组蛋白去乙酰化酶抑制剂S25的代谢稳定性和表型研究  

Investigation of metabolism of S25 in liver microsomes

作　　者：温琥玲[1] 田瑞敏[2] 文丹 胥正敏[3] WEN Hu-ling;TIAN Rui-min;WEN Dan;XU Zheng-min(Department of Nuclear Medicine, Affiliated Hospital of North Sichuan Madical College;Institute of Materia Medica;School of Pharmacy, North Sichuan Medical College, Nanchong 63700, Sichuan, China)

机构地区：[1]川北医学院附属医院核医学科 [2]川北医学院药学院,四川南充637000 [3]川北医学院药物研究所

出　　处：《川北医学院学报》2018年第2期177-180,191,共5页Journal of North Sichuan Medical College

基　　金：四川省教育厅项目(18ZA0202)

摘　　要：目的:探讨抗癌药物组蛋白去乙酰化酶抑制剂S25在不同种属中代谢稳定性差异并确定S25药物的代谢表型。方法:将S25置于人、小鼠、大鼠、犬和猴的肝微粒体中孵育,运用超高效液相色谱-质谱(UPLC-MS/MS)方法检测经过孵育代谢后S25剩余浓度,分析其代谢稳定性并推导出其在体内的半衰期及清除率;通过肝微粒体中细胞色素P450酶(CYP450)同工酶特异性抑制剂的化学抑制剂方法鉴定S25在小鼠肝微粒体中的代谢表型。结果:S25在人、小鼠、大鼠、犬和猴5个种属肝微粒体中半衰期(t1/2)分别为45.00、187.30、43.31、130.75、198.00 min;肝微粒体中固有清除率CLint分别为30.8、7.4、32、10.6、7/m L·min-1·mg-1;在人肝微粒体中S25主要通过CYP2E1、CYP2C9、CYP2C19催化代谢。结论:在肝微粒体研究体系中,S25通过多种酶催化而迅速代谢降解;该药在人和小鼠的代谢动力学无差异,小鼠肝微粒体代谢系统可用于S25在人体内发生不良反应的风险评估。Objective： To investigate the metabolic stability of S25 in different species and to determine the metabolic phenotype of S25. Methods： S25 were incubated with liver microsomes from human,mouse,rat,beagle dog and monkey,respectively. Then the concentrations of S25 were measured by UPLC-MS/MS to evaluated the metabolic stability of S25,and derived the half-life period and scavenging rate in the body. The metabolic phenotyping of S25 was identified by specific inhibitors of isoforms of CYP450 in rat microsomal incubation system. Results： The corresponding half-life period（ t1/2） were 45,187. 3,43. 31,130. 75 and 198 min,intrinsic clearance（ CLint） were 30. 8,7. 4,32,10. 6 and 7/m L·min^-1·mg^-1 protein,respectively. In human liver microsomes,S25 was mainly metabolized by CYP2 E1,CYP2 C9,and CYP2 C19. Conclusion： S25 are metabolized by Several CYP450 isoforms rapidly in liver microsomes. There is no difference in metabolic kinetics between human and rat. The liver microsomal metabolic system of rat can be used for evaluation the adverse reactions of S25 in human.

关 键 词：S25 肝微粒体 超高效液相色谱-质谱(UPLC-MS/MS) 

分 类 号：R965[医药卫生—药理学]