Impact of cytochrome P450 2C19 polymorphisms on the pharmacokinetics of tacrolimus when coadministered with voriconazole

Chiyo K. Imamura; Kenichi Furihata; Shinichiro Okamoto; Yusuke Tanigawara

doi:10.1002/jcph.605

Impact of cytochrome P450 2C19 polymorphisms on the pharmacokinetics of tacrolimus when coadministered with voriconazole

Chiyo K. Imamura, Kenichi Furihata, Shinichiro Okamoto, Yusuke Tanigawara

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

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 (AUC_0-24) was observed for all genotypes. AUC_0-12 of voriconazole in IMs and PMs were significantly higher than that in EMs (P <.05 and P <.01, respectively). Consequently, AUC_0-24 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.

Original language	English
Pages (from-to)	408-413
Number of pages	6
Journal	Journal of Clinical Pharmacology
Volume	56
Issue number	4
DOIs	https://doi.org/10.1002/jcph.605
Publication status	Published - 2016 Apr 1

Keywords

CYP2C19 polymorphism
CYP3A
drug interaction
tacrolimus
voriconazole

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)

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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.",

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author = "Imamura, {Chiyo K.} and Kenichi Furihata and Shinichiro Okamoto and Yusuke Tanigawara",

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AU - Tanigawara, Yusuke

N1 - Publisher Copyright: © 2015, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.

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Y1 - 2016/4/1

N2 - 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.

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Impact of cytochrome P450 2C19 polymorphisms on the pharmacokinetics of tacrolimus when coadministered with voriconazole

Abstract

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