Effects of erythromycin on voriconazole pharmacokinetics and association with CYP2C19 polymorphism.
OBJECTIVE
To assess the impacts of erythromycin on the pharmacokinetics of voriconazole and its association with CYP2C19 genotypes in healthy Chinese male subjects.


METHODS
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(½), 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.


CONCLUSIONS
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.
Shi
Hui-Yan
HY
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, 110# Xiangya Road, Changsha, Hunan, 410078, China.
Yan
Jin
J
Zhu
Wen-Hui
WH
Yang
Guo-Ping
GP
Tan
Zhi-Rong
ZR
Wu
Wei-Hua
WH
Zhou
Gan
G
Chen
Xiao-Ping
XP
Ouyang
Dong-Sheng
DS
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D002681:China; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004917:Erythromycin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics*; D065819:Voriconazole; D055815:Young Adult
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D011500:Protein Synthesis Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D004917:Erythromycin; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole