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.
摘要：
据报道，雌激素相关受体（ERRs）激动剂GSK-9089（DY-131）具有增加运动耐力的潜力。基于高分辨率质谱（HRMS）的分析在检测中至关重要，identification,或表征分子，包括其在人体中的代谢物。在这项研究中,在与肝微粒体和S9级分孵育后，研究了GSK-9089的体外代谢谱。此外,在血浆中鉴定了该分子的体内代谢物，尿液,和老鼠的粪便样本.通过数据依赖和数据独立的挖掘策略，采用基于计算机工具和HRMS的分析揭示了所有潜在代谢物的结构。已鉴定出9种未知的GSK-9089代谢物，发现它们在体内基质中以痕量存在。该分子的大多数体外和体内I相代谢物是在亚胺键水解后再脱酰胺后形成的，氧化，和N-氧化。该分子经历了II期代谢，主要通过葡糖苷酸产生更多的极性代谢物，硫酸盐缀合生物转化反应。GSK-9089的体外和体内代谢物可用于将来鉴定这种ERRs激动剂的滥用。
