Synergistic inhibitory effects of enzalutamide and its phase I metabolite on UDP-glucuronosyltransferase 1A1 (UGT1A1) and risk prediction of drug-drug interactions

Enzalutamide (formerly called MDV3100), a second-generation androgen receptor inhibitor primarily used for treating castration-resistant prostate cancer (CRPC), has been shown to regulating UDP-glucuronosyltransferases (UGTs) expression, while its effects on the activity of UGT isoforms remain unclear. This study aimed to systemically investigate the effects of enzalutamide and its phase I metabolite on the UGT activities, and to assess the risk of drug-drug interactions (DDIs) resulting from UGT inhibition. Using high-performance liquid chromatography (HPLC) and enzyme kinetic studies, we evaluated the inhibitory effects of enzalutamide and its main phase I metabolite, N-desmethyl enzalutamide on 12 UGT isoforms and inhibition patterns. Our findings demonstrated that both enzalutamide and its metabolite exhibited potent inhibition against UGT1A1, with evidence of synergistic effects. Enzyme kinetic analysis revealed that both enzalutamide and its metabolite acted as competitive inhibitors of UGT1A1. In vitro-in vivo extrapolation (IVIVE) prediction indicated that concomitant use of enzalutamide with UGT1A1 substrates could induce clinically significant DDIs. Therefore, special caution should be warranted when administering enzalutamide alongside other drugs metabolized by UGT to mitigate potential DDIs.