【作者】 陈丹； 林秀贤； 黄卫华； 张伟； 谭志荣； 彭静波； 王一成； 郭莹； 胡东莉； 陈尧；

【Author】 D.Chen;X.X.Lin;W.H.Huang;W.Zhang;Z.R.Tan;J.B.Peng;YC.Wang;Y.Guo;D.-L.Hu;Y.Chen;Department of Clinical Pharmacology,Xiangya Hospital,Central South University;Institute of Clinical Phannacology,Central South University;

【机构】 中南大学湘雅医院临床药理研究所； 中南大学临床药理研究所；

【摘要】 目的:丹参酮ⅡA磺酸钠(STS)是治疗心血管疾病的传统中药丹参酮ⅡA的水溶性衍生物,但药物代谢酶CYP450对STS的代谢作用尚不明确。本研究主要通过筛选STS的主要药物代谢酶CYP450,并考察其体外药物相互作用。方法:利用人肝微粒体或CYP重组酶方法,从7个主要的CYPs中筛选可能参与STS代谢的酶类,并研究STS参与CYP介导的人体I相代谢的潜在作用方式,采用非那西丁、香豆素、甲苯磺丁脲、美托洛尔、氯唑沙宗、S-美芬妥英和咪达唑仑分别作为CYP1A2、CYP2A6、CYP2C9、CYP2D6、CYP2E1、CYP2C19和CYP3A4相应的探药底物,利用酶促动力学参数评估酶与底物相互作用的抑制模型。结果:显示在人肝微粒体中STS能够以剂量依赖的方式显著抑制CYP3A4的代谢活性,而其他CYP代谢酶如CYP1A2,CYP2A6,CYP2C9,CYP2D6,CYP2E1以及CYP2C19对STS的代谢无影响。结论:体外STS主要抑制CYP3A4的活性,并且STS与CYP3A4其他底物间有潜在的药物相互作用可能。更多还原

【Abstract】 1.Sodium tanshinone ⅡA sulfonate(STS) is a water-soluble derivative of tanshinone ⅡA,a famous Chinese medicine used for many years to treat cardiovascular disorders.However,the role of cytochrome P450 enzymes(CYPs) in the metabolism of STS was unclear.In this study,we screened the main CYPs for the metabolism of STS and studied their interactions in vitro.2.Seven CYPs were screened for the metabolism of STS by human liver microsomes(HLMs) or recombinant CYP isoforms.To determine the potential of STS to affect CYP-mediated phase I metabolism in humans,phenacetin(CYP1 A2),coumarin(CYP2 A6),tolbutamide(CYP2 C9),metoprolol(CYP2 D6),chlorzoxazone(CYP2 E1),S-Mephenytoin(CYP2 C19) and midazolam(CYP3 A4) were used as the respective probe substrates.Enzyme kinetic studies were performed to investigate the mode of inhibition of the enzyme-substrate interactions.3.STS inhibited the activity of CYP3 A4 in a dose-dependent manner in the HLMs and CYP3 A4 isoform.Other CYP isoforms,including CYP1 A2,CYP2 A6,CYP2 C9,CYP2 D6,CYP2 E1,and CYP2 C19,showed minimal or no effect on the metabolism of STS.4.The results suggested that STS primarily inhibits the activities of CYP3 A4 in vitro,and STS has the potential to perpetrate drug-drug interactions with other CYP3 A4 substrates.更多还原