title: Impact of cytochrome P450 2C19 polymorphisms on the pharmacokinetics of tacrolimus when coadministered with voriconazole.
abstract: This study evaluated the effects of cytochrome P450 (CYP) 2C19 polymorphisms on tacrolimus pharmacokinetics when coadministered with voriconazole. Eighteen healthy volunteers, including 6 individuals in each CYP2C19 genotype (extensive metabolizers [EMs], intermediate metabolizers [IMs], and poor metabolizers [PMs]), received a single oral dose of 3 mg tacrolimus alone or in combination with 200 mg voriconazole twice daily at steady state. When tacrolimus was coadministered with voriconazole, a significant increase in area under its concentration-time curve (AUC0-24 ) was observed for all genotypes. AUC0-12 of voriconazole in IMs and PMs were significantly higher than that in EMs (P < .05 and P < .01, respectively). Consequently, AUC0-24 of tacrolimus in combination with voriconazole in IMs and PMs were also significantly higher than that in EMs (P < .05). These results demonstrate that CYP2C19 genotypes influenced the exposure of tacrolimus when coadministered with voriconazole, although tacrolimus is mainly metabolized by CYP3A.
authors.affiliation: Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Chiyo K
authors.initials: CK
authors.lastname: Imamura
authors.affiliation: P-One Clinic, Keikokai Medical Corporation, Hachioji, Tokyo, Japan.|Department of Clinical Pharmacology, School of Medicine, Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Furihata
authors.affiliation: Division of Hematology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanigawara
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000493:pharmacokinetics; D019540:Area Under Curve; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004359:Drug Therapy, Combination / Q000379:methods; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D016559:Tacrolimus / Q000493:pharmacokinetics*; D065819:Voriconazole / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole; D016559:Tacrolimus
keywords: CYP2C19 polymorphism; CYP3A; drug interaction; tacrolimus; voriconazole