Inhibition of testosterone biosynthesis in testicular microsomes by various imidazole drugs. Comparative study with ketoconazole.

Ketoconazole (KCZ), an imidazole-containing antimycotic, has been demonstrated to inhibit testosterone biosynthesis in man. In this study, the inhibitory activities of various imidazole drugs such as miconazole (MCZ), cimetidine (CIM), ozagrel (OZA) and its metabolites (M-1 and M-2) on the pathway of testosterone biosynthesis in testicular microsomes were compared with that of KCZ in vitro. Additionally, the changes in serum testosterone level in the patients by the treatments with MCZ were followed. KCZ inhibited 17 alpha-hydroxylase and C17,20-lyase activities in a dose-dependent manner, while it did not affect 17 beta-hydroxysteroid dehydrogenase activity. Although the patterns of the inhibitory actions and the interaction of either imidazole drugs with cytochrome P-450 as 17 alpha-hydroxylase and C17,20-lyase were similar to those of KCZ, the inhibitory potencies and affinities for the cytochrome P-450 system decreased in the order of KCZ greater than MCZ greater than OZA greater than M-2 greater than M-1 greater than CIM. At the end of the intravenous injection of 200 mg MCZ to the patients, the serum testosterone levels decreased by about 16% of the original level and then returned to the original level 5 h after the end of injection. These results indicate that either imidazole drugs tested could inhibit a cytochrome P-450 enzyme C17,20-lyase mainly in testicular microsomes, and suggest that MCZ, a potent inhibitor subsequent to KCZ, induces a slight alteration in the testosterone biosynthesis in its clinical use.