Interindividual Variation in Sunitinib Metabolism in Primary Human Hepatocytes

Abstract

Sunitinib is a multitargeted tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity. The mechanisms of this toxicity are unknown. Sunitinib is metabolized primarily by cytochrome P450 (CYP) 3A4/5 to form the major active metabolite N‐desethylsunitinib (M1). Recent studies from our lab have also shown that sunitinib undergoes oxidative defluorination via CYP1A and CYP3A enzymes to form a chemically reactive, potentially toxic quinoneimine metabolite. We hypothesized that P450 genetic variations contribute to individual differences in sunitinib metabolism and bioactivation, which may play a role in development of sunitinib‐induced hepatotoxicity. The purpose of this study was to characterize the metabolism of sunitinib in CYP3A5‐genotyped primary human hepatocytes, and evaluate the influence of genetic variation and other individual factors on metabolite formation. Commercially available human hepatocytes from individual donors were purchased from BioIVT. CYP3A5 genotype and P450 enzyme activities for each donor were provided by the company. Donor genotypes were reported as: CYP3A5*1/*1, CYP3A5*1/*3, and CYP3A5*3/*3. Sunitinib (10 uM) was incubated with the hepatocytes in suspension for 2 h, and drug metabolites were analyzed by liquid chromatography‐tandem mass spectrometry. In experiments with individual genotyped hepatocytes, M1 formation varied 13.5‐fold between donors but did not significantly differ by CYP3A5genotype. However, M1 formation was significantly higher in female donors compared to male donors. Generation of defluorinated sunitinib (M3) varied 5.6‐fold between donors but did not significantly differ by CYP3A5genotype or sex. These results suggest that donor sex, but not CYP3A5genotype, may influence the metabolism of sunitinib to the major metabolite M1. Additional studies are needed to identify the individual factors that impact the bioactivation of sunitinib to form the reactive quinoneimine product. Studies are currently underway to determine the relationship between P450 enzyme activity and sunitinib metabolite formation in individual human hepatocytes.Support or Funding InformationThis research was supported by the American Association of Colleges of Pharmacy, Lipscomb University College of Pharmacy and Health Sciences, and the National Cancer Institute of the National Institutes of Health (K01CA190711). Research reported here is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.