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

作　　者：Yong ZENG Yi-jing HE Fu-yuan HE Lan FAN Hong-hao ZHOU 

机构地区：[1]Pharmacogenetics Research Institutej Institute of Clinical Pharmacology~ Central South University~ Changsha 410078, China

出　　处：《Acta Pharmacologica Sinica》2009年第4期478-484,共7页中国药理学报（英文版）

基　　金：This work was supported by research grants from the National Natural Science Foundation of China （No 30672497）, the China Medical Board of New York （grant No 01-755）, and the Hunan Health Research Foundation of Traditional Chinese Medicine （grant No 204041）.

摘　　要：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.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.

关 键 词：BIFENDATE CYCLOSPORINE PHARMACOKINETICS CYP3A4＊18B 

分 类 号：R969.2[医药卫生—药理学] R979.5[医药卫生—药学]