There are four aspects of drug metabolism studies which a p p p -the evaluation of drug toxicity (TABLE I ) . Knowledge of species differences in drug metabolism aids in extrapolating pharmacological and toxicological data from experimental animals t80 man. Numerous examples of such differences have been cited in pa'pers given in this monograph and this subject has been recently reviewed.' In most instances, drugs are npabolized in the body to inactive products which are then rapidly excreted in urine and bile. However, formation of metaboli'tes contributes to the pharmacological activity .of some drugs such as prontosil, phenylbutazone and imipramine, and certain organophosphate insecticides owe their toxicity to formation of oxy-derivatives by enzymes in liver microsames.Marked individual differences exist in the metabolism of many drugs. Because of this variability, some individuals metabolize a drug so rapidlly that therapeutically effective blood and tissue levels are not achieved while others may metahlize the same drug so slowly as to result in accumulation wi,th resuking toxic effects. The im.portance of genetic differences in 'explaining this individual variability in drug metabolism has been pointed out in several papers presented in this monograph. However, recent work indicates that environmental factors may also be important in explaining such individual differences in drug metabolism. For instance, the administration of a drug can lead to a marked increase in its own metabolism or that of a subsequent dose of another drug. Drugs exert this effect by stimulating the activity of drug-metabolizing enzymes in liver microsomes. Available evidence indicates that this results from increased synthesis of these enzymes and the mechanisms involved have been the subject of recent rev i e w~.~-~ Drug induced synthesis ,of liver microsomal enzymes occurs in many animal species including rat, mouse, guinea pig, dog, rabbit, .cat and man. A recent compilation showed that this adaptive effect has been observed with over 100 drugs and other c o m p o~n d s .~ It is the purpose of the present paper to show how enzyme induction is important for the evaluation of drug ,toxicity. Exam.ples wlill be presen,ted which demonstrate that the chronic administration of a drug to dogs increases the drug's own metabolism. Results will be presented showing how pretreatment with a drug can alter the toxicity of .a subsequent dose of another drug by stimulating its me.tabolism, and evidence will be given that enzyme induction may be important in human drug therapy. Stimulatory Eflect of Drugs on Their Own Metabolism in DogsSin,ce the chronic administration of the antirheumatic drug, phenylbutazone, to rats increases the activity of enzymes in liver microsomes which metabolize the drug,' we have studied this effect in the dog. Three dogs were given a 100 mg./kg. oral dose of phenylbutazone and plasma levels o f the drug were determined 24 hours later (FIGURE 1). The dogs then received 25-100 mg./kg. of phenylbutazone daily for 14 day...

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Many drugs are metabolized by enzyme systems localized in liver microsomes. 1 Reactions catalyzed by these enzymes include: A-dealkylation, deamination, aromatic hydroxylation, ether cleavage, sulfoxide formation, alkyl chain oxidation, nitro group reduction, azo-link cleavage, and glucuronide formation. The activity of these drug-metabolizing enzymes in liver microsomes can be influenced markedly by the administra tion of various foreign compounds and hormones and by the age, sex, strain, and the nutritional status of the animal. 2 We have been par ticularly interested in the stimulatory effect of chronic drug administration on drug metabolizing enzymes in liver microsomes. These observations may have considerable importance in interpreting results of prolonged toxicity experiments in animals and in explaining changes in drug action observed when drugs are given chronically, either alone or in combination, to experimental animals and man. Examples of compounds eliciting this adaptive response include antihistaminics, hypnotics, antirheumatics, analgesics, muscle relaxants, and polycyclic hydrocarbons. Studies in RatsThe liver microsomal enzyme that hydroxylates zoxazolamine has been chosen for detailed study as an example of a drug-metabolizing enzyme that is stimulated by drug administration (FIGURE l). 3 Zoxazolamine is hydroxylated in the 6-position by liver microsomes to give a pharma cologically inactive metabolite, so that any increase in the activity of this enzyme system would be expected to decrease the duration of action of zoxazolamine. The effect of phénobarbital and 3,4-benzpyrene on the zoxazolamine hydroxylase system is shown in FIGURE 2. In this experi ment, 50 gm. rats were given a single intraperitonal injection of 20 mg./kg. of 3,4-benzpyrene or daily injections of 75 mg./kg. of phénobarbital. The rats were killed at intervals, their livers were homogenized, and microsomes were assayed for ability to metabolize zoxazolamine in the presence of excess cofactors. A single injection of 3,4-benzpyrene rapidly stimulated the zoxazolamine hydroxylase system to maximum activity within 24 hours; 881