表小檗碱体外大鼠肝微粒体孵育代谢产物鉴定及对CYP2D6酶活性的抑制作用  

Identification of metabolites of epiberberine in rat liver microsomes and its inhibiting effects on CYP2D6

作　　者：杨晓燕[1] 叶静[1] 孙桂霞[1] 薛宝娟[1] 赵园园[1] 苗培培 苏瑾[1] 张玉杰[1] 

机构地区：[1]北京中医药大学中药学院,北京100102

出　　处：《中国中药杂志》2014年第19期3855-3859,共5页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金项目(81073140;81274177);北京中医药大学自主选题项目(2013-JYBZZ-XS-108;2013-JYBZZ-XS-077)

摘　　要：表小檗碱是黄连中一种主要的异喹啉类生物碱,具有多种重要的药理活性。该实验利用体外大鼠肝微粒体孵育体系,采用LC-MS/MS分析鉴定表小檗碱体外大鼠肝微粒体(RLM)共孵育后的Ⅰ相和Ⅱ相代谢产物,采用cocktail探针药物法,通过同时测定美托洛尔、氨苯砜、非那西丁、氯唑沙宗、甲苯磺丁脲的含量变化,评价不同浓度表小檗碱对大鼠肝微粒体CYP2D6,CYP3A4,CYP1A2,CYP2E1,CYP2C9亚型活性的影响。结果表明,表小檗碱在大鼠肝脏可发生Ⅰ相和Ⅱ相代谢,从表小檗碱的大鼠体外肝微粒体温孵体系中鉴定出2个Ⅰ相代谢产物和3个Ⅱ相代谢产物;表小檗碱对肝脏CYP2D6酶呈显著抑制作用,半数抑制浓度IC50为35.22μmol·L-1,而对CYP3A4,CYP1A2,CYP2E1,CYP2C9酶的活性没有明显的影响,提示表小檗碱可能存在基于CYP2D6酶的药物相互作用。该研究可为合理开发利用表小檗碱提供实验依据。Epiberberine, one of the most important isoquinoline alkaloid in Coptidis Rhizoma, possesses extensive pharmacological activities. In this paper, the liquid chromatography-tandem mass spectrometry （LC-MS/MS） was used to study phase Ⅰ and phase Ⅱ metabolites. A Thermo HPLC system （including Surveyor AS, Surveyor LC Pump, Surveyor PDA. USA） was used. The cocktail probe drugs method was imposed to determine the content change of metoprolol, dapsone, phenacetin, chlorzoxazone and tolbutamide simultaneously for evaluating the activity of CYP2D6, CYP3A4, CYP1A2, CYP2E1 and CYP2C9 under different concentrations of epiberberine in rat liver microsomes. The result showed that epiberberine may have phase Ⅰ and phase Ⅱ metabolism in the rat liver and two metabolites in phase Ⅰ and three metabolites in phase Ⅱ are identified in the temperature incubation system of in vitro liver microsomes. Epiberberine showed significant inhibition on CYP2D6 with IC50 value of 35. 22 μmol · L^- 1, but had no obvious inhibiting effect on the activities of CYP3A4, CYP1A2, CYP2E1 and CYP2C9. The results indicated that epiberberine may be caused drug interactions based on CYP2D6 enzyme. This study aims to provide a reliable experimental basis for its further research and development of epiberberine.

关 键 词：表小檗碱 大鼠 肝微粒体 代谢产物 CYP450酶 

分 类 号：R285.5[医药卫生—中药学]