title: Effects of erythromycin on voriconazole pharmacokinetics and association with CYP2C19 polymorphism.
abstract: 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.
authors.affiliation: Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, 110# Xiangya Road, Changsha, Hunan, 410078, China.
authors.forename: Hui-Yan
authors.initials: HY
authors.lastname: Shi
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Zhu
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Yang
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Tan
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Wu
authors.forename: Gan
authors.initials: G
authors.lastname: Zhou
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Chen
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Ouyang
mesh_terms: 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
chemical_list: 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