Small molecule tyrosine kinase inhibitors (TKIs) are widely used as anticancer drugs approved by U.S. FDA. However, the toxicities of TKIs to multiple organs have greatly limited their clinical applications. The metabolism of TKIs generates several potentially toxic metabolites in vivo, that can disturb the endogenous metabolism as well as cellular function, leading to organ damage. Therefore, it is essential to identify the toxic metabolites and elucidate the underlying mechanism of TKI-induced toxicity. Metabolomics is a powerful tool for the identification of the xenobiotic metabolites and metabolic derangement associated with xenobiotic exposure, that is helpful to understand the toxicity of TKIs. The study using metabolomics approach has revealed that the reactive metabolites/intermediates (e.g., N-oxide metabolite, primary amine metabolite, 1,4-benzoquinone intermediate) and adducts with glutathione, cysteine and mercapturic acid can be derived from TKIs. Fourteen metabolic pathways could be affected following the TKI treatment, including lipid metabolism, bile acid metabolism, and gut microbiota-related pathway. Modulation of xenobiotic receptor signaling, inhibition of xenobiotic metabolism, and supplementation of endogenous metabolites are potential strategies to protect against TKI-induced toxicity. In this review, studies on the metabolism of TKIs and the alterations of endogenous metabolism are discussed, and the potential preventions against TKI-induced toxicity are summarized.

小分子酪氨酸激酶抑制剂（TKI）被广泛用作美国FDA批准的抗癌药物。然而，TKI对多个器官的毒性极大地限制了其临床应用。TKIs 的代谢在体内会产生几种具有潜在毒性的代谢物，这些代谢物会干扰内源性代谢和细胞功能，导致器官损伤。因此，有必要鉴定毒性代谢物并阐明 TKI 诱导毒性的潜在机制。代谢组学是识别与外源性接触相关的外源性代谢物和代谢紊乱的有力工具，有助于了解 TKI 的毒性。使用代谢组学方法的研究表明，活性代谢物/中间体（例如，N-氧化物代谢物、伯胺代谢物、1,4-苯醌中间体）和与谷胱甘肽、半胱氨酸和硫脲酸的加合物可以衍生自 TKI。TKI 治疗后可能会影响 14 种代谢途径，包括脂质代谢、胆汁酸代谢和肠道微生物群相关途径。调节外源性受体信号传导、抑制外源性代谢和补充内源性代谢物是防止 TKI 诱导的毒性的潜在策略。在这篇综述中，讨论了关于 TKI 代谢和内源性代谢改变的研究，并总结了 TKI 诱导毒性的潜在预防措施。