly decrease the plasma levels of

Whereas acute ethanol intake depresses metab- phenacetin in healthy volunteers (Kappas et al., olism, chronic ethanol intake enhances the rate of 1978a). Whether the process of enzyme induction drug metabolism in man. Chronic ethanol intake has would fully explain the observations outlined remains been associated with increased binding of ethanol to to be seen. However animal studies suggest that cytochrome P-450. The repeated exposure produces dietary protein augments hepatic microsomal cyto- an increase in microsomal mass and a greater activity chrome P-450 content, liver weight and mitotic indi- of the monooxygenase system, thus enhancing the ces (Campbell and Hayes, 1974). elimination of drugs (Videla et al., 1973). Since a number of endogenous substrates are

Chronic intake has been found to decrease the metabolized by hepatic monooxygenases it is not elimination half life of meprobamate and pheno- surprising that induced alterations of enzyme activity barbitone. The elimination of tolbutamide was in- will alter the metabolism of these substrates. Such creased by 50% in chronic alcoholic patients (Kater endogenous substrates include bilirubin, vitamins, et al., 1969). Other drugs whose elimination is in- hormones and lipids. The alteration in metabolism of creased during chronic alcohol intake include pheny- these substrates results in a variety of implications of toin and antipyrine. The problems associated with enzyme induction. anticoagulation in chronic alcoholics may be due in part to alterations in the elimination of warfarin, usually increased in these patients, hence the difficulty 5. IMPLICATIONS OF ENZYME in maintaining constant levels of warfarin. INDUCTION

Phase two reactions may also be affected by chronic ethanol intake with increased levels of glu- The ability of enzyme inducers to stimulate phase curonyltransferase. As is seen with other inducers of two biotransformation has provided a therapeutic drug metabolism, e.g. phenobarbitone, withdrawal of application of phenobarbitone in conditions such as the inducing agent may in itself precipitate a drug Crigler-Najjar syndrome type II and Gilbert's syn- interaction. In patients with alcoholic withdrawal the drome (Black and Sherlock, 1970). In these patients elimination of chlormethiazole also decreased, with unconjugated hyperbilirubinemia there is a re-

Aside from the direct influence of ethanol on drug duction in the activity of glucuronyl transferase en- metabolism an indirect mechanism may possibly zyme. The resultant jaundice is ameliorated by come into play involving ethanol induced release of treatment with phenobarbitone which increases the corticosterone which may secondarily influence the clearance of bilirubin by increasing the activity of rate of drug metabolism, glucuronyl transferase enzyme. Phenobarbitone may,

however, produce a number of additional changes 4.7. DIET AND NUTRITION such as increased liver blood flow, increased trans-

port of bilirubin into cells and an increase in bile flow. Concomitant food intake may influence the bid- The relative contribution of enzyme induction is not

availability of medications. The bioavailability of the defined (Black et al., 1974). antihypertensive agents propranolol, metoprolol and It is well established that long term treatment of hydrochlorothiazide may be increased (Melander, epilepsy with known enzyme inducers, e.g. pheno- l978). In the case of propranolol a transient inhi- barbitone and phenytoin, may lead to abnormalities


[ Vltamln O Choleca,clfero, l

I Spec|flc mono-oxygenases In l iver and Intestinal mucosa

[_25, OH Cholecalclfev'ol ]

~ , ~ Speclftc mono-oxygenases Unspecific mlcrosoma]

mono-oxygenases / ~ kidney , "Inducible" ~

FIG. 4. Vitamin D metabolism, the effect of inducing agents.

in plasma calcium metabolism and resultant osteo- (Maisey et al., 1974), the nonresponsiveness in the malacia (Cinti et al., 1978). The interference by nephrotic syndrome (Hendrikse et al., 1979) and the enzyme inducers on Vitamin D metabolism is thought requirement of increased corticosteroid doses in the to be the underlying mechanism. Vitamin D, essential treatment of tuberculous pericarditis in patients on for normal calcium metabolism, is hydroxylated by concurrent rifampicin therapy (Van Marie et al., hepatic microsomal enzymes to 25 hydroxycholecal- 1979). cifero]. This in turn is converted by the kidney to 1 .25 Enzyme induction is known to interfere with per- dihydroxycholecalciferol, the active form of the vita- ipheral thyroid metabolism. The decrease in protein min. With enzyme induction there is a diversion in the bound plasma iodine in animals and man following hepatic metabolism of vitamin D to bioligically inac- phenytoin treatment is well recognized (Mendoze rive metabolites (Hahn et al., 1972) (Fig. 4). Since the et al., 1966). Further studies with chronic phenytoin level of 25 hydroxycholecalciferol regulates the for- treatment demonstrated an increased turnover of marion of the active Vitamin D an increased break- thyroxine (T4) in rats (Oppenheimer et al., 1968). A down can easily be compensated by an enhanced 60% increase in the peripheral conversion of T 4 to the conversion rate. Therefore a sufficient intake of Vita- more active form of thyroid hormone, triiodothy- min D can prevent any deficiency. This may explain ramine (T3) following diphenylhydantoin adminis- why Vitamin D deficiency develops in only a small tration in humans has been found. A decrease in percentage of patients receiving antiepileptics. The thyroxine and the biologically inactive reverse T 3 of ability of enzyme inducing agents to affect Vitamin D approximately 14% together with a 25% increase in metabolism has been used in the clinical setting of T 3 has been found following administration of the Vitamin D poisoning, where agents like phenobarbi- enzyme inducer rifampicin (Ohnhaus et al., 1981). tone and glutethimide have been used to decrease The clinical relevance of these findings with respect to Vitamin D concentrations (Lukaskiewicz et al., 1987; overall thyroid function remains to be established. Iqbal and Taylor, 1982). Experimental studies indicate a link between the

A complication of long term anticonvulsant treat- hepatic microsomal carbohydrate and drug metab- ment is anemia thought to be due to folic acid olizing systems (Stengard et al., 1984). Phenobarbi- deficiency. The underlying mechanism is unclear but tone has been found to enhance insulin mediated impairment of folate absorption with associated inhi- glucose metabolism in healthy nondiabetic subjects bition of intestinal conjugation leading to polygluta- (Lahtela et al., 1984). Furthermore, addition of bep- mate malabsorption has been suggested (Hoffbrand atic microsomal enzyme inducing compounds to the and Necheles, 1968). Increased requirement of folate therapy of NIDDM patients improves the glycemic as a consequence of enzyme induction has also been control (Sotaniemi et al., 1983). suggested as an underlying cause (Labadarios et al., Glucose 6 phosphatase, a multicomponent enzyme 1978). system, and glycogen synthetase, are both micro-

Increased cortisol metabolism occurs following somal glucose metabolizing enzymes (Wordlie, 1979). treatment with phenobarbitone, phenytoin and other Therefore drugs having an effect on the mixed rune- enzyme inducers (Werk et al., 1964). An increased tion oxidase system may nonspecifically influence excretion of 6 fl hydroxycortisol in urine has been other enzymes located in the endoplasmic reticulum found. Thus, results of dexamethasone suppression of hepatocytes. Utilizing the euglycemic clamp tech- tests in patients receiving enzyme inducers may be nique Lahtela et al. studied the effect of phenobarbi- unreliable (Werk et al., 1969). The underlying mech- tone on insulin mediated glucose metabolism in anism is thought to be enhanced hepatic conjugation noninsulin dependent diabetics on sulfonylurea treat- and biliary excretion of the steroid. A significant ment. Addition of phenobarbitone to the sulfonyl- interaction between enzyme inducing agents and urea therapy resulted in a reduction in fasting glucose corticosteroids has been suggested in the following and immunoreactive insulin levels. A significant clinical settings: increased corticosteroid dosage re- increase in glucose disposal rate and metabolic quirements in the treatment of Addisons disease clearance rate of glucose resulted. The authors


demonstrated a corresponding increased activity of damage produced. The production of reactive the mixed function oxidase system as antipyrine metabolite may be offset by enzyme activity deacti- clearance and insulin mediated glucose metabolism vating the metabolite. The situation may be exem- both enhanced by 30% following phenobarbital plified by the hepatotoxicity of the reactive treatment (Lahtela et al., 1985). The activation of intermediate to paracetamol with the deactivating postreceptor events in hepatocytes through micro- reduced glutathione, A reduction of the reduced somal enzyme inducing agents may therefore offer a glutathione results in unopposed toxic intermediate new approach to the improvement of insulin sensi- with resultant hepatotoxicity (Mitchell et al., 1974). tivity in noninsulin-dependent diabetes mellitus. Con- Animal studies have demonstrated the potential tox- versely, inhibitors of the mixed function oxidase icity of inducing agents in the enhancement of toxic system, e.g. cimetidine, may decrease the metabolic intermediate production (Garner and McLean, 1969) clearance rate of glucose and therefore impair glucose and have also demonstrated that inhibition of oxi- tolerance (Lahtela et al., 1986). dative metabolism modifies the toxicity of tom-

The beneficial effects of enzyme inducing compounds like carbon tetrachloride, isoniazid and pounds may also extend to lipid metabolism. Drugs paracetamol that require activation by hepatic micro- such as phenobarbitone, phenytoin, carbamazepine somal enzymes before producing cellular toxicity and alcohol, which induce the microsomal enzyme (Homan et al., 1985; Lauterburg et aL, 1983; Mitchell system, may also influence serum lipid and apolipo- et al., 1981). Further studies are required to clarify protein concentrations. They result in increased con- the situation in humans (Lauterburg et al., 1983). centrations of high density lipoproteins (HDL) which A number of phase one biotransformations are are cardioprotective and a reduction in low density thought to increase the carcinogenicity of certain lipoproteins (LDL) which are atherogenic with a compounds. Metabolic products from aromatic resultant increase in the HDL:LDL ratio (Luoma, carbon oxidation with the resultant production of 1987). epoxide intermediates may play a role in the carcino-

Serum HDL concentrations have been shown to be genicity of polycyclic arbmatic hydrocarbons, e.g. directly proportional to cytochrome P-450 content of benzopyrine. Hydroxylation of amines adjacent to human liver (Luoma et al., 1985) and also directly aromatic ring structures is well described and the related to plasma antipyrine clearance (Luoma et al., resultant N oxidation products correlate with the 1984). Therefore enzyme inducing drugs by lowering appearance of bladder carcinoma (Vaught and King, the concentration of atherogenic lipids may favorably 1984). Enzyme inducing agents through the pro- influence coronary heart disease. Indeed mortality motion of intermediate formation may enhance the from ischemic heart disease is approx 30% lower in carcinogenicity of many compounds. epileptic subjects treated with anticonvulsants when compared with age and sex matched members of the general population (Muuronen et al., 1985). Not all enzyme inducing drugs influence lipid metabolism 6. INDUCTION OF EXTRAHEPATIC DRUG as rifampicin and antipyrine failed to affect serum METABOLIZING ENZYMES lipoprotein profile (Ohnhaus et al., 1979a).

The administration of enzyme inducing drugs may There exists a marked variability in the ability of also be associated with adverse effects and they may enzyme inducers to stimulate metabolism in various exacerbate certain pathological states, e.g. acute in- extrahepatic organs, this ability varying further with termittent porphyria. This disorder is inherited as the different species (Jenner and Testa, 1976). The autosomal dominant and is characterized by exces- failure of inducers to increase oxidative drug sire urinary excretion of 5 aminolevulinic acid and metabolism in the rat extrahepatic tissues including porphobilinogen. The patients develop disorders of kidney, brain, intestines and adrenals has been the nervous system such as psychosis and abdominal demonstrated. Phenobarbitone was shown to be pain with tachycardia and raised blood pressure. The without effect on aminopyrine demethylase, aniline underlying mechanism is thought to be an increase in hydroxylase, coumarin 3-hydroxylase and hexobarbi- the activity of hepatic 5 aminolevulinic acid syn- tal oxidase in these tissues. However, administration thetase, the rate limiting enzyme in the biosynthetic of inducing agents to the rabbit resulted in increased chain. Acute attacks may be precipitated by enzyme cytochrome P-450 levels and drug metabolizing inducing drugs like phenobarbitone (Cohn and Roth, ability at extrahepatic sites, e.g. kidney. The rate of 1983). response of extrahepatic tissues to inducing agents

The increased activity of the microsomal mono- has been found to vary markedly suggesting qualitat- oxygenase system following enzyme inducing agents ire as well as quantitative differences between the may have toxicological implications. It is becoming monooxygenases in various tissues. Recent animal increasingly recognized that the formation of chemi- studies suggest that extrahepatic metabolism may cally reactive metabolites may produce a range of afford a protective mechanism as increases in cyto- toxic effects. The reactive intermediate may react chrome P-450 and NADPH cytochrome C reductase covalently with cellular macromolecules disrupting activities have been found in extrahepatic sites, e.g. cellular activity. The toxicity produced will depend on kidney in animals, with hepatic dysfunction second- a number of factors, e.g. the proportion of drug ary to pharmacological and surgical interventions converted to the reactive intermediate, the proportion (Barry et al., 1987). Induction of enzyme activities in of metabolites bound covelently, the proportion of tissues such as gut, skin and lymphocytes have been reactive metabolite binding to certain macromol- demonstrated in man. Induction of extrahepatic ecules within the cell and the resultant irreversible metabolism is a fruitful area for future research.


7. ENZYME INHIBITION, U N D E R L Y I N G the most important mechanism in relation to xeno- MECHANISM biotic metabolism it is not the only one as many cases

of noncompetitive and mixed kinetics have been Inhibition of the metabolism of drugs which are reported. Inhibition of hexobarbitone metabolism by

biotransformed in the liver often leads to serious chloramphenicol or the inhibition of diphenylhydan- adverse effects because of accumulation of drugs to toin metabolism by isoniazid have been shown to be toxic concentrations. Interactions involving inhibi- noncompetitive (Kutt et aL, 1968). The type of tors of drug metabolism are probably of greater inhibition obtained appears to be influenced by such clinical significance than those involving enzyme in- factors as the nature of the substrate, the concen- duction (Kato et aL, 1964). The onset of inhibition is tration of the inhibitor, more than one enzyme system usually rapid following a single administration of the metabolizing the substrate and metabolism of the inhibitory compound. The increased plasma level of inhibitor during the course of the reaction (Sasame a drug following inhibition o f its metabolism reaches and Gillette, 1970). The demonstration of an inter- a new steady state often approximately five half lives action between the inhibitor and a component of the later. Therefore potentiation of the pharmacological monooxygenase system supports the mechanism of effect usually occurs quickly if the drug has a short an alternate substrate mechanism. Cytochrome P-450 half life (e.g. tolbutamide t~/2 = 4-10 hr). is capable of combining with exogenous compounds

The prediction of drug interactions following en- to produce difference spectra of two basic types, i.e. zyme inhibition is difficult as many different xeno- type I and type II. The results of spectral studies biotics may inhibit metabolism. However, the most provide further information with regard to the inter- clinically relevant interactions will involve drugs with action of the inhibitor with the monooxygenase sys- a narrow therapeutic ratio (e.g. warfarin, phenytoin, tem. The production of a type II binding spectrum by theophylline) (McInnes and Brodie, 1988). Drug cimetidine supports the suggestion that cimetidine metabolizing enzyme systems may be inhibited in interacts with the heme iron of cytochrome P-450 numerous ways either indirectly by alterations of both with its imidazole and cyano coordinating physiological parameters including hormonal levels ~groups (Reilly et al., 1983). The interaction of in- and nutritional status and by inhibitors of the syn- hibitors with cytochrome P-450 reductase is further thesis of microsomal components, or more commonly evidence of the interaction of inhibitors with a com- by directly arising from interaction at the monooxy- ponent of the drug metabolizing enzyme system genase site. Enzyme destruction may be implicated (Sasame and Gillette, 1970). with some drugs (Muakkassah and Yang, 1981). The route(s) of drug metabolism is an important

That the hepatic monooxygenases exhibit low sub- parameter when looking at the clinical consequence strate specificity is well recognized and on this basis of inhibition of drug metabolism. If a drug is metab- substrate competition for the active sites may be olized by a single route only then inhibition of this expected to explain the mechanism of enzyme inhi- route may be expected to produce a clinically signifi- bition. This has been demonstrated for a large num- cant interaction, e.g. tolbutamide (Thomas and ber of drugs, e.g. hexobarbitone, chlorpromazine, Ikeda, 1966). However, most drugs are metabolized phenylbutazone and acetanilide which are competi- by more than one route and inhibition of a single tive inhibitors of N-demethylation of ethylmorphine pathway would be less likely to produce a significant (Rubin et al., 1964). Competition for the same sub- interaction. A pharmacokinetic expression for the strate binding site is probably the most prevalent effect of inhibition on the ratio (R) of the new half mechanism of inhibition of drug metabolism in man. life of a drug in the presence of inhibitor to the However, not all substrates have the ability to inhibit normal half life or for the steady state concentration the metabolism of an alternate substrate. The agent in the absence and presence of inhibitor was devel- SKF 525 A while exhibiting marked inhibitory action oped by Rowland (1975). Determination of R re- on the metabolism of a large number of substrates quires knowledge of the fraction of the dose fails to influence the N dealkylation of N methyl- eliminated by the particular metabolic pathway in the amine or the sulfoxidation of chlorpromazine absence of inhibitor (fro), the amount of inhibitor (I) (Gillette and Kamm, 1960). The mechanism of altern- and the inhibitor constant (Kt). ate substrate inhibition requires that the inhibition must be competitive and the inhibitor must also serve R = t~/2 inhibited Css inhibited as substrate. The efficacy of the inhibitor will depend on the magnitude of the inhibitory constant (KI) of ll/2 normal C~ normal the inhibitor relative to the Michaelis constant (Kin) 1 of the drug whose metabolism is inhibited. The lower q- (1 - f r o ) . the K~ value the higher is the inhibitory activity. The f m / ( l + I/K2) inhibitor should not have a Vma x greatly exceeding If all the drug is eliminated by the inhibited route that of the substrate if its presence at the metabolic f m = 1 then the ratio will change dramatically with site is to be maintained (Anders and Mannering, increasing inhibitor concentration. If less than 50% is 1966). The inhibitory capacity increases as Vmax for eliminated by the inhibited route then it is unlikely metabolism of the inhibitor decreases. That the in- that a clinically significant interaction will result, hibitor should be metabolized itself is not a prerequi- unless the therapeutic index of the drug is very site, as exemplified by the potent inhibitor 2.4 narrow (Rowland, 1975). dichloro 6 phenyl-phenoxyethylamine (D.P.E.A.) Examples of enzyme inhibitors are found in a which is a relatively poor substrate for the monooxy- variety of drug groups including chemotherapeutic, genase system. While competitive inhibition may be anti-inflammatory, cardiovascular, and neuroleptic

agents (Table 9).


TABLE 9. Some Enzyme Inhibitors 20

Allopurinol Metronidazole ~ ~ ~ 10 ~ u - t~ - 15.8h18"6 h Amiodarone Miconazole '~ - ~ ~ { ~ t ~ - Azapropazone Nortriptyline ~ .~ "-J.~.- '-- . .~ . " ~ " ' ~ . Chloramphenicol Oral contraceptives ~ ~ t~ -13.3 h ~ ~ " - . ~ ~------'-'--~_ - - Cimetidine 400 mg Chlorpromazine Oxyphenbutazone ~ t,h = 10.5 h ---J ~ , . ~ Cimetidlne 200 mg Cimetidine Perphenazine Cimetidine 100 mg Danazol Phenylbutazone i i l = i Placebo Dextropropoxyphene Primaquine 3 6 9 12 24 30

(propoxyphene) Propranolol "ntr~ (h) Diltiazem Quinidine Disulfiram Sodium valproate Fro. 5. Antipyrine concentrations and elimination half-life Ethanol (acute) Sulfinpyrazone (tt/2) during treatment with either placebo, cimetidine Erythromycin Sulfonamides 100 mg, 200 mg or 400 mg four times daily. Imipramine Thioridazine Isoniazid Trimethoprim The degree of enzyme inhibition may be related to Ketoconazole Verapamil the initial oxidizing capacity of the liver enzymes. An Metoprolol increased inhibitory effect by cimetidine on theo-

phyUine clearance in rats who had been pretreated with enzyme inducing agents has been found (Grygiel

8. ENZYME INHIBITORS et al., 1981). The effect of cimetidine was also more 8.1. CIMETIDINE AND OTHER ULCER HEALING DRUGS marked on the clearance of theophylline in smokers

who had higher initial clearance rates, presumably The histamine H2 antagonist cimetidine, widely due to enzyme induction related to smoking (Miners

used in the treatment of peptic ulcer, is a recognized et al., 1981). The percentage reduction in antipyrine enzyme inhibitor (Serlin et al., 1979). As cimetidine is clearance has been shown to be greater in subjects relatively nontoxic and is one of the most widely used pretreated with the enzyme induced Rifampicin than drugs in clinical practice today, it is a useful agent for in the control uninduced state (Fig. 6). the further study of factors affecting the response to Studies suggest that the effect of cimetidine on inhibition of drug metabolism in man. Cimetidine has oxidative metabolism is independent of the duration been shown in man to impair the oxidative of pretreatment. Theeffectofpretreatmentbegunjust metabolism of a wide range of drugs including an- 1 hr before administration of the test drug antipyrine tipyrine, chlordiazepoxide, diazepam, propranolol was similar to that of 24hr pretreatment and and warfarin. The broad specificity of enzyme inhi- that reported for chronic cimetidine pretreatment bition which was previously accepted is now being (Somogyi and Gugler, 1982). re-examined in the light of recent evidence suggesting The responsiveness of hepatic enzymes to inducing selectivity of inhibition of cytochrome P-450 drug agents may be reduced in the elderly (Wood et al., metabolism by cimetidine (Puurunen et al., 1980). 1979). However, the same may not be the case for Cimetidine has been found to inhibit the 3 and 7 enzyme inhibitors as elderly subjects are as sensitive demethylation of theophylline with no inhibition of to the inhibitory effects of cimetidine on oxidative the 8 oxidation pathway. The absence of an inhibi- metabolism as young subjects (Fig. 7). It has been tory effect by cimetidine on the clearance of tolbu- shown in animals and in man that the effects of tamide, ibuprofen, mexilitine and metronidazole has cimetidine on oxidative metabolism dissipate rapidly been demonstrated (Dey et al., 1983). Steroid hydrox- following cessation of therapy (Vestal et aL, 1983). ylation and epoxidation of carbamazepine are also Tolerance does not occur during chronic therapy spared of inhibition by cimetidine (Peden et al., 1984; (Patwardhan et al., 1981). Thus as with enzyme Levine et al., 1984). The explanation may be forth- induction the process of inhibition appears readily coming from recent studies showing cimetidine bind- reversible but at a faster rate. This may also lead to ing differentially to various forms of cytochrome P-450 enzyme which are known to exist (Boobis and Davies, 1984). The indications are therefore that 20 Rifampicin cimetidine cannot be considered a universal inhibitor --- g , ,~p /~ , . of phase one metabolism. However, cimetidine does .~_ ~ 10 provide useful information on the inhibition of drug ~- ~ -,~_ .--:z- t.~. metabolism in man. "~

cimetidine is dose dependent was suggested from the 2 &

in vitro study of benzo[a]pyrine hydroxylation by ¢ ¢ ~ human liver microsomes (Puurunen et al., 1980). A e6 concentration related effect on propranolol metabolism in man was also shown (Feely et al., 1981b). i i ~ i The dose-dependent inhibitory effect of cimetidine on 3 6 12 24 30 36 antipyrine clearance in healthy volunteers has also Time (h) been shown (Fig. 5). The half life of antipyrine FIG. 6. Elimination half-life of antipyrine as control (pla- increased with increasing cimetidine concentration, cebo) during treatment with rifampicin (day 15; t~2 = 6.5 hr) the greater reduction in antipyrine clearance was and day 21 when cimetidine (400 mg four times daily) was associated with the higher cimetidine concentrations, commenced 12 hr following antipyrine.


- - 60 elimination of the calcium antagonist verapamil has ._g "Young ~ Elderly been shown to be more rapid after the first dose than

.~ , after chronic administration (Schwartz et al., 1982). 4 0 7"* T * The mean serum concentrations of verapamil may be

t twice that predicted, during long term administration. Long term administration of verapamil has

"6 been found to be associated with prolongation of its ,.-° 20 half-life (64%) (Shand et al., 1981). This apparent self "~ inhibition of its metabolism is supported by further e~ '= = studies on antipyrine clearance which is reduced by .a: 66% in patients on long term verapamil treatment

Control Cimetidlne Control C imet id ine (Rumiantsev et al., 1986). The ability ofverapamil to FIG. 7. Comparison of the reduction in antipyrine clearance inhibit oxidative metabolism is likely to be of clinical produced by cimetidine (800 mg/day) in young and elderly consequence as exemplified by the recent reported

subjects (mean _+ SE mean, n = 6, *P < 0 .05 ) . interaction with the antiepileptic agent carbamazepine (CBZ) (MacPhee et al., 1986). Adminis- tration of verapamil to patients with refractory

a pharmacological interaction with concurrently ad- partial epilepsy treated with carbamazepine resulted ministered drugs. Cessation of cimetidine would re- in symptoms of CBZ neurotoxicity within a few days. suit in decreased drug levels following removal of the A mean rise of 46% in total, and 33% in free plasma inhibitory effect. Clinically important drug inter- CBZ concentrations in five out of six patients studied actions resulting from enzyme inhibition have been and a simultaneous fall of 36% in the ratio of the described for cimetidine (Table 10). principal metabolite CBZ-10, 1 l-epoxide to CBZ was

The inhibitory effect of cimetidine is not shared by observed. Verapamil was found to increase the area other H 2 antagonists such as famotidine and nita- under the CBZ concentration-time curve by 42% in zidine. Ranitidine may have minor effects but these one patient. The consequence of withdrawal of an are not associated with clinically important inter- enzyme inhibiting agent was demonstrated by the actions (Smith and Kendall, 1988). Another antiulcer reduction of CBZ concentration from 12 mg/! to drug omeprazole, a substituted benzimidazole corn- 7 mg/l following cessation of verapamil treatment. pound, has also been found to inhibit the activity of This was of clinical significance as seizure break- drug metabolizing enzyme systems. In vitro studies through was seen in the patient. As carbamazepine using human liver microsomes demonstrated the in- induces its own metabolism an inhibitory interaction hibitory effect of omeprazole on both the high and is likely to produce a greater than expected increase low affinity components of 7 ethoxycoumarin de- in carbamazepine concentration. Verapamil also in- ethylase (Jensen and Gugler, 1986). Omeprazole has hibits prazosin metabolism resulting in a greater been found to increase the half life and decrease the hypotensive effect of the drug (Pasanisi et al., 1984). clearance of diazepam by 130% and 54% respect- Inhibition of theophylline metabolism resulting in ively. A clinically significant interaction may result toxic side effects has also been described (Burnakis from the administration ofomeprazole to patients on et al., 1983). A recent case report suggests that phenytoin as omerazole may decrease phenytoin verapamil may inhibit metabolism of cyclosporin clearance by 15% (Gugler and Jensen, 1985). (Robson et aL, 1988).

Diltiazem is another calcium antagonist that in- 8.2. CARDIOVASCULAR DRUGS INCLUDING CALCIUM hibits oxidative drug metabolism. Diltiazem reduced

ANTAGONISTS AND fl-BLOCKERS antipyrine clearance by approximately 25% (Carrum et al., 1986) and may also increase concentrations of

A number of cardiovascular drugs are known to be cyclosporin (Grimo et al., 1986). The calcium antag- inhibitors of oxidative drug metabolism. These onist nifedipine does not produce significant enzyme include fl-biockers, calcium antagonists and the inhibition in man (Bauer et al., 1986). antiarrhythmics amiodarone and quinidine. The Some fl-blocking agents also demonstrate the abil-

ity to inhibit oxidative drug metabolism (Bax et al., 1981). Greenblatt et al. (1978) showed that propra-

TABLE I0. Some Important Interactions with Cimetidine nolol inhibits the metabolism of antipyrine. Sub- Warfarin Anticonvulsants sequently both propranolol and metoprolol were Theophylline --Phenytoin found to inhibit antipyrine and theophylline metab- Antiarrhythmics--Lignocaine Carbamazepine olism (Bax et al., 1983). Propranolol may increase

Procainamide Valproic Acid plasma chlorpromazine concentrations accounting fl-blockers--Propranolol Benzodiazepines for the additive antipsychotic effects seen when these

Metoprolol Chlordiazepoxide Labetolol Clobazam drugs are coadministered (Peet et al., 1980). fl-block-

Desmethyldiazepam ing drugs also inhibit lignocaine metabolism in rat Calcium Antagonists--Nifedipine Diazepam liver microsomes and propranolol pretreatment in

Verapamil Midazolam rats impaired its own metabolism and this may in Diltiazem Nitrazepam part explain the unexpected accumulation of the drug

Triazolam with chronic dosing (Wood et al., 1978). From Smith and Kendall, 1988. Reprinted with per- The antiarrhythmic agent quinidine has been

mission of the authors and the copyright holder, ADIS shown to inhibit metoprolol metabolism (Leeman et Press, Ltd, Auckland. al., 1986). It is a potent inhibitor of both sparteine

86 M. BARRY and J. FELLY

and debrisoquine oxidation in healthy volunteers, the metabolism of other drugs including phenytoin, thus raising the possibility that quinidine may inter- tolbutamide and warfarin. The trimethoprim fete with phenotyping and convert an extensive sulfamethoxazole complex (Septrin) produces a metabolizer (Inaba et al., 1986). stereoselective inhibition of warfarin, decreasing the

Amiodarone is another antiarrhythmic agent that clearance of the more potent S isomer of warfarin by may produce clinically important drug interactions, approx 20%, increasing anticoagulant effect by 65% Potentiation of warfarin anticoagulation (Hamer (O'Reilly, 1980). The heterocyclic nitro derivative et al., 1982) and increased serum concentrations of metronidazole also inhibits the metabolism of S- concomitant quinidine or procainamide treatment warfarin increasing the anticoagulant effect by 40% has been found, enzyme inhibition by amiodarone (O'Reilly, 1976). was the proposed underlying mechanism (Saal et al., In vitro studies suggest isoniazid to be a noncom- 1984). Animal studies have demonstrated that amiD- petitive inhibitor of drug metabolism. Isoniazid im- darone is a potent inhibitor of oxidative drug paired the metabolism of phenytoin in patients found metabolism in the rat and markedly reduces cyto- to be slow inactivators of isoniazid (Miller et al., chrome P-450 concentration (Duenas-Laita et al., 1979). This interaction is of clinical importance as 1987). one study of twenty-two hospitalized medical patients

who received phenytoin and isoniazid for at least five 8.3. CHEMOTHERAPEUTIC AGENTS days reported a 27% incidence of central nervous

system toxicity due to phenytoin. The incidence of A number of chemotherapeutic agents have been phenytoin toxicity without isoniazid has been esti-

found to inhibit drug metabolism. Pharmacokinetic mated to be approximately 3%. Isoniazid has also interactions involving the macrolide antibiotics been found to inhibit the metabolism of carba- erythromycin and triacetyloleandomycin have been mazepine (Wright et al., 1982). described. Both drugs are known to affect the cyto- The new synthetic quinolone antibiotics have been chrome P-450 drug metabolizing system and in vitro found to reduce the hepatic clearance of some co- studies suggest that a metabolite of these compounds administered drugs (Edwards et al., 1988). Enoxacin forms a stable complex with the heme portion of appears to be the most potent inhibitor consistently reduced cytochrome P-450 thus producing enzyme decreasing theophylline clearance by 50% or more inhibition (Pessayre et al., 1981). Of the two agents (Wijands et al., 1985). Ciprofloxacin and pefloxacin triacetyloleandomycin appears to be the more potent reduce theophylline clearance to a smaller extent, inhibitor ofmicrosomal drug metabolism. It has been ~ approximately 20~-30% (Wijands et al., 1986). found to significantly decrease the metabolism of Enoxacin decreases the clearance of R-warfarin and methylprednisolone, theophylline ( W e i n b e r g e r e t a l . , antipyrine with no effect on chlorpropamide, 1977) and carbamazepine (Wroblewski et al., 1986), glibenclamide or phenytoin (Edwards et al., 1988). the inhibition of methylprednisolone metabolism Norfloxacin, ofloxacin and nalidixic acid appear to being dose dependent and time related (Szefler et al., have minimal effects on theophylline clearance. 1982). The ability of triacetyioleandomycin to cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in patients receiving oral contra- 8.4. ANTI-INFLAMMATORY AND ANALGESIC DRUGS ceptives may also be related to the inhibitory effect on drug metabolism (Matthews and Havill, 1979). Ery- Phenylbutazone is an anti-inflammatory agent thromycin appears to be a weaker inhibitor of drug capable of enzyme inhibition. The interaction be- metabolism and in some individuals the metabolism tween phenylbutazone and warfarin was one of the of methylprednisolone, theophylline, carbamazepine earliest examples of inhibition of metabolism and the and warfarin may be affected (Ludden, 1985). complexity of the interaction was of interest (Lewis et

Inhibition by erythromycin of the conversion of al., 1974). Coadministration of phenylbutazone pro- carbamazepine to its 10, I I epoxidemetabolite results duced an augmented anticoagulant effect without in a significant clinical interaction with patients devel- altering the apparent plasma concentration of war- oping carbamazepine toxicity (Barzaghi et al., 1987). farin. Study of the individual isomers revealed a Recent studies suggest the possibility of an inter- reduction in clearance of the S isomer but an acceler- action between erythromycin and cyclosporin with ated clearance of the R isomer. As the S isomer is five a resultant increase in cyclosporin concentration times more potent than the R isomer inhibition of (Freeman et al., 1987). The mean change in drug its metabolism provides one mechanism for the clearance is a reduction of the order of 25% in increased anticoagulant effect. patients administered the macrolide antibiotics men- Sulfinpyrazine, a derivative of phenylbutazone, is tioned above, also capable of inhibition of drug metabolism in man.

Hypoglycemic coma has resulted from the con- Clinically important interactions are potentiation of comitant administration of chloramphenicol and the effects of oral anticoagulants, theophylline and sulfaphenazole to noninsulin-dependent diabetic tolbutamide as a result of enzyme inhibition (Miners patients treated with the oral hypoglycemic agent et al., 1982a,b). tolbutamide presumably due to enzyme inhibition Dextropropoxyphene is similar structurally to (Hansen and Christensen, 1977). Tolbutamide ex- methadone but it is a weaker analgesic and not cretion is almost completely dependent on a single classified as a narcotic despite having several proper- route of metabolism that is particularly sensitive to ties in common with that group. Dextrapropoxy- inhibition. Sulfamethazole, another sulfonamide, has phene may be involved in clinically significant similar though less pronounced inhibitory effects on interactions as a result of its ability to inhibit drug


metabolism. It inhibits the metabolism of anti- producing increased sedation are seen when valproic convuisants phenytoin, phenobarbitone and carba- acid is given to patients treated with phenobarbitone. mazepine (Kutt, 1971; Dam et al., 1977), drug A 32% increase in phenobarbitone half life with an concentrations may be increased by approximately associated 28% decrease in clearance follows valproic 70% and central nervous system adverse effects be- acid administration (Bruni et al., 1980). Valproic acid come apparent (Hansen et al., 1980). Concurrent also inhibits the elimination of ethosuxamide and administration with the oral anticoagulant warfarin carbamazepine (MacPhee et al., 1988). may result in raised warfarin levels and hemorrhage (Jones, 1976). Recent studies suggest that dextropro- 8.8. DISULFIRAM poxyphene may also inhibit theophylline metabolism (Robson et al., 1987). Inhibition of the enzyme aldehyde dehydrogenase

resulting in accumulation of acetaldehyde is the 8.5. NEUROLEPTICS underlying mechanism of action of this drug used in

the treatment of chronic alcoholism. It does, how- The phenothiazine derivative chlorpromazine has ever, possess the ability to inhibit the monooxygenase

been shown to inhibit competitive drug metabolism in enzymes system and impairs the metabolism of anti- vitro. Chiorpromazine also inhibits the metabolism of pyrine, warfarin and phenytoin (Vesell et al., 1975). propranolol in man, the clearance of propranolol The clearance of chlordiazepoxide and diazepam are being reduced by 30%. As a result of this inhibition reduced by 50% and 40% respectively when given an 80% increase in steady state propranolol concen- with disulfiram. The drug does not inhibit phase two trations was found (Vestal et al., 1979). reactions.

Thioridazine, another phenothiazone drug, has been reported to produce phenytoin toxicity when the 8.9. ALLOPURINOL drugs are administered concomitantly (Vincent, 1980). Recent studies suggest that the hydroxylation Allopurinol is another example of a drug capable of debrisoquine is decreased in patients receiving of inhibiting both monooxygenase enzymes and en- therapeutic doses of thioridazine and levomepro- zymes not involved in drug metabolism. Inhibition of mazine (Syvalahti et al., 1986). High plasma concen- xanthine oxidase decreasing the production of uric trations of imipramine and desipramine have been acid is the underlying basis of its use in treatment of observed in patients simultaneously treated with oral gout. As xanthine bxidase'is also involved in the imipramine and intramuscular fluphenazine (Nelson metabolism of mercaptopurine it is not surprising and Tatlow, 1980). Tricyclic antidepressants may also that an interaction between these two drugs has been inhibit the metabolism ofneuroleptics if the oxidation reported. Concurrent use of these agents results in is catalyzed by the same form of cytochrome P-450. increased mercaptopurine activity and toxicity (Ellen Warfarin metabolism is also inhibited by tricyclic et al., 1963). Allopurinol has also been found to antidepressants (Barber and Douglas, 1980). inhibit the metabolism of antipyrine, bishydroxy-

coumarin and theophylline (Vesell et al., 1970; 8.6. ORAL CONTRACEPTIVES Manfredi and Vesell, 1981). Recently we described a

significant interaction between allopurinol and war- Oral contraceptives have been shown to influence farin. Using the ~4C aminopyrine breath test as an

the kinetics of concurrently administered drugs, index of drug metabolism an increase in the mean Drugs eliminated by oxidative pathways such as ~4C-aminopyrine half life by 44% following allopuri- antipyrine and diazepam have decreased metabolic nol treatment was noted (Barry and Feely, 1988). It clearance and prolonged elimination half life in oral is possible that the effect of allopurinol on oxidative contraceptive users (Carter et al., 1974). Ethy- metabolism is greater than hitherto appreciated. nylestradiol administered for five days decreased the cytochrome P-450 content of rat livers and was 8.10. MONOAMINEOXIDASEINHIBITORS associated with a decreased turnover of the P-450 (Mackinnon et al., 1977). Oral contraceptives may Drugs may also alter the pharmacological action of also decrease the metabolism of corticosteroids other drugs by inhibiting nonmicrosomal pathways (Hunter et al., 1973). In contrast some drugs metab- of metabolism. The use of monoamine oxidase inhibi- olized by phase II conjugation reactions show in- tors, e.g. tranylcypromine, render patients sensitive to creased clearance, e.g. paracetamol (Legler and subsequent treatment with sympathomimetic agents Benet, 1986). which are metabolized by the mitochondrial enzyme.

The clinical significance of these interactions is not Patients treated with these inhibitors have developed entirely clear but the widespread use of oral contra- hypertensive reactions following ingestion of cheese, ceptives suggests caution in patients receiving the other foods rich in tyramine, amphetamines or direct combination of potent drugs and oral contraceptives, and indirect sympathomimetic agents (Tollefson,

1983). 8.7. VALPROIC ACID The importance of genetic factors in determining

susceptibility of an individual to drug interactions Valproic acid is a relatively recent addition to the involving enzyme inhibition is exemplified by the

treatment of epilepsy. However its ability to produce phenytoin-isoniazid interaction mentioned above. clinically significant drug interactions following en- All cases occur in slow metabolizers of isoniazid. zyme inhibition is already apparent (Levy and Koch, Therefore many factors, both genetic and environ- 1982). Elevated blood levels of phenobarbitone mental, influence the rate of drug elimination and


hence drug response in man. The ability of drugs to Adverse Drug Interactions. Cardiovascular and Respiratory modify the activity of drug metabolizing enzyme Disease Therapy, Vol. l, pp. 141-152, PETRIE, J. (ed.) systems may result in increased or decreased activity Elsevier, Amsterdam. of concurrently administered drugs. Clinically signifi- BARRY, M. and FELLY, J. (1988) Inhibition of drug

metabolism by allopurinol. Br. J. clin. Pharmac. 26: cant interactions are more likely following enzyme 649P-650P. inhibition and when drugs with a narrow therapeutic BARRY, M., DUENAS-LAITA, A., MAC MATHUNA, P. and index are used. FELLY, J. (1986) Amiodarone inhibition of hepatic oxi-

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BARRY, M., DUENAS LAITA, A., MAC MATHUNA, P. and 9. C O N C L U S I O N FELLY, J. (1987) Increase in renal cytochrome P-450 and

Too many of the interactions noted above as a NADPH cytochrome c reductase activity following drug consequence of induction or inhibition were at the inhibition of hepatic monooxygenase activity. Biochem.

Pharmac. 36: 768--769. expense of patient toxicity. Assessment o f the poten- BARZAGH1, N., GATTI, G., CREMA, F., MONTELEONE, M., tial for such effects using animal, in vitro and human AUIONE, C., LEONE, L. and PERUCCA, E. (1987) Inhibition screening studies should be mandatory in the assess- by erythromycin of the conversion of carbamazepine to ment of new drugs. It is clear that no single test has its active 10, I l-epoxide metabolite. Br. J. clin. Pharmac. a high predictive value. Nonetheless it is possible by 24: 836-838. combining in vitro and in vivo studies both in animal BAUER, L. A., STENWALL, M., HORN, J. R., DAVIS, R., and man to identify drugs at particular risk. Close OPHEIM, K. and GREENE, L. (1986) Changes in antipyrine monitoring, including frequent measurement of drug and indocyanine green kinetics during nifedipine, vera-

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