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Effect of CYP2C19 Polymorphism on the Pharmacokinetics of Voriconazole After Single and Multiple Doses in Healthy Volunteers
Author(s) -
Lee SeungHwan,
Kim BoHyung,
Nam WonSeok,
Yoon Seo Hyun,
Cho JooYoun,
Shin SangGoo,
Jang InJin,
Yu KyungSang
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010395510
Subject(s) - cyp2c19 , voriconazole , pharmacokinetics , dosing , tolerability , medicine , pharmacology , bioavailability , pharmacogenetics , cmax , cyp2c9 , area under the curve , genotype , adverse effect , chemistry , cytochrome p450 , antifungal , biochemistry , dermatology , metabolism , gene
The current study assessed the influence of the CYP2C19 genotype on the pharmacokinetics and tolerability of voriconazole after single and multiple oral doses in healthy volunteers. Six subjects for the CYP2C19 homozygous extensive metabolizer (EMs), 6 for heterozygous extensive metabolizer (HEMs), and 6 for poor metabolizer (PMs) were enrolled, and their CYP2C9, CYP3A5, and MDR1 genotypes were analyzed. After a single intravenous infusion or single and multiple oral doses of 200 mg of voriconazole, plasma concentrations of voriconazole were measured. Bioavailability was not significantly different among the CYP2C19 genotypes. Voriconazole exposure in PMs was approximately 3 times higher compared with EMs after a single intravenous or oral dose. At steady state, the plasma concentration just before the next dosing and area under the concentration‐time curve from dosing to the time point of the next dosing for PMs were about 5 times and 3 times higher than EMs, respectively. These results suggest that the CYP2C19 genotype is the major determinant of the wide PK variability of voriconazole.