Identification and characterization of GSK-9089 metabolites through high resolution-mass spectrometry based in vitro and in vivo rat biological sample analysis

IF 2.8 3区医学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of Chromatography B Pub Date : 2024-07-22 DOI:10.1016/j.jchromb.2024.124242

Manish Kumar Sharma , Ravi P. Shah , Dinesh Kumar , Pinaki Sengupta

{"title":"Identification and characterization of GSK-9089 metabolites through high resolution-mass spectrometry based in vitro and in vivo rat biological sample analysis","authors":"Manish Kumar Sharma , Ravi P. Shah , Dinesh Kumar , Pinaki Sengupta","doi":"10.1016/j.jchromb.2024.124242","DOIUrl":null,"url":null,"abstract":"<div>Estrogen related receptors (ERRs) agonist GSK-9089 (DY-131) reported to pose a potential in increasing exercise endurance. High resolution mass spectrometry (HRMS) based analysis has utmost importance in the detection, identification, or characterization of a molecule including its metabolites in human body. In this study, in vitro metabolism profile of GSK-9089 was investigated after incubation with liver microsomes and S9 fractions. Additionally, in vivo metabolites of the molecule were identified in plasma, urine, and faeces samples of rats. Structures of all the potential metabolites were revealed by employing an in silico tool and HRMS based analysis through data-dependent and data-independent mining strategies. Nine unknown metabolites of GSK-9089 have been identified which were found to be present in a trace amount in in vivo matrices. Most of the in vitro and in vivo phase I metabolites of the molecule were formed after imine bond hydrolysis followed by deamidation, oxidation, and N-oxidation. The molecule underwent phase II metabolism to generate more polar metabolites mainly through glucuronide, sulfate conjugation biotransformation reactions. The in vitro and in vivo metabolites of GSK-9089 could be useful to identify the abuse of this ERRs agonist in the future.</div>","PeriodicalId":348,"journal":{"name":"Journal of Chromatography B","volume":"1244 ","pages":"Article 124242"},"PeriodicalIF":2.8000,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Chromatography B","FirstCategoryId":"1","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1570023224002514","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}

引用次数: 0

Abstract

Estrogen related receptors (ERRs) agonist GSK-9089 (DY-131) reported to pose a potential in increasing exercise endurance. High resolution mass spectrometry (HRMS) based analysis has utmost importance in the detection, identification, or characterization of a molecule including its metabolites in human body. In this study, in vitro metabolism profile of GSK-9089 was investigated after incubation with liver microsomes and S9 fractions. Additionally, in vivo metabolites of the molecule were identified in plasma, urine, and faeces samples of rats. Structures of all the potential metabolites were revealed by employing an in silico tool and HRMS based analysis through data-dependent and data-independent mining strategies. Nine unknown metabolites of GSK-9089 have been identified which were found to be present in a trace amount in in vivo matrices. Most of the in vitro and in vivo phase I metabolites of the molecule were formed after imine bond hydrolysis followed by deamidation, oxidation, and N-oxidation. The molecule underwent phase II metabolism to generate more polar metabolites mainly through glucuronide, sulfate conjugation biotransformation reactions. The in vitro and in vivo metabolites of GSK-9089 could be useful to identify the abuse of this ERRs agonist in the future.

查看原文本刊更多论文

通过基于高分辨率质谱的体外和体内大鼠生物样本分析，鉴定和表征 GSK-9089 代谢物。

据报道，雌激素相关受体（ERRs）激动剂 GSK-9089 (DY-131) 具有增强运动耐力的潜力。基于高分辨质谱（HRMS）的分析对于检测、鉴定或描述人体内的分子（包括其代谢物）具有极其重要的意义。本研究调查了 GSK-9089 与肝脏微粒体和 S9 馏分培养后的体外代谢概况。此外，还鉴定了大鼠血浆、尿液和粪便样本中该分子的体内代谢物。通过采用依赖数据和不依赖数据的挖掘策略，利用硅学工具和基于 HRMS 的分析，揭示了所有潜在代谢物的结构。已鉴定出 GSK-9089 的九种未知代谢物，发现这些代谢物在体内基质中以微量存在。该分子的大多数体外和体内 I 期代谢物都是在亚胺键水解后形成的，然后是脱氨基、氧化和 N-氧化。该分子主要通过葡萄糖醛酸、硫酸盐共轭生物转化反应进行二期代谢，生成极性更强的代谢物。GSK-9089 的体外和体内代谢物有助于确定这种ERRs 激动剂在未来的滥用情况。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Chromatography B 医学-分析化学

CiteScore

5.60

自引率

3.30%

发文量

306

审稿时长

44 days

期刊介绍： The Journal of Chromatography B publishes papers on developments in separation science relevant to biology and biomedical research including both fundamental advances and applications. Analytical techniques which may be considered include the various facets of chromatography, electrophoresis and related methods, affinity and immunoaffinity-based methodologies, hyphenated and other multi-dimensional techniques, and microanalytical approaches. The journal also considers articles reporting developments in sample preparation, detection techniques including mass spectrometry, and data handling and analysis. Developments related to preparative separations for the isolation and purification of components of biological systems may be published, including chromatographic and electrophoretic methods, affinity separations, field flow fractionation and other preparative approaches. Applications to the analysis of biological systems and samples will be considered when the analytical science contains a significant element of novelty, e.g. a new approach to the separation of a compound, novel combination of analytical techniques, or significantly improved analytical performance.