新型降糖化合物LSM-13在大鼠肝微粒体中的稳定性研究及代谢产物分析  

Stability Study of Novel Hypoglycemic Compound LSM-13 in Rat Liver Microsomes and Its Metabolites Analysis

作　　者：杜瑶 陈瑞 朱高峰 张吉泉 汤磊 DU Yao;CHEN Rui;ZHU Gaofeng;ZHANG Jiquan;TANG Lei(College of Pharmacy,Guizhou Medical University,Guiyang 550004,China;Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D,Guiyang 550004,China)

机构地区：[1]贵州医科大学药学院,贵阳550004 [2]贵州省化学合成药物研发利用工程技术研究中心,贵阳550004

出　　处：《中国药房》2021年第17期2059-2065,共7页China Pharmacy

基　　金：国家自然科学基金资助项目(No.82060632);贵州省科技计划项目(No.黔科合基础[2020]1Z073)。

摘　　要：目的:考察新型降糖化合物LSM-13在大鼠肝微粒体中的代谢稳定性,并分析其可能的代谢产物。方法:将LSM-13溶解于由还原型烟酰胺腺嘌呤二核苷酸磷酸启动的大鼠肝微粒体孵育体系中,置于37℃水浴中进行孵育,分别于孵育0、5、10、15、20、30、45、60min时用乙腈终止反应。以吲哚美辛为内标,采用高效液相色谱法测定孵育体系中LSM-13的质量浓度。以孵育0min时LSM-13的质量浓度为参照,计算其在不同孵育时间下的剩余百分比和酶动力学参数。采用超高效液相色谱-串联四极杆飞行时间质谱法检测并定性分析LSM-13在大鼠肝微粒体中的代谢产物。结果:孵育60min时,LSM-13在大鼠肝微粒体中的剩余百分比为(56.07±0.95)%,半衰期为42.78min,固有清除率为0.0324mL/(min·mg)。与大鼠肝微粒体空白样品的总离子流图比较,孵育60min样品中新增了3个色谱峰,对应的准分子离子峰分别为m/z505.1338、417.1024、293.1117[M+H]+,可能是LSM-13脱氢、O-脱苄基、水解的产物。结论:化合物LSM-13在大鼠肝微粒体中的稳定性为中等,并可能发生了脱氢、O-脱苄基和水解反应。OBJECTIVE:To i nvestigate the metabolism stabilities of novel hypoglycemic compound LSM-13 in rat liver microsomes,and to analyze the possible metabolites.METHODS:LSM-13 was dissolved in rat liver microsome incubation system initiated by reduced nicotinamide adenine dinucleotide phosphate,and was incubated in water at 37℃.The reaction was terminated with acetonitrile at 0,5,10,15,30,45 and 60 min,respectively.Using indomethacin as internal standard,the concentration of LSM-13 in incubation system was determined by HPLC.The residual percentage and enzyme kinetic parameters of LSM-13 were calculated at different incubation time points with the concentration of LSM-13 incubated for 0 min as reference.UPLC-Q-TOF/MS was used to analyze and speculate the metabolites of LSM-13 in rat liver microsomes.RESULTS:After 60 min incubation,the remaining percentage of LSM-13 was(56.07±0.95)%,the half-life was 42.78 min,and the intrinsic clearance was 0.0324 mL/(min·mg).Compared with total ion flow diagram of rat liver microsome blank samples,three chromatographic peaks were added in the samples incubated for 60 min;the corresponding molecular ion peaks were m/z 505.1338,417.1024,293.1117[M+H]+;the possible metabolites may be dehydrogenation,O-debentylation and hydrolysis products of LSM-13.CONCLUSIONS:The compound LSM-13 has moderate stability in rat liver microsomes,and may undergo dehydrogenation,O-debentylation and hydrolysis.

关 键 词：降糖化合物 LSM-13 大鼠肝微粒体 稳定性 代谢产物 

分 类 号：R917[医药卫生—药物分析学] R969.1[医药卫生—药学]