Cocktail探针药物法评价丹参注射液和心可舒片对家兔CYP450酶5种亚型的作用  

Effect of Danshen Injection and Xinkeshu Tablets on the Metabolism of CYP1A2,CYP2C9,CYP2C19,CYP2D6 and CYP3A4 in Rabbits by Cocktail Probe Substrates Method

作　　者：张云轩[1,2] 崔学艳[1,3] 陆优丽[4] 刘罡一[4] 宋钟娟[2] 施孝金[1] 钟明康[1] 

机构地区：[1]复旦大学附属华山医院药剂科,上海200040 [2]复旦大学附属华东医院药剂科,上海200040 [3]山东省千佛山医院药剂科,济南250014 [4]上海市徐汇区中心医院中心实验室,上海200032

出　　处：《中国药学杂志》2015年第10期881-887,共7页Chinese Pharmaceutical Journal

摘　　要：目的采用"Cocktail"探针药物法考察丹参注射液和心可舒片对家兔CYP酶5种亚型CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4代谢的影响。方法将16只雄性家兔同时空腹给予混合探针药咖啡因、甲苯磺丁脲、奥美拉唑、右美沙芬和咪达唑仑,采用LC-MS/MS检测特定时间点的探针药物代谢率(代谢产物浓度与探针原型药物浓度的比值)。家兔随机分为丹参注射液组和心可舒片组,设计为自身对照实验,分3个周期,按顺序分别给药丹参低剂量组(0.5 m L·kg-1)、中剂量组(1 m L·kg-1)、高剂量组(2 m L·kg-1)和心可舒低剂量组(90 mg·kg-1)、中剂量组(180 mg·kg-1)和高剂量组(360 mg·kg-1)。每个周期经7 d洗净期后,连续给药7 d,第15天再给予探针药物后测代谢率。采用ANOVA方差分析比较各剂量组家兔和用药前探针药物的代谢率的变化。结果与用药前相比,各剂量组的混合探针药物代谢率均有下降趋势。结论丹参注射液、心可舒片使用7 d后可能抑制家兔体内CYP450酶代谢,与体外实验结果一致。这些药物与经过CYP450酶代谢的药物联合应用时,可能会引起药物相互作用,临床联合使用应提高警惕。OBJECTIVE To study the effect of Danshen injection and Xinkeshu tablets on the metabolism of CYP1A2,CYP2C9,CYP2C19,CYP2D6 and CYP3A4 in rabbits by cocktail probe substrates method. METHODS Sixteen healthy fasted male rabbits were simultaneously given cocktail probe substrates including caffeine,tolbutamide,omeprazole,dextromethorphan and midazolam.The metabolic rates of cocktail probe substrates were determined by LC MS / MS methods at some specific time following the administration. Then the rabbits were randomly assigned to receive either Danshen injection or Xinkeshu tablets. The whole self-control trial was consisted of 3 cycles. The low,middle and high dosage（ 0. 5,1 and 2 m L·kg- 1） of Danshen injection group would be administrated in 3 cycles in sequence. The low,middle and high dosage（ 90,180 and 360 mg·kg- 1） of Xinkeshu tablets group would be administrated in 3 cycles in sequence. Each cycle includes wall-out period of 7 d followed by administration of the 2 herbal medicines for consecutive 7 d. On the 15 th day the cocktail probe substrates were administrated and the metabolic rates were determined. The differences of the metabolic rates between after and before admininstration of the 2 herbal medicines were assessed by one-way analysis of variance（ ANOVA）. RESULTS After taking the agents of Danshen injection and Xinkeshu tablets,the metabolic rates of the five cocktail probe substrates had a tendency to decline compared with the before-administration. CONCLUSION The outcome in vivo is in accordance with that in vitro. Danshen injection and Xinkeshu tablets can inhibit the metabolism of five CYPs（ 1A2,2C9,2C19,2D6 and 3A4） activities in rabbits. At sometimes precautions are needed to co-administrate either Danshen injection or Xinkeshu tablets forpossible herb-drug interactions.

关 键 词：细胞色素P450 混合探针底物法 丹参注射液 心可舒片 

分 类 号：R969.1[医药卫生—药理学]