Deimidazolation of antimycotic croconazole through epoxide formation in rabbit liver microsomes.
Incubation of croconazole with rabbit microsomes in the presence of NADPH + 18O2 produced the major metabolite, 2-(3-chlorobenzyloxy)phenacyl alcohol (M2) containing one 18O atom. Also detected in the ethyl acetate extracts from the incubation mixture was the remainder of the product, imidazole. These results indicate that the deimidazolation process from croconazole involves the intermediate, croconazole epoxide, which is hydrolyzed immediately to M2 and imidazole. This reaction is mediated by cytochrome P-450 as indicated by the requirement of NADPH, the incorporation of 18O, and inhibition by 10 mM metyrapone, 0.1 mM SKF 525-A, and CO/O2 (50/50, 80/20). Double reciprocal plots of M2 formation give a straight line, suggesting that the reaction may be mediated by an isozyme of cytochrome P-450 families.
Nakano
M
M
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Mizojiri
K
K
D000098:Acetophenones / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000302:isolation & purification / Q000493:pharmacokinetics*; D002248:Carbon Monoxide / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004852:Epoxy Compounds / Q000493:pharmacokinetics*; D004988:Ethers, Cyclic / Q000493:pharmacokinetics*; D007093:Imidazoles / Q000302:isolation & purification / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D009249:NADP / Q000378:metabolism; D010100:Oxygen / Q000493:pharmacokinetics; D010634:Phenobarbital / Q000494:pharmacology; D011817:Rabbits
D000098:Acetophenones; D000935:Antifungal Agents; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D007093:Imidazoles; C061824:2-(3-chlorobenzyloxy)phenacyl alcohol; C038008:croconazole; D009249:NADP; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D010100:Oxygen; D010634:Phenobarbital; D008797:Metyrapone