聚氧乙烯脱水山梨醇单油酸酯对大鼠体内细胞色素P450酶活性的影响  

Effect of polysorbate 80 on activity of Cytochrome P450 in rats

作　　者：葛韬 彭慧[1,2,3] 张变 张玲 孙言才[4] 

机构地区：[1]安徽中医药大学,合肥230012 [2]安徽省中医药科学院,合肥230012 [3]安徽中医药大学药物代谢研究所,合肥230012 [4]安徽省立医院,合肥230031

出　　处：《中南药学》2017年第12期1699-1703,共5页Central South Pharmacy

基　　金：国家自然科学基金面上项目(No.81773988);茯苓中药饮片标准化建设项目(No.2017HZ5)

摘　　要：目的采用Cocktail混合探针药物法,探究聚氧乙烯脱水山梨醇单油酸酯(吐温80)对大鼠体内Cyp450同工酶活性的影响,为提高临床低生物利用度药物的疗效提供新的途径,也为药物研发领域研制新型制剂选择合适的辅料提供理论依据。方法选用非那西丁、奥美拉唑、安非他酮和咪达唑仑分别作为大鼠体内4种Cyp450酶(Cyp1a2、Cyp2c11、Cyp2b1、Cyp3a1)的探针药物。SD雄性大鼠连续尾静脉注射吐温80溶液14 d,第14日给药30 min后,尾静脉注射混合探针药物后于各时间点取血。采用LC-MS/MS法测定试验组和对照组混合探针药物的血药浓度,用DAS 2.0软件拟合药代动力学参数。结果吐温80连续尾静脉注射2周后,与空白对照组相比,非那西丁、奥美拉唑、安非他酮的代谢明显减慢,而咪达唑仑的代谢无明显差异。结论吐温80对大鼠体内Cyp2c11、Cyp2b1、Cyp1a2酶有明显抑制作用,而对大鼠体内Cyp3a1无明显影响。因此,在临床上吐温80与CYP1A2、CYP2B6、CYP2C19酶相关的底物合用时,应注意给药剂量,防止药物在体内的血药浓度过高从而导致不良反应。Objective To determine the effect of Tween 80 on the activity of Cytochrome P450 enzymes in rats by Cocktail probe drug method, to provide a new way to improve bioavailability, to develop new formulations and provide theoretical basis for drug development. Methods Phenacetin, omeprazole, bupropion, and midazolam were selected as the probe substrate of Cypla2, Cyp2c11, Cyp2b1 and Cyp3a1. SD male rats were intravenously injected Tween 80 for 14 days. On day 14, blood samples were collected at the time points after the intravenous injection of the probe drugs. The plasma concentration of the 4 kinds of Cyp450 enzymes （Cyp1a2, Cyp2c11, Cyp2b1 and Cyp3a1） in the experimental groups and the control group were determined by LC-MS/MS after plasma sample treatment. The pharmacokinetic parameters of the probe drug were calculated by DAS 2.0 software. Results After 2 weeks of Tween 80 intravenous injection, the metabolism of phenacetin, omeprazole and bupropion was significantly reduced compared with that in the blank control group. While the metabolism of midazolam was not significantly different. Conelusion Tween 80 may significantly inhibit Cyp2c11, Cyp2b1 and Cyp1a2 enzymes in rats, but has significant effect on Cyp3al. Attention should be paid to the dosage of Tween 80 when taken together with substrates such as CYP 1A2, CYP2B6 and CYP2C 19 to try to avoid adverse reactions.

关 键 词：聚氧乙烯脱水山梨醇单油酸酯 细胞色素P450酶 探针药物 COCKTAIL 

分 类 号：R285[医药卫生—中药学]