中药降脂方与阿托伐他汀代谢性相互作用的体外研究

目的：本研究旨在评估降脂中药复方2（Fang-2）及其6个饮片（虎杖、泽泻、甘草、苍术、厚朴和夏枯草）的水提物对肝脏细胞色素CYP3A4的抑制作用，及对阿托伐他汀的代谢性药物相互作用。方法：（1）应用中药标准化制备技术，制备降脂中药复方2及其6个饮片的水提物；采用超速离心法制备肝微粒体。（2）评价降脂中药复方2及其饮片对CYP3A4抑制作用。（3）评价降脂中药复方2及其饮片的水提物对阿托伐他汀的代谢的影响。结果：（1）体外实验的结果提示复方2的水提物显著地抑制了微粒体CYP3A4的活性，其IC50值为9．884mg／mL。虎杖水提物对微粒体CYP3A4的活性具有显著的抑制作用，其IC50值为0．5491mg／mL。（2）阿托伐他汀是首过代谢CYP3A4的底物，在肝脏微粒体中大于70％的母体被代谢，其体外清除率Clint和半数清除时间分别为41．10mL／mg／min和60．43分钟。降脂中药复方2水提物与肝微粒体孵育后，阿托伐他汀的首过代谢显著减慢。降脂中药复方2及其6个饮片水提取物对CYP3A4的抑制强度与避免阿托伐他汀首过代谢的潜力成正比。结论：本文首次应用体外方法研究了在临床上共同使用与PCI术后的阿托伐他汀和降脂中药复方2之间的代谢性相互作用，揭示了后者及其饮片通过抑制CYP3A4改善了前者的强烈的首过代谢，从而可能优化临床治疗方案。

Metabolism based Herb-Drug Interaction-Lipid-lowering Herbs and Atorvastatin in vitro

Objective： To investigate the metabolism based herb-drug interaction between AVT and lipid-lowering Herb Medicine （Fang-2） and its six individual herbs （Rhizoma Et Radix Polygoni Cuspidati, Rhizoma Alismatis, Rhizoma Atractylodis, Radix Et Rhizoma Glycyrrhizae, Cortex Magnoliae Officinalis, and Spica Prunellae） by using in vitro technologies. Method： （1） The test articles of herbs were prepared by a standard procedure using liquid extraction. （2） CYP3A4 inhibition study： Human and rat liver microsomes were incubated with extract of Fang-2 or its individual herb at 37℃ for 15 minutes, and then with testosterone, probe substrate of CYP3A4 in the presence of β-NADPH. Enzyme activity of CYP3A4, 6β-hydroxylation of testosterone was quantified by using LC-MS/MS. （3） Herb-Drug interaction study： Liver microsomes were preincubated with extract of Fang-2 or its individual herb at 37℃ for 15 minutes, and then with AVT in the presence of β-NADPH. Parent depletion of AVT was quantified by using developed LC-MS/MS methods. Results： （1） CYP3A4 inhibition： Fang-2 showed inhibitive potential on CYP3A4 activity with IC50 of 9.884 mg/mL. （2） AVT was extensively depleted by the 1st pass metabolism with intrinsic clearance rate （Clint） of 41.10 ml/mg/min and T1/2 of 60.43 min in liver microsomal incubation. The parent depletion of AVT was affected by preincubation with Fang-2. The inhibition of CYP3A4 by Fang-2 and its herbs was correlated with their preventing AVT from 1st pass metabolism by Fang-2 and its element positively. Conclusions： The article first studied the metabolism based herb-drug interaction between AVT and lipid-lowering herbs by using in vitro technologies. Furth investigation for metabolism based Herb-Drug interaction between Fang-2 and AVT will have significant clinical benefits in cardiovascular clinical pharmacology.