Induction of hepatic oxidative and conjugative drug metabolism in the hamster by N-substituted imidazoles

Abstract

Three antimycotic N-substituted imidazoles, clotrimazole, tioconazole and miconazole, were able to induce hepatic microsomal cytochrome P-450 and monooxygenase reactions in both male and female hamsters to an extent similar to that seen with phenobarbital treatment. Imidazole treatment did not alter the cytochrome P-450 concentration, and ketoconazole treatment decreased it. Cytosolic sulfo- and glutathione transferases were not significantly altered by any imidazole. Induction of microsomal morphine glucuronosyltransferase activity by each compound generally paralleled the effect on cytochrome P-450 in females but induction was not evident in males. Clotrimazole treatment, in contrast to phenobarbital treatment, also caused a large induction of l-naphthol glucuronosyltransferase in females. The potential for antimycotic imidazoles to alter the hepatotoxicity of compounds will require consideration of the inductive changes in both Phase I and Phase II drug metabolizing enzymes in addition to their known inhibitory effects on Phase I oxidations. The inductive effects differ for each imidazole, and in the hamster model, depend upon the sex of the animal