Effects of antimycotics on hepatic steroid metabolism.
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.
Morita
K
K
Hospital Pharmacy, Shiga University of Medical Science, Ohtsu, Japan.
Ono
T
T
Shimakawa
H
H
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002675:Child, Preschool; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008825:Miconazole / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010105:Oxygenases / Q000378:metabolism; D010424:Pentobarbital / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*
D000935:Antifungal Agents; D013739:Testosterone; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D010424:Pentobarbital; D007654:Ketoconazole; D006854:Hydrocortisone