Cocktail探针药物法评价红禾麻提取物对大鼠CYP450酶活性的影响  

Effect of Laportea bulbifera extract on CYP450 enzyme activities in rats by Cocktail probe drug method

作　　者：杨惠林 李莹 陈艺 陈思颖 李月婷 黄勇 郑林 黄静 王永林 巩仔鹏 YANG Hui-in;LI Ying;CHEN Yi;CHEN Si-ying;LI Yue-ting;HUANG Yong;ZHENG Lin;HUANG Jing;WANG Yong-in;GONG Zi-peng(Provincial Key Laboratory of Pharmaceutics in Guizhou Province,Engineering Research Center for the Development and Application of Ethnic Medicine and Traditional Chinese Medicine(Ministry of Education),School of Pharmaceutical Sciences,GuizhouMedical University,Guiyang550004,China)

机构地区：[1]贵州医科大学药学院、贵州省药物制剂重点实验室、民族药与中药开发应用教育部工程研究中心,贵州贵阳550004

出　　处：《中国中药杂志》2022年第23期6320-6332,共13页China Journal of Chinese Materia Medica

基　　金：贵阳市科技计划项目(筑科合同[2021]43-12号);贵州医科大学优秀青年人才计划项目(2022-104);贵州医科大学博士启动基金项目(校博合J字[2020]014号);国家自然科学基金项目(81560693,U1812403);贵州省科学技术厅-贵州医科大学国家自然科学基金(学术新苗类)培育项目(19NSP029);贵州省高层次创新型人才项目(黔科合平台人才-GCC[2022]031-1)。

摘　　要：采用Cocktail探针药物法评价红禾麻提取物对大鼠CYP450不同亚型酶活性的影响,为其临床合理用药提供依据。首先将大鼠随机分为红禾麻高(0.45 g·kg^(-1)·d^(-1))、低(0.09 g·kg^(-1)·d^(-1))剂量组,分别连续灌胃红禾麻提取物溶液7、14 d后尾静脉注射探针药物咖啡因、咪达唑仑、甲苯磺丁脲、奥美拉唑、美托洛尔和氯唑沙宗,不同时间点尾静脉取血,建立超高效液相色谱串联质谱法(UPLC-MS)测定大鼠血浆中6种探针药物的浓度,运用DAS 2.0软件计算其药动学参数,考察红禾麻对大鼠体内CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP3A46种亚型酶活性的影响。结果表明,与空白对照组相比,奥美拉唑指标下7 d给药组和14 d高剂量组的AUC_(0-t)、AUC_(0-∞)显著减小,CLz、Vz明显增大;咪达唑仑指标下7 d低剂量组和14 d给药组的AUC_(0-t)、AUC_(0-∞)显著减小,CLz显著增大,另外7 d高剂量组的AUC_(0-∞)也显著减小;美托洛尔指标下各实验组的AUC_(0-t)、AUC_(0-∞)显著减小,7 d低剂量组的CLz以及14 d低剂量组CLz、Vz显著增大;咖啡因指标下7 d给药组的AUC_(0-t)、AUC_(0-∞)显著增大,CLz显著降低,14 d高剂量组t_(1/2z)明显增大;氯唑沙宗指标下7 d低剂量组的AUC_(0-t)、AUC_(0-∞)显著增大,CLz显著降低;甲苯磺丁脲指标下,各药动学参数差异无统计学意义。以上结果提示红禾麻提取物可诱导CYP2C19、CYP3A4、CYP2D6的活性,抑制CYP1A2、CYP2E1的活性,不影响CYP2C9的活性。The Cocktail probe drug method was used to evaluate the effect of Laportea bulbifera extract on the different subtypes of CYP450 enzyme activities in rats,and to provide references for its clinical rational drug use.The rats were randomly divided into a high-dose L.bulbifera group(0.45 g·kg^(-1)·d^(-1))and a low-dose L.bulbifera group(0.09 g·kg^(-1)·d^(-1)).After continuous gavage for 7 and 14 days,the Cocktail probe mixing solution,including caffeine,midazolam,tolbutamide,omeprazole,metoprolol,and chlorzoxazone,was injected into the tail vein,and the blood sample was obtained from the tail vein at different time points.Ultra-high performance liquid chromatography-mass spectrometry(UPLC-MS)was established to determine the concentration of six probe drugs in rat plasma.DAS 2.0 was used to calculate its pharmacokinetic parameters,and the effect of L.bulbifera extract on CYP1A2,CYP2C9,CYP2C19,CYP2D6,CYP2E1,and CYP3A4 in rats was investigated.As compared with the blank control group,under the omeprazole index,the AUC_(0-t)and AUC_(0-∞)of the 7-day administration groups and the 14-day high-dose group were significantly decreased,and the CLz and Vz were significantly increased.Under the midazolam index,the AUC_(0-t)and AUC_(0-∞)of the 7-day low-dose group and the 14-day administration group were significantly decreased,and the CLz was significantly increased.In addition,the AUC_(0-∞)of the 7-day high-dose group was also significantly decreased.Under the index of metoprolol,the AUC_(0-t)and AUC_(0-∞)of each experimental group were decreased significantly,and the CLz and Vz of the 7-day low-dose group and the 14-day low-dose group were increased significantly.Under the caffeine index,the AUC_(0-t)and AUC_(0-∞)of the 7-day administration groups were increased significantly,the CLz was decreased significantly,and the t_(1/2z)of the 14-day high-dose group was increased significantly.Under the chlorzoxazone index,the AUC_(0-t)and AUC_(0-∞)of the 7-day low-dose group were increased significantly,and the CLz wa

关 键 词：红禾麻提取物 COCKTAIL探针药物法 CYP450 药物相互作用 

分 类 号：R285.5[医药卫生—中药学]