新型他克林衍生物ST09与ST10的体外代谢研究

发布时间：2018-01-31 10:14

本文关键词： ST ST 代谢稳定性酶抑制液质联用　出处：《中国药学杂志》2017年11期 　论文类型：期刊论文

【摘要】：目的研究新型他克林衍生物ST09、ST10的体外代谢稳定性并分别考察了其对人肝微粒CYP450各亚型酶的抑制作用。方法采用人肝微粒体模型分别孵育ST09、ST10,液相色谱-质谱联用法测定不同孵育时间体系中剩余底物浓度,通过底物消除法计算其消除半衰期。利用LC-MS/MS测定6种CYP450主要代谢产物生成量,计算得到IC50,分别评价ST09、ST10对主要人CYP450酶的抑制活性。结果 ST09在0.1 mg·m L~(-1)人肝微粒体中消除半衰期小于1 min;其主要代谢产物ST10为NADPH非依赖性代谢,体外消除半衰期为32 min,体外固有清除率为0.043 m L·min~(-1)·mg(protein)~(-1)。ST09与ST10抑制人肝微粒体CYP3A4(咪达唑仑为底物)、CYP3A4(睾酮为底物)、CYP1A2、CYP2C9、CYP2C19、CYP2D6的IC50分别为0.42/0.25、1.27/0.81、24.92/18.21、36.53/54.34、67.64/144.9、6.43/5.30μmol·L~(-1)。结论 ST09与ST10在人肝微粒体系统代谢消除较快,两者均对人肝微粒体中CYP3A4及CYP2D6有显著抑制作用。
[Abstract]:Objective to study a novel tacrine derivative ST09. The metabolic stability of ST10 in vitro and its inhibitory effect on CYP450 subtypes of human liver microsomes were investigated. Methods the human liver microsomal model was used to incubate ST09 ST10. Liquid chromatography-mass spectrometry (LC-MS) was used to determine the residual substrate concentration in different incubation time systems. The elimination half-life was calculated by substrate elimination method. Six main metabolites of CYP450 were determined by LC-MS/MS, and IC50 was calculated to evaluate ST09. Results the elimination half-life of ST10 in 0.1 mg 路mL ~ (-1) human liver microsomes was less than 1 min. Its main metabolite ST10 was NADPH independent metabolism, and the elimination half-life in vitro was 32 min. In vitro intrinsic clearance was 0.043 mL 路min-1) 路mg(protein)~(-1).ST09 and ST10 inhibited human liver microsomal CYP3A4 (. Midazolam as substrate). The IC50 of CYP2C9, CYP2C19, CYP2D6 was 0.42 / 0.25 / 1.27 / 0.81, respectively. 24.92/18.21,36.53/54.34,67.64/144.9. Conclusion ST09 and ST10 were eliminated rapidly in human liver microsomal system. Both of them had significant inhibitory effects on CYP3A4 and CYP2D6 in human liver microsomes.
【作者单位】：华中科技大学同济医学院药学院;武汉市第一医院药学部;华中科技大学同济医学院基础医学院;
【基金】：国家新药创制重大专项资助项目(2012ZX09103-101-045)
【分类号】：R96
【正文快照】： 他克林是美国食品药品监督局(FDA)批准上市的用于治疗阿尔茨海默症的第一个乙酰胆碱酯酶抑制剂,其选择性良好但存在较大肝脏毒性。为改善缺点,一般选择对其芳环、脂环和侧链氨基部分进行结构修饰[1]。ST09是一种通过对他克林侧链氨基及其芳环修饰而合成的新型他克林巯酯类衍生

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