利用LC-MS基于代谢组学的方法在体外鉴定酪氨酸激酶抑制剂Pexidartinib的反应性代谢产物。
Identifying the Reactive Metabolites of Tyrosine Kinase Inhibitor Pexidartinib In Vitro Using LC-MS-Based Metabolomic Approaches.
发表日期：2023 Aug 02
作者：
Xuan Qin, Yong Wang, Kevin R MacKenzie, John M Hakenjos, Si Chen, Saleh M Khalil, Sung Yun Jung, Damian W Young, Lei Guo, Feng Li
来源：
PHARMACOLOGY & THERAPEUTICS
摘要：
有选择性和强效抑制巨噬细胞集落刺激因子-1受体的噻吗喹啉（Pexidartinib，PEX，TURALIO）已获批用于治疗滑膜巨细胞肿瘤。然而，临床报告频繁和严重的不良反应，导致PEX被妆盒警告其肝损伤风险。目前对PEX相关肝毒性尤其是代谢相关毒性机制尚不明确。本研究使用谷胱甘肽（GSH）和甲氧胺（NH2OMe）作为捕获试剂，在人/小鼠肝微粒体（HLM/MLM）和原代人类肝细胞（PHH）中研究了PEX的代谢活化。采用基于液相色谱质谱的代谢组学方法，在HLM/MLM中鉴定了11个PEX-GSH和7个PEX-NH2OMe加合物。此外，在PHH中检测到4个PEX-GSH加合物。采用重组人P450和CYP3A化学抑制剂酮康唑，鉴定CYP3A4和CYP3A5为形成这些加合物的主要酶。综上所述，我们的研究表明PEX代谢可以产生由CYP3A介导的活性代谢物，需要进一步研究活性代谢物与PEX肝毒性的关联。
Pexidartinib (PEX, TURALIO), a selective and potent inhibitor of the macrophage colony-stimulating factor-1 receptor, has been approved for the treatment of tenosynovial giant cell tumor. However, frequent and severe adverse effects have been reported in the clinic, resulting in a boxed warning on PEX for its risk of liver injury. The mechanisms underlying PEX-related hepatotoxicity, particularly metabolism-related toxicity, remain unknown. In the current study, the metabolic activation of PEX was investigated in human/mouse liver microsomes (HLM/MLM) and primary human hepatocytes (PHH) using glutathione (GSH) and methoxyamine (NH2OMe) as trapping reagents. A total of 11 PEX-GSH and 7 PEX-NH2OMe adducts were identified in HLM/MLM using an LC-MS-based metabolomics approach. Additionally, 4 PEX-GSH adducts were detected in the PHH. CYP3A4 and CYP3A5 were identified as the primary enzymes responsible for the formation of these adducts using recombinant human P450s and CYP3A chemical inhibitor ketoconazole. Overall, our studies suggested that PEX metabolism can produce reactive metabolites mediated by CYP3A, and the association of the reactive metabolites with PEX hepatotoxicity needs to be further studied.