中国中药杂志

2016, v.41(01) 124-128

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UPLC-MS/MS研究披针灰叶素B在不同种属肝微粒体中的代谢稳定性及代谢酶表型
Metabolic stability and metabolic enzyme phaenotypes of lanceolatin B in liver microsomes of different species by UPLC-MS/MS

王海蓉;李小彬;杨楸楠;汤明海;肖昌彬;万丽;
WANG Hai-rong;LI Xiao-bin;YANG Qiu-nan;TANG Ming-hai;XIAO Chang-bin;WAN Li;School of pharmacy,Chengdu University of Traditional Chinese Medicine;State Key Laboratory of Biotherapy,Sichuan University;

摘要(Abstract):

应用体外肝微粒体孵育体系,研究披针灰叶素B(lanceolatin B)在大鼠、人、比格犬、猴肝微粒体中的代谢稳定性及体外代谢参数,确定主要代谢披针灰叶素B的CYP酶表型。将披针灰叶素B与不同种属肝微粒体共同孵育,应用UPLC-MS/MS检测孵育液中披针灰叶素B的含量,考察其代谢稳定性与体外代谢动力学参数。将披针灰叶素B与各CYP450同工酶CYP2E1,2C19,1A2,2D6,2C9,3A4,2A1的特异性抑制剂共同孵育,确定其代谢酶表型。研究结果显示,披针灰叶素B在人、比格犬肝微粒体中不代谢,而在大鼠与猴肝微粒体中可代谢,它们的体外半衰期(T_(1/2))与固有清除率(CL_(int))分别为11.57,8.07min和0.12,0.17 m L·min-1·mg-1,结果没有显著性差异;披针灰叶素B在肝微粒体中的代谢存在种属差异,在大鼠肝微粒体中由多个酶共同参与代谢,其中CYP1A2酶的作用最强,是主要代谢披针灰叶素B的酶。
To investigate the metabolic stability and parameters in vitro of lanceolatin B in liver microsomes of rats,human,Beagle dogs,and monkeys,and to identify the phaenotypes of CYP enzymes of lanceolatin B by using the liver microsome incubation system in vitro. After incubated with different species of liver microsomes,lanceolatin B was quantified by UPLC-MS / MS method to evaluate its metabolic stability and metabolic kinetic parameters in vitro. Lanceolatin B was incubated with specific inhibitors of CYP450 isoforms( CYP2E1,2C19,1A2,2D6,2C9,3A4,and 2A1) to determine the phaenotypes of metabolic enzymes. The results showed that lanceolatin B was metabolized in the liver microsomes of rats and monkeys but not in the human and Beagle dogs. Their in vitro half-life T_(1 /2) and intrinsic clearance rate CL_(int) in rat and monkey liver microsomes were 11. 57,8. 07 min,and 0. 12,0. 17 mL·min~(-1)·mg~(-1) without significant difference. The results of metabolic phenotyping indicated that CYP1A2 was mainly involved in the metabolism of lanceolatin B. There existed a difference in the metabolism of lanceolatin B in different types of liver microsomes. Several of CYP450 isoforms metabolized lanceolatin B together in liver microsomes of rats,in which CYP1A2 was the major enzyme mainly responsible for the metabolism of lanceolatin B.

关键词(KeyWords): 披针灰叶素B;肝微粒体;代谢稳定性;酶表型;UPLC-MS/MS
lanceolatin B;liver microsome;metabolic stability;metabolic phenotype;UPLC-MS/MS

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基金项目(Foundation): 国家自然科学基金项目(81374017)

作者(Author): 王海蓉;李小彬;杨楸楠;汤明海;肖昌彬;万丽;
WANG Hai-rong;LI Xiao-bin;YANG Qiu-nan;TANG Ming-hai;XIAO Chang-bin;WAN Li;School of pharmacy,Chengdu University of Traditional Chinese Medicine;State Key Laboratory of Biotherapy,Sichuan University;

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