Inhibitory effects of ketoconazole and miconazole on cytochrome P-450-mediated oxidative metabolism of testosterone and xenobiotics in mouse hepatic microsomes - Comparative study with cimetidine.

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Abstract
The inhibitory effects of ketoconazole (KCZ) and miconazole (MCZ), imidazole containing antimycotics, on the hydroxylations of testosterone as a model for endogenous steroids, and the N-demethylation of aminopyrine and the hydroxylation of aniline as models for xenobiotics were compared with those of cimetidine in mouse hepatic microsomes. In vitro, both KCZ and MCZ inhibited these enzyme activities in a dose-dependent manner. The inhibitory potencies of KCZ and MCZ for testosterone hydroxylations and aminopyrine N-demethylation were much greater, with 50% inhibition concentration (IC50) values 2-3 orders of magnitude lower than those of cimetidine, while the potencies of these antimycotics for aniline hydroxylation were similar to that of cimetidine. Although KCZ, MCZ and cimetindine produced type II difference spectra, the difference between the antimycotics (405 nm) and cimetidine (392-405 nm) was found in the trough position of the difference spectra. Spectral dissociation constants (KS) of these antimycotics (2.2 .times. 10-7 - 5.4 .times. 10-6 M) were also 1-2 orders of magnitude lower than those of cimetidine (1.3 .times. 10-5 - 1.6 .times. 10-4 M), and both KCZ and cimetidine had two kinds of KS, while MCZ had a single KS. Pentobarbital sleeping time was prolonged in a dose-dependent manner by the i.p. administration of 10-50 mg/kg of KCZ, MCZ or cimetidine, and the potencies for the prolongation of sleeping time decreased in the order of MCZ > KCZ > cimetidine. These results indicated that the inhibitory potencies of KCZ and MCZ for the cytochrome P-450-mediated oxidative metabolism of testosterone and xenobiotics in hepatic microsomes were greater than those of cimetidine, and that the affinities of KCZ and MCZ for some cytochrome P-450 species in hepatic microsomes differed from one another.