The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers

To study the pharmacokinetic characteristics of voriconazole in healthy Chinese male volunteers in relation to cytochrome P450 (CYP) 2C19 genotype status, including ultra-rapid metabolizers (URMs), homozygous extensive metabolizers (EMs), and poor metabolizers (PMs). Twenty healthy Chinese male volunteers were recruited for the study. Of these, four were CYP2C19 heterozygous URMs (*1/*17), eight were CYP2C19 homozygous EMs (*1/*1), and eight were CYP2C19 PMs (*2/*2). After a single oral dose of 200 mg voriconazole, plasma concentrations of voriconazole were determined for a 24-h period by liquid chromatography-mass spectrometry/mass spectrometry. In Chinese male subjects, the allele frequencies of the CYP2C19*17 and CYP2C19*2 alleles were 0.64 and 35.6%, respectively, and both alleles were in Hardy-Weinberg equilibrium. The area under the concentration-time curve (AUC) from predose to 24 h (AUC(0-24)) and from predose to infinity (AUC(0-az)), and apparent oral clearance (CL/F) of voriconazole were statistically different among all three genotypic groups (P < 0.001, respectively). The maximum plasma concentration (C-max) value of URMs also showed statistically significant differences from those of EMs and PMs (P = 0.036 and P = 0.035, respectively). The elimination half-life (t(A1/2)) in URMs was 87% (P = 0.58) of that in EMs and 51% (P= 0.002) of that in PMs. Our data indicate that the presence of the CYP2C19*17 allele results in ultra-rapid metabolism of voriconazole after a single oral dose.