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Spectral and kinetic studies of the interaction of imidazole anti-fungal agents with microsomal cytochromes P-450


, : Spectral and kinetic studies of the interaction of imidazole anti-fungal agents with microsomal cytochromes P-450. Xenobiotica; the Fate of Foreign Compounds in Biological Systems 17(11): 1315-1327

1. The imidazole antifungal agents, ketoconazole, miconazole and clotrimazole have been shown to be potent inhibitors of the phenobarbital-induced cytochromes P-450 and the 3-methylcholanthrene-induced cytochromes P-448-dependent rat hepatic microsomal mixed-function oxidases. 2. All three drugs were more potent inhibitors of the phenobarbital-induced O-deethylation of ethoxycoumarin than of the 3-methylcholanthrene-induced activity indicating selective inhibition of the phenobarbital-induced cytochromes P-450. In both types of microsomes ketoconazole was always the weakest inhibitor. 3. All three compounds elicited type II spectral interactions with both types of microsomes, and had similar Ks values. Miconazole and clotrimazole, and to a lesser extent ketoconazole, also interacted with the substrate binding sites of both phenobarbital-induced cytochromes P-450 and to a lesser extent with the 3-methylcholanthrene-induced cytochrome P-448. 4. It is concluded that at least part of the inhibitory effect of these antifungal agents may reflect competitive inhibition at the substrate binding site.

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Accession: 041408720

PMID: 3433801

DOI: 10.3109/00498258709047162

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