Journal
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY
Volume 66, Issue 11, Pages 1131-1136Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00228-010-0869-3
Keywords
Voriconazole; Erythromycin; CYP2C19; Genetic polymorphism; Chinese
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Funding
- National Science Foundation of China [C03050205]
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To assess the impacts of erythromycin on the pharmacokinetics of voriconazole and its association with CYP2C19 genotypes in healthy Chinese male subjects. A single-center, open, crossover clinical study with two treatment phases was carried out. Eighteen healthy male volunteers, including 6 CYP2C19 homozygous extensive metabolizers (EMs, *1/*1), 6 heterozygous EMs (HEMs, *1/*2 or *1/*3), and 6 CYP2C19 poor metabolizers (PMs, *2/*2 or *2/*3), were enrolled in this study. A single oral dose of 200 mg voriconazole was administrated to all subjects after 3-day pretreatment with either 500 mg erythromycin or placebo three times daily. Periods were separated by a washout period of 14 days. Serial venous blood samples were collected, and plasma concentrations of voriconazole were determined by HPLC. Results C(max), AUC(0-24), and AUC(0-infinity) of voriconazole were increased significantly, while oral clearance of voriconazole was decreased significantly by erythromycin administration (p<0.001, respectively). Compared with individuals with CYP2C19 PM genotypes, individuals with CYP2C19 EM and HEM genotypes showed significantly decreased T, AUC(0-24), AUC(0-infinity), and increased oral clearance of voriconazole (p<0.05, respectively). In addition, significant increases in AUC(0-24) and AUC(0-infinity) and decreases in oral clearance of voriconazole after erythromycin treatment were observed in CYP2C19 HEMs and PMs (p<0.05, respectively), but not in CYP2C19 EMs. Conclusion Both CYP2C19 genotypes and CYP3A4 inhibitor erythromycin can influence the plasma concentration of voriconazole, and erythromycin increases plasma concentration of voriconazole in a CYP2C19 genotype-dependent manner.
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