Regorafenib is a novel tyrosine kinase inhibitor, which has been approved by the United States Food and Drug Administration for the treatment of various tumors. The purpose of the present study was to describe the metabolic map of regorafenib, and investigate its effect on liver function. Mass spectrometry-based metabolomics approach integrated with multiple mass defect filter was used to determine the metabolites of regorafenib in vitro incubation mixtures (human liver microsomes and mouse liver microsomes), serum, urine and feces samples from mice treated with 80 mg/kg regorafenib. Eleven metabolites including four novel metabolites were identified in the present investigation. As halogen substituted drug, reductive defluorination and oxidative dechlorination metabolites of regorafenib were firstly report in present study. By screening using recombinant cytochrome P450 s (CYPs), CYP3A4 was found to be the principal isoforms involved in regorafenib metabolism. The predication with a molecular docking model confirmed that regorafenib had potential to interact with the active sites of CYP3A4, CYP3A5 and CYP2D6. Serum chemistry analysis revealed no evidence of hepatic damage from regorafenib exposure. This study provided a global view of regorafenib metabolism and its potential side-effects.
Keywords: Metabolomics; Molecular docking; Multiple mass defect filters; Regorafenib.
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