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中药降脂方与阿托伐他汀代谢性相互作用的体外研究
引用本文:郭峰,李燕娜,毛玉昌,沈智杰,徐德铎,侴桂新,王肖龙,胡卓汉. 中药降脂方与阿托伐他汀代谢性相互作用的体外研究[J]. 生物磁学, 2014, 0(9): 1611-1615,1621
作者姓名:郭峰  李燕娜  毛玉昌  沈智杰  徐德铎  侴桂新  王肖龙  胡卓汉
作者单位:[1]上海交通大学药学院,上海200240 [2]瑞德肝脏疾病研究上海有限公司,上海201203 [3]上海中医药大学附属曙光医院,上海201203 [4]上海中医药大学中药研究所,上海201203
基金项目:基金项目:国家十一五科技重大专项(2008ZX10501)
摘    要: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。

关 键 词:降脂中药  阿托伐他汀  细胞色素P450  药物相互作用

Metabolism based Herb-Drug Interaction-Lipid-lowering Herbs and Atorvastatin in vitro
GUO Feng,LI Yan-na,MAO Yu-chang,SHEN Zhi-jie,XU De-duo,CHOU Gui-xin,WANG Xiao-long,HU Zhuo-han. Metabolism based Herb-Drug Interaction-Lipid-lowering Herbs and Atorvastatin in vitro[J]. Biomagnetism, 2014, 0(9): 1611-1615,1621
Authors:GUO Feng  LI Yan-na  MAO Yu-chang  SHEN Zhi-jie  XU De-duo  CHOU Gui-xin  WANG Xiao-long  HU Zhuo-han
Affiliation:1 Shanghai Jiao Tong University School of Pharmacy, Shanghai, 200240, China; 2 Research Institute for Liver Disease (shanghai), Shanghai, 201203, China; 3 Shanghai Shu Guang Hospital Affiliated to Shanghai University of TCM, Shanghai, 201203, China; 4 Shanghai University of TCM, Shanghai, 201203, China)
Abstract: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.
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