Metabolic profiling of the anti-tumor drug regorafenib in mice

Area of Science:

• Pharmacology and Toxicology
• Drug Metabolism
• Biochemistry

Background:

• Regorafenib is an approved tyrosine kinase inhibitor for various cancers.
• Understanding its metabolic pathways and potential liver effects is crucial for safe clinical use.

Purpose of the Study:

• To elucidate the comprehensive metabolic map of regorafenib.
• To investigate the impact of regorafenib on liver function.
• To identify the primary cytochrome P450 enzymes involved in its metabolism.

Main Methods:

• Mass spectrometry-based metabolomics and multiple mass defect filtering were employed.
• Metabolites were analyzed in vitro (human and mouse liver microsomes) and in vivo (mouse serum, urine, feces).
• Recombinant cytochrome P450 (CYP) screening and molecular docking were used to identify metabolic enzymes.

Main Results:

• Eleven regorafenib metabolites were identified, including four novel compounds.
• Reductive defluorination and oxidative dechlorination metabolites were reported for the first time.
• CYP3A4 was identified as the principal enzyme in regorafenib metabolism, with potential interactions with CYP3A5 and CYP2D6.

Conclusions:

• This study provides a detailed metabolic profile of regorafenib.
• Regorafenib metabolism involves novel pathways, including dehalogenation.
• No evidence of hepatic damage was observed, suggesting a favorable liver safety profile.