中国中药杂志

2020, v.45(21) 5289-5295

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丹参主要活性成分与他克莫司体外代谢性相互作用的研究
An in vitro study on metabolic interaction between main active components of Salviae Miltiorrhizae Radix et Rhizoma and tacrolimus

李雪;陈潮;陈倩倩;郑培永;杨铭;
LI Xue;CHEN Chao;CHEN Qian-qian;ZHENG Pei-yong;YANG Ming;Longhua Hospital, Shanghai University of Traditional Chinese Medicine;

摘要(Abstract):

该研究旨在考察丹参主要活性成分对CYP3A4/5酶代谢他克莫司活性的影响,从而预测在临床联合用药时两者间潜在的药物相互作用(DDI)。实验首先利用人肝微粒体和重组人CYP3A4/5酶3种体外孵育体系,考察5种丹参活性成分单体(丹参酮Ⅰ、丹参酮Ⅱ_A、隐丹参酮、丹酚酸B、二氢丹参酮Ⅰ)对他克莫司代谢的可逆性抑制作用;然后选择有较强抑制作用的丹参活性成分,计算其剂量依赖性抑制作用强度;最后利用单点抑制法实验考察5种丹参主要活性成分在高浓度下的时间依赖性抑制作用。此外,该研究建立了生物样品中他克莫司的HPLC-MS/MS测定方法,通过测定体系中他克莫司的剩余量,计算丹参主要活性成分的抑制活性。实验结果显示二氢丹参酮Ⅰ在3种体外孵育体系中对他克莫司的代谢均具有较强的抑制作用,在人肝微粒体中抑制强度IC_(50)为6.0μmol·L~(-1),其余4种活性成分的抑制作用较弱(10μmol·L~(-1)时抑制率均<30%);较高浓度的丹参活性成分单体(50μmol·L~(-1))在人肝微粒体中,对他克莫司的时间依赖性抑制强度为5.5%~15.9%。以上结果提示当丹参活性成分体内浓度达到一定限值时,可能会发生具有临床意义的DDI,此时和他克莫司合用时需要提高警惕。该研究对指导临床合理用药提供了一定的理论基础和数据支持。
The purpose of this study was to investigate the inhibitory effects of the main active components of Salviae Miltiorrhizae Radix et Rhizoma on the metabolism of tacrolimus mediated by CYP3 A4/5 enzyme, so as to predict the potential drug-drug interaction(DDI) in clinical use. First, the reversible inhibitory activities of five active components of Salviae Miltiorrhizae Radix et Rhizoma(tanshinone Ⅰ, tanshinone Ⅱ_A, cryptotanshinone, salvianolic acid B, dihydrotanshinone Ⅰ) on the metabolism of tacrolimus was investigated by using human liver microsomes(HLM) and recombinant human CYP3 A4/5 enzyme in vitro, then the dose-dependent inhibition of CYP3 A4/5 activity was calculated in HLM. Finally, the time-dependent inhibition(TDI) activities of five active components were studied in HLM through the robust single point inhibition test. In addition, a simple and rapid liquid chromatography tandem mass spectrometry method(HPLC-MS/MS) for the determination of tacrolimus was established in this study. The results showed that dihydrotanshinone Ⅰ had a strong inhibitory effect on the metabolism of tacrolimus in both HLM and rCYP3 A4/5 enzyme systems, and the inhibitory potential IC_(50) in HLM was 6.0 μmol·L~(-1), while the other four active components of Salviae Miltiorrhizae Radix et Rhizoma exhibited relatively weak inhibition on CYP3 A4/5 activity with inhibition rate less than 30% at 10 μmol·L~(-1). Furthermore, the TDI activity of five active components of Salviae Miltiorrhizae Radix et Rhizoma at 50 μmol·L~(-1) was 5.5%-15.9%. The above results suggested that clinical DDI between tacrolimus and Salviae Miltiorrhizae Radix et Rhizoma may occur when the active components of Salviae Miltiorrhizae Radix et Rhizoma achieved a relative high concentration in human. In conclusion, this study provided a data reference for the research on drug interaction of tacrolimus and Salviae Miltiorrhizae Radix et Rhizoma as well as rational drug use in clinical practice.

关键词(KeyWords): 丹参;他克莫司;人肝微粒体;重组人CYP3A4/5酶;药物相互作用
Salviae Miltiorrhizae Radix et Rhizoma;tacrolimus;human liver microsomes;recombinant human CYP3A4/5 enzyme;drug-drug interaction

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金青年基金项目(81803825);; 上海中医药大学预算内科研项目(18LK036);; 国家“重大新药创制”科技重大专项(2017ZX09304001);; 国家“十三五”传染病防治科技重大专项(2017ZX10305501-002)

作者(Author): 李雪;陈潮;陈倩倩;郑培永;杨铭;
LI Xue;CHEN Chao;CHEN Qian-qian;ZHENG Pei-yong;YANG Ming;Longhua Hospital, Shanghai University of Traditional Chinese Medicine;

Email:

DOI: 10.19540/j.cnki.cjcmm.20200715.201

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