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 wholeblood 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 (AUC0-24 and AUC0-∞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 AUC0-24 and AUC0-∞ 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.
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