SPECIES DIFFERENCE IN THE INHIBITION OF DRUG METABOLISM BY LIVER MICROSOMES BY DIFFERENT INHIBITORS

Abstract

It has been reported that the activities of drug-metabolizing enzymes of liver microsomes are inhibited by different kind of drugs (1). SKF 525-A (β-diethylaminoethyl-diphenylpropylacetate HCl) was discovered for the first time and it has been known as the most popular and typical inhibitor of microsomal drug-metabolizing enzymes (2-4), while DPEA (2, 4-dichlorophenylphenoxyethylamine HCl) has been known as the most potent inhibitor (5-6). Moreover, Kato et al. (1, 7, 8) reported that the inhibitors of the microsomal enzymes, such as SKF 525-A, DPEA and MG 3062 (phenyl-(4-chlorophenyl)-4-piridylmethanol) increase the activities of drug-metabolizing enzymes, on the other hand, the inducers of the microsomal enzymes, such as chlorcyclizine, glutethimide and phenaglycodol inhibit the activities of drug-metabolizing enzymes. It has been established that a number of commonly used drugs of high lipid-solubility inhibit the activities of drug-metabolizing enzymes and the in vivo metabolism of various drugs (1, 9-11). The inhibition in the metabolism of drugs seems to be popular phenomenon in combined administration of more than two drugs and sometimes even mutual inhibition may be occurred, therefore, these phenomena are important for the evaluation of drug activity and for the determination of dosage schedule in drug therapy (1). However, the mechanism by which many drugs produce the inhibition of the activities of drugmetabolizing enzymes has not yet been elucidated (12, 13). Netter (14) observed that SKF 525-A noncompetitively inhibited the O-demethylation of o-nitroanisole. In contrast, McMahone (5) reported that SKF 525-A and DPEA competitively inhibited the N-demethylation of butynamine. Moreover, Rubin et al. (11) reported that SKF 525-A competitively inhibited the N-demethylations of morphine and ethylmorphine. In a previous work (15), we briefly reported that N-demethylation of aminopyrine and hydroxylation of hexobarbital in rat liver microsomes were competitively inhibited by SKF 525-A, while they were noncompetitively inhibited by SKF 525-A in rabbit liver microsomes. The present communication is concerned with the species difference in the inhibition of various pathways of drug metabolisms in liver microsomes by different inhibitors. The differences in the type and potency of the inhibition between rats, rabbits and mice may offer some insight for the mechanism of the inhibition of drug-metabolizing enzymre.