Induction of hepatic oxidative and conjugative drug metabolism in the hamster by N-substituted imidazoles.
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.
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003022:Clotrimazole / Q000633:toxicity*; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D007093:Imidazoles / Q000633:toxicity*; D007654:Ketoconazole / Q000633:toxicity; D008297:Male; D008647:Mesocricetus; D008825:Miconazole / Q000633:toxicity*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000633:toxicity; D012737:Sex Factors
D005965:Glucuronates; D007093:Imidazoles; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D003022:Clotrimazole; D007654:Ketoconazole; C020527:tioconazole; D010634:Phenobarbital