Publication Date

8-21-2023

Journal

Chemical Research in Toxicology

DOI

10.1021/acs.chemrestox.3c00164

PMID

37531179

PMCID

PMC10445284

PubMedCentral® Posted Date

8-2-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Mice, Humans, Animals, Cytochrome P-450 CYP3A, Chromatography, Liquid, Tyrosine Kinase Inhibitors, Tandem Mass Spectrometry, Protein Kinase Inhibitors, Cytochrome P-450 CYP3A Inhibitors, Microsomes, Liver, Metabolomics, Chemical and Drug Induced Liver Injury, Glutathione

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 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.

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