Nintedanib is a promising tyrosine kinase inhibitor for clinically treating idiopathic pulmonary fibrosis (IPF). Some clinical cases reported that nintedanib treatment can cause hepatotoxicity and myocardial toxicity. U. S. FDA warns the potential drug-drug interaction when it is co-administrated with other drugs. In order to understand the potential toxicity of nintedanib and avoid drug-drug interaction, the metabolism of nintedanib was systematically investigated in human liver microsomes and mice using metabolomics approach, and the toxicity of metabolites was predicted by ADMET lab. Nineteen metabolites were detected in vivo and in vitro metabolism, and 8 of them were undescribed. Calculated partition coefficients (Clog P) were used to distinguish the isomers of nintedanib metabolites in this study. The major metabolic pathways of nintedanib majorly included hydroxylation, demethylation, glucuronidation, and acetylation reactions. The ADMET prediction indicated that nintedanib was a substrate of the cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). And nintedanib and most of its metabolites might possess potential hepatotoxicity and cardiotoxicity. This study provided a global view of nintedanib metabolism, which could be used to understand the mechanism of adverse effects related to nintedanib and its potential drug-drug interaction.

中文翻译：

---

使用代谢组学对酪氨酸激酶抑制剂nintedanib进行代谢分析。

Nintedanib是一种有前途的酪氨酸激酶抑制剂，可用于临床治疗特发性肺纤维化（IPF）。一些临床病例报道，任他尼布治疗可引起肝毒性和心肌毒性。当与其他药物共同使用时，美国FDA警告说潜在的药物相互作用。为了了解nintedanib的潜在毒性并避免药物相互作用，采用代谢组学方法系统地研究了nintedanib在人肝微粒体和小鼠中的代谢，并通过ADMET实验室预测了代谢产物的毒性。在体内和体外代谢中检测到19种代谢物，其中8种没有描述。在本研究中，使用计算的分配系数（Clog P）来区分Nintedanib代谢产物的异构体。Nintedanib的主要代谢途径主要包括羟基化，去甲基化，葡糖醛酸化和乙酰化反应。ADMET预测表明，nintedanib是细胞色素P450 3A4（CYP3A4）和P-糖蛋白（P-gp）的底物。Nintedanib及其大多数代谢物可能具有潜在的肝毒性和心脏毒性。这项研究为人们提供了关于nintedanib代谢的整体观点，可用于了解与nintedanib相关的不良反应机制及其潜在的药物相互作用。Nintedanib及其大多数代谢物可能具有潜在的肝毒性和心脏毒性。这项研究为人们提供了关于nintedanib代谢的整体观点，可用于了解与nintedanib相关的不良反应机制及其潜在的药物相互作用。Nintedanib及其大多数代谢物可能具有潜在的肝毒性和心脏毒性。这项研究为人们提供了关于nintedanib代谢的整体观点，可用于了解与nintedanib相关的不良反应机制及其潜在的药物相互作用。