Identifying the Reactive Metabolites of Tyrosine Kinase Inhibitor Pexidartinib In Vitro Using LC-MS-Based Metabolomic Approaches.

ABSTRACT: 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 appr

SUBMITTER: Qin X 

PROVIDER: S-EPMC10445284 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature