Metabolomics has been increasingly applied to biomarker discovery, as untargeted metabolic profiling represents a powerful exploratory tool for identifying causal links between biomarkers and disease phenotypes. In the present work, we used untargeted metabolomics to investigate plasma specimens of rats, dogs, and mice treated with small-molecule drugs designed for improved glycemic control of type 2 diabetes mellitus patients via activation of GPR40. The in vivo pharmacology of GPR40 is not yet fully understood. Compounds targeting this receptor have been found to induce drug-induced liver injury (DILI). Metabolomic analysis facilitating an integrated UPLC-TWIMS-HRMS platform was used to detect metabolic differences between treated and non-treated animals within two 4-week toxicity studies in rat and dog, and one 2-week toxicity study in mouse. Multivariate statistics of untargeted metabolomics data subsequently revealed the presence of several significantly upregulated endogenous compounds in the treated animals whose plasma level is known to be affected during DILI. A specific bile acid metabolite useful as endogenous probe for drug–drug interaction studies was identified (chenodeoxycholic acid-24 glucuronide), as well as a metabolic precursor indicative of acidic bile acid biosynthesis (7α-hydroxy-3-oxo-4-cholestenoic acid). These results correlate with typical liver toxicity parameters on the individual level.

代谢组学已被越来越多地应用于生物标志物的发现，因为非靶向代谢谱分析是一种强大的探索性工具，可用于识别生物标志物与疾病表型之间的因果关系。在目前的工作中，我们使用非靶向代谢组学研究了用小分子药物治疗的大鼠，狗和小鼠的血浆标本，这些药物设计用于通过激活GPR40改善2型糖尿病患者的血糖控制。的体内GPR40的药理作用尚未完全了解。已经发现靶向该受体的化合物诱导药物诱导的肝损伤（DILI）。代谢组学分析促进了集成的UPLC-TWIMS-HRMS平台用于在大鼠和狗的两个4周毒性研究和小鼠的一个2周毒性研究中检测治疗和未治疗动物之间的代谢差异。随后，针对未靶向代谢组学数据的多变量统计显示，在治疗动物中存在几种显着上调的内源性化合物，这些动物的血浆水平已知在DILI期间受到影响。确定了一种特定的胆汁酸代谢物，可用作药物-药物相互作用研究的内源性探针（鹅去氧胆酸-24葡糖醛酸），以及指示酸性胆汁酸生物合成的代谢前体（7α-羟基-3-氧代-4-胆甾烯酸）。这些结果与个体水平的典型肝毒性参数相关。