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

• Published in: Acta pharmacologica Sinica Vol. 30; no. 4; pp. 478 - 484
• Main Author: Yong ZENG Yi-jing HE Fu-yuan HE Lan FAN Hong-hao ZHOU
• Format: Journal Article
• Language: English
• Published: 23.04.2009
• Subjects: CYP3A4; 基因型; 正常人; 环孢素A; 联苯双酯; 药代动力学; 药物相互作用; 高效液相色谱法
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2009.27

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.