新型他克林衍生物ST09与ST10的体外代谢研究  

In Vitro Metabolism of Two Novel Tacrine Derivates ST09 and ST10

作　　者：饶静[1] 刘剑敏[2] 吴鹏飞[3] 斯陆勤[1] 黄建耿[1] 李高[1] 

机构地区：[1]华中科技大学同济医学院药学院,武汉430030 [2]武汉市第一医院药学部,武汉430022 [3]华中科技大学同济医学院基础医学院,武汉430030

出　　处：《中国药学杂志》2017年第11期965-970,共6页Chinese Pharmaceutical Journal

基　　金：国家新药创制重大专项资助项目(2012ZX09103-101-045)

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。OBJECTIVE To determin the in vitro metabolic stability of ST09 and ST10 in human liver microsomes （HLMs） , and to evaluate their potential inhibitions on five HLM eytochrome P450 isoforms. METHODS A liquid chromatography-tandem mass spectrometry （LC-MS/MS） was used to assess remaining concentration of ST09 and ST10 at designed time points during the HLM incubation. Six major metabolites of cytochrome P450 were simuhaneously measured with LC-MS/MS, and the inhibitory effects of ST09 and ST10 were respectively evaluated with ICs0 values. RESULTS ST09 was extremely unstable in vitro, and t1/2 was less than 1 min. However, ST10, the major metabolite of ST09, was NADPH-independent metabolized in HLMs, while its t1/2 and microsomal intrinsic clearance （CLint） were 32 min and 0. 043 mL · min-1· mg（protein）-1, respectively. IC50 values of ST09 and ST10 on CYP3A4 （midazolam as substrate）, CYP3A4 （testosterone as substrate）, CYP1A2, CYP2C9, CYP2C19 and CYP2D6 were 0.42/0.25, 1.27/0.81, 24.92/18.21, 36.53/54.34, 67.64/144.90, 6.43/5.30μmol· L-1 , respectively. CONCLUSION ST09 and ST10 are extensively metabolized in vitro and both compounds had significant inhibition on CYP3A4 and CYP2D6.

关 键 词：ST09 ST10 代谢稳定性 酶抑制 液质联用 

分 类 号：R969.1[医药卫生—药理学]