组蛋白去乙酰化酶抑制剂S25的代谢稳定性和表型研究

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。

Investigation of metabolism of S25 in liver microsomes

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 con-centrations 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 micro-somal incubation system.Results:The corresponding half-life period(t1/2) were 45,187.3,43.31,130.75 and 198min,intrinsic clear-ance(CLint) were 30.8,7.4,32,10.6 and 7/mL·min-1·mg-1protein,respectively.In human liver microsomes,S25 was mainly me-tabolized by CYP2E1,CYP2C9,and CYP2C19.Conclusion:S25 are metabolized by Several CYP450 isoforms rapidly in liver micro-somes.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.