Effect of bifendate on the pharmacokinetics of cyclosporine in relation to the CYP3A4 18B genotype in healthy subjects

Abstract

Aim: 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-) 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- 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. Conclusion: These results suggest that bifendate decreases the plasma concentration of cyclosporine in a CYP3A4 genotype-dependent manner. © 2009 CPS and SIMM.