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When male ddY mice were treated with consecutive doses of 10 and 100 mg/kg of miconazole (MCZ) or ketoconazole (KCZ), imidazole-containing antimycotics, once a day for 3 d, a dose-dependent shortening of pentobarbital sleeping time was observed for MCZ, while no change in the sleeping time was observed for KCZ. Even at a low dose (10 mg/kg), MCZ significantly increased cytochrome P-450 content and reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase activity. Simultaneously, hydroxylase activities of testosterone as a model of endogenous steroids, and aminopyrine N-demethylase and 7-ethoxycoumarin O-deethylase activities were increased, while KCZ lacked inducing properties even at a high dose (100 mg/kg). The change in hepatic oxidative metabolism of cortisol (F) in a patient before, during and after treatment with progressively increasing doses of 2-10 mg/kg/d of MCZ for 14 d was examined by monitoring urinary 6 beta-hydroxycortisol (6 beta-OHF), an oxidative metabolite of F. The ratio of 6 beta-OHF to F in 24-h urine decreased by 15% from the original level on day 1, and then it began to increase on day 7 to reach 2.4 times the original level on day 14. These results suggest that MCZ, but not KCZ, has inducing activity for hepatic cytochrome P-450-dependent oxidative metabolism of steroids and xenobiotics, in addition to its known inhibitory activity.

Effects of antimycotics on hepatic steroid metabolism.