title: The Effect of Genetic Polymorphism on the Inhibition of Azole Antifungal Agents Against CYP2C9-Mediated Metabolism.
abstract: We investigated the effect of cytochrome P450 (CYP) 2C9 polymorphism on the inhibition of methylhydroxylation activity of tolbutamide, a typical CYP2C9 substrate, by triazole antifungal agents, fluconazole and voriconazole. Although the Michaelis constants (Km), maximal velocities (Vmax), and Vmax/Km values for CYP2C9.1 (wild type) and CYP2C9.2 (Arg144Cys) were similar and CYP2C9.3 (Ile359Leu) had a higher Km and a lower Vmax than CYP2C9.1 and CYP2C9.2, the inhibition constants of fluconazole and voriconazole against CYP2C9.2 were lower than that against CYP2C9.1 and CYP2C9.3. These results suggest that more careful administration of azole antifungals to patients with the CYP2C9*2 allele might be required because of the strong inhibitory effects.
authors.affiliation: School of Pharmacy, Shujitsu University, Okayama, Japan. Electronic address: tniwa@shujitsu.ac.jp.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niwa
authors.affiliation: School of Pharmacy, Shujitsu University, Okayama, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Hata
mesh_terms: D000483:Alleles; D000935:Antifungal Agents / Q000378:metabolism* / Q000627:therapeutic use*; D001393:Azoles / Q000378:metabolism* / Q000627:therapeutic use*; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015725:Fluconazole / Q000378:metabolism / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D006900:Hydroxylation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D014044:Tolbutamide / Q000378:metabolism / Q000627:therapeutic use; D065819:Voriconazole / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D065729:Cytochrome P-450 CYP2C9; D065819:Voriconazole
keywords: CYP2C9 polymorphism; azole antifungal agents; fluconazole; tolbutamide; voriconazole