title: Fluconazole is a potent inhibitor of antipyrine metabolism in vivo in mice.
abstract: Fluconazole, a bis-triazole antifungal, is distinguished from imidazole antifungals (e.g. ketoconazole) by its potency and pharmacokinetic characteristics. Imidazole-containing compounds are well documented to inhibit the hepatic cytochrome P-450-dependent enzyme system; whether this effect occurs with a bis-triazole agent is unknown. The [14C]antipyrine breath test was employed to investigate the effects of fluconazole on this enzyme system in CD-1 male mice. Control, ketoconazole (100 mg/kg), and fluconazole (1 and 10 mg/kg) were studied in single- and multiple-dose experiments. Fluconazole had potent inhibitory effects on the total (mean = -73% +/- 2%), demethylase (mean = -90% +/- 2%), and nondemethylase (mean = -60% +/- 4%) elimination rate constants (all p less than 0.001). The fraction of the administered radioactivity excreted as 14CO2 was decreased by 50-80% in the fluconazole groups (p less than 0.001). These effects were seen after single- and multiple-dose studies; however, return to baseline occurred more quickly in the multiple-dose group. These effects were significantly more pronounced than those observed with equipotent doses of ketoconazole. These results provide evidence that fluconazole is a potent, partially selective, and reversible inhibitor of the cytochrome P-450-dependent enzyme system in mice. Future studies will be required to assess this property and possible interactions with drugs metabolized by this enzyme system in humans.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, CA 94305.
authors.forename: I
authors.initials: I
authors.lastname: La Delfa
authors.forename: Q M
authors.initials: QM
authors.lastname: Zhu
authors.forename: Z
authors.initials: Z
authors.lastname: Mo
authors.forename: T F
authors.initials: TF
authors.lastname: Blaschke
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001944:Breath Tests; D002250:Carbon Radioisotopes; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015725:Fluconazole; D008297:Male; D051379:Mice; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D002250:Carbon Radioisotopes; D014230:Triazoles; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D000983:Antipyrine