Induction of Cytochrome P450 (CYP) 1A2 and CYP3A Influences Sunitinib Metabolism and Bioactivation in Primary Human Hepatocytes

• DOI: 10.1096/fasebj.2022.36.s1.r3054
• Publication Date: 2022-05-03T08:19:46Z
• Authors: Klarissa D. Jackson; Jonghwa Lee; Jessica L. Beers; Dasean T. Nardone...
• Keywords: CYP3A

Sunitinib is an orally administered tyrosine kinase inhibitor used to treat renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. The product label for sunitinib carries a boxed warning idiosyncratic hepatotoxicity; however, the mechanisms of this toxicity remain unclear. We have previously shown that cytochrome P450 (CYP) 1A2 CYP3A4 catalyze metabolic activation via oxidative defluorination form chemically reactive, potentially toxic quinoneimine, trapped as glutathione (GSH) conjugate. purpose study was determine effects CYP1A2 CYP3A induction on bioactivation in human hepatocytes vitro. Sandwich-cultured from single donor were pretreated with inducers, omeprazole (50 μM) rifampicin (25 μM), respectively, 72 hours followed by incubation (10 24 hours. metabolites analyzed liquid chromatography - tandem mass spectrometry. reduced levels 48% increased formation primary active metabolite N-desethylsunitinib (M1) 2.0-fold, compared control without inducer. caused depletion 93% led corresponding increase M1 4.9-fold. For defluorosunitinib (M3), M3 7.4-fold, but decreased 72%, control. In addition, we identified putative quinoneimine-cysteine conjugate (M6) formed downstream quinoneimine-GSH Omeprazole M6 7.7-fold, had minimal effect M6. non-selective 1-aminobenzotriazole (1 mM) each these (M1, M3, M6), confirming involvement P450-mediated metabolism. Collectively, findings indicate enhances clearance N-dealkylation M1, increases quinoneimine metabolite. Modulation activity due enzyme or other environmental genetic factors may influence risk metabolism-mediated adverse reactions associated sunitinib.