托伐普坦在大鼠体内的代谢产物鉴定分析  

Identification of In Vivo Metabolites of Tolvaptan in Rats

作　　者：徐国佳 蒋欣 夏滨 斯陆勤[3] 黄建耿[3] 李丹 张永军[1,6] XU Guojia;JIANG Xin;XIA Bin;SI Luqin;HUANG Jiangeng;LI Dan;ZHANG Yongjun(College of Pharmacy,Shihezi University,Shihezi 832003,China;Department of Pharmacy,the First Affiliated Hospital of Shihezi University,Shihezi 832008,China;School of Pharmacy,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China;Department of Pharmacy,the First Hospital of Wuhan,Wuhan 430022,China;Department of Pharmacy,Peking University Shenzhen Hospital,Shenzhen 518000,China;The Third Affiliated Hospital of School of Medicine,Shihezi University,Shihezi 832099,China)

机构地区：[1]石河子大学药学院,石河子832003 [2]石河子大学第一附属医院药学部,石河子832008 [3]华中科技大学同济医学院药学院,武汉430030 [4]武汉市第一医院药学部,武汉430022 [5]北京大学深圳医院药学部,深圳518000 [6]石河子大学医学院第三附属医院,石河子832099

出　　处：《医药导报》2023年第12期1772-1779,共8页Herald of Medicine

基　　金：国家自然科学基金资助项目(81302837,81803834);湖北省科技厅重点研发计划项目(2020BCB045)。

摘　　要：目的采用超高效液相色谱-四极杆-静电场轨道阱高分辨质谱(UFLC-Q-Exactive Orbitrap MS)对托伐普坦在大鼠体内的代谢产物进行鉴定,并探讨托伐普坦在大鼠体内的可能代谢途径。方法收集单剂量灌胃60 mg·kg-1托伐普坦固体分散体溶液后大鼠的血浆、尿液和粪便样品,乙腈沉淀蛋白,采用UFLC-Q-Exactive Orbitrap MS技术进行分析,然后经Xcalibur 2.0版软件对所得数据进行处理。结果根据各化合物的保留时间、精确相对分子质量、特征碎片离子及相关文献报道,在大鼠生物样品中共鉴定出35种代谢物,血浆、尿液和粪便中分别鉴定出23、26和30种,托伐普坦的主要代谢途径为羟基化、羧基化、水解、脱氢、葡萄糖醛酸化和乙酰化等。结论实验结果确证了托伐普坦在大鼠体内的主要代谢物,丰富了托伐普坦的体内代谢产物谱,为托伐普坦的药效物质基础的深入研究提供实验依据。Objective The metabolites of tolvaptan in rats were identified by ultra-performance liquid chromatography-quadrupole-exactive orbitrap high-resolution mass spectrometry(UFLC-Q-Exactive Orbitrap MS),and the possible metabolic pathways of tolvaptan in rats were discussed.Methods Plasma,urine and fecal samples from rats were collected after a single oral administration of 60 mg·kg-1 tolvaptan solid dispersion solution.The protein in the samples was precipitated with acetonitrile.UFLC-Q-exactive orbitrap MS technology was adopted for the sample analysis and the data were processed by Xcalibur 2.0 software.Results According to the retention time,precise relative molecular mass,characteristic fragment ions and related literature reports of each compound,35 metabolites were identified in rat biological samples.Moreover,23,26 and 30 metabolites in the plasma,urine and feces were identified,respectively.The major metabolic pathways of tolvaptan were identified as hydroxylation,carboxylation,hydrolysis,dehydrogenation,glucuronidation and acetylation.Conclusion Our study confirmed the major metabolites of tolvaptan in rats,enriched the metabolite spectrum of tolvaptan in vivo,and provided an experimental basis for the in-depth study of the pharmacodynamic substance basis of tolvaptan.

关 键 词：托伐普坦 高分辨质谱 代谢产物 

分 类 号：R972.4[医药卫生—药品] R927[医药卫生—药学]