title: CYP3A4∗18B and CYP3A5∗3 polymorphisms contribute to pharmacokinetic variability of cyclosporine among healthy Chinese subjects.
abstract: OBJECTIVE
  Cyclosporine is an immunosuppressant drug used to prevent allograft rejection. It is metabolized by CYP3A4 and CYP3A5, has a narrow therapeutic index, and variable pharmacokinetics. Here, we investigated whether CYP3A5∗3 and CYP3A4∗18B polymorphisms contribute to inter-individual pharmacokinetic variability in healthy subjects.
  
  
  METHODS
  Fifty-six healthy Chinese subjects were enrolled in the study after signing a written consent. The subjects received 5mgkg(-1) of cyclosporine orally and were genotyped for CYP3A5∗3 and CYP3A4∗18B using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Blood concentrations of cyclosporine were measured by high-performance liquid chromatography for up to 30h post-dose.
  
  
  RESULTS
  The mean cyclosporine AUC0→30 and AUC0→∞ in the male group was significantly higher than that in the female group (P=0.037 and 0.035); the CL/F in the male group was significantly lower than that in the female group (P=0.033). The Cmax of cyclosporine in CYP3A4∗1/∗1 was significantly greater than that in CYP3A4∗1/∗18B in the male group (P=0.023), but not the female group. In addition, the Cmax in CYP3A5∗1/∗3 was significantly lower than that in CYP3A5∗3/∗3 in the male group (P=0.01).
  
  
  CONCLUSIONS
  The results indicate that gender and polymorphism in CYP3A4∗18B and CYP3A5∗3 significantly affect cyclosporine pharmacokinetics in healthy subjects.
authors.affiliation: Department of Pharmacy, Fuzhou General Hospital of Nanjing Command PLA, Fuzhou, Fujian 350025, China; Department of Pharmacy, Children's Hospital of Zhengzhou, Zhengzhou, Henan 450000, China. Electronic address: taoxr2010@sina.cn.
authors.forename: Xing-ru
authors.initials: XR
authors.lastname: Tao
authors.affiliation: Department of Pharmacy, Fuzhou General Hospital of Nanjing Command PLA, Fuzhou, Fujian 350025, China. Electronic address: 504278483@qq.com.
authors.forename: Xiu-yuan
authors.initials: XY
authors.lastname: Xia
authors.affiliation: Department of Pharmacy, Fuzhou General Hospital of Nanjing Command PLA, Fuzhou, Fujian 350025, China. Electronic address: 303385326@qq.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Emergency, Fuzhou General Hospital of Nanjing Command PLA, Fuzhou, Fujian 350025, China. Electronic address: 13515029809@139.com.
authors.forename: Lian-ying
authors.initials: LY
authors.lastname: Tong
authors.affiliation: Department of Emergency, Fuzhou General Hospital of Nanjing Command PLA, Fuzhou, Fujian 350025, China. Electronic address: zh-easy@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Fuzhou General Hospital of Nanjing Command PLA, Fuzhou, Fujian 350025, China. Electronic address: 13959188386@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pharmacy, Fuzhou General Hospital of Nanjing Command PLA, Fuzhou, Fujian 350025, China. Electronic address: liuzh827@sina.cn.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Fuzhou General Hospital of Nanjing Command PLA, Fuzhou, Fujian 350025, China. Electronic address: sohoto@vip.163.com.
authors.forename: Hong-tao
authors.initials: HT
authors.lastname: Song
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics*; D001682:Biological Availability; D002681:China; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D010597:Pharmacogenetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012737:Sex Factors; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CYP3A4∗18B; CYP3A5∗3; Cyclosporine; Gender; Pharmacogenomics; Pharmacokinetics