Interactions of imidazole antifungal agents with purified cytochrome P-450 proteins.
The imidazole N-substituted antifungal agents ketoconazole, miconazole and clotrimazole have been shown to be potent inhibitors of oxidative metabolism by both a phenobarbital-induced cytochrome P-450 (P-450b) and a 3-methylcholanthrene-induced cytochrome P-448-protein (P-450c) in reconstituted systems. All three compounds inhibited the cytochrome P-450b-dependent 7-pentoxyresorufin-O-dealkylase and the cytochrome P-450c-dependent 7-ethoxyresorufin-O-deethylase activities. When 7-benzyloxyresorufin and 7-ethoxycoumarin were employed as substrates with both cytochrome preparations, all three antifungal compounds exhibited selective inhibition of the cytochrome P-450b preparation; ketoconazole was always the weakest inhibitor. The three antifungal agents were also shown to elicit a type II difference spectral interaction with both isoenzymes, the magnitude of the spectral interaction being greater with the cytochrome P-450b preparation.
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D003022:Clotrimazole / Q000494:pharmacology*; D019362:Cytochrome P-450 CYP2B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008825:Miconazole / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010105:Oxygenases / Q000037:antagonists & inhibitors; D051381:Rats; D013057:Spectrum Analysis
D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D008825:Miconazole; D010088:Oxidoreductases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D019362:Cytochrome P-450 CYP2B1; D003022:Clotrimazole; D007654:Ketoconazole