title: Effect of bifendate on the pharmacokinetics of cyclosporine in relation to the CYP3A4*18B genotype in healthy subjects.
abstract: OBJECTIVE
  To evaluate the potential drug-drug interactions between bifendate and cyclosporine, a substrate of CYP3A4, in relation to different CYP3A4*18B genotype groups.
  
  
  METHODS
  Eighteen unrelated healthy subjects (six CYP3A4*1*1, six CYP3A4*1/*18B, and six CYP3A4*18/*18B) were selected for this study. After repeated oral administration of a placebo or bifendate (three times daily for 14 d), the whole-blood level of cyclosporine was measured using high performance liquid chromatography-electrospray mass spectrometry (HPLC/ESI-MS). This study was carried out in a two-phase randomized crossover manner.
  
  
  RESULTS
  After the treatment with bifendate, the areas under the curve (AUC(0-24) and AUC(0-infinity)) decreased significantly by 9.7%+/-3.7% (P=0.01) and 19.2%+/-16.8% (P=0.001) in CYP3A4*1/*1 subjects, 11.3%+/-9.4% (P=0.03) and 10.5%+/-9.6% (P=0.043) in CYP3A4*1/*18B subjects, and 40.2%+/-14.7% (P=0.02) and 37.5%+/-15.8% (P=0.003) in CYP3A4*18B/*18B subjects. Meanwhile, the decreases in the AUC(0-24) and AUC(0-infinity) values in the three groups were significantly different (using one-way analysis of variance, P=0.001 and P=0.001), and the change in the CYP3A4*18B/*18B group was greater than that in the other two groups. The oral clearance of cyclosporine was altered in all the subjects, with substantial increases by 10.2%+/-4.4% (P=0.004) in CYP3A4*1/*1 subjects, 14.0%+/-12.0% (P=0.048) in CYP3A4*1/*18B subjects, and 32.4%+/-21.7% (P=0.013) in CYP3A4*18B/*18B subjects.
  
  
  CONCLUSIONS
  These results suggest that bifendate decreases the plasma concentration of cyclosporine in a CYP3A4 genotype-dependent manner.
authors.affiliation: Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zeng
authors.forename: Yi-jing
authors.initials: YJ
authors.lastname: He
authors.forename: Fu-yuan
authors.initials: FY
authors.lastname: He
authors.forename: Lan
authors.initials: L
authors.lastname: Fan
authors.forename: Hong-hao
authors.initials: HH
authors.lastname: Zhou