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Inhibition of human UDP‐glucuronosyltransferase enzymes by midostaurin and ruxolitinib: implications for drug–drug interactions

Cancer therapy with tyrosine kinase inhibitors (TKIs) is a rapidly developing field, and several TKIs have been reported to have an impact on the activities of UDP‐glucosyltransferases (UGTs), implying a potential risk for drug–drug interaction (DDI). Herein, we investigated the inhibitory effects of two commonly used TKIs, midostaurin and ruxolitinib, on human UGTs and quantitatively evaluated their DDI potential via UGT inhibition. It was found that midostaurin was a potent inhibitor of the majority of human UGTs, including UGT1A3, 1A4, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15, and 2B17, with IC50 values lower than 4 μM (IC50 0.0128–3.85 μM), while ruxolitinib exhibited weak inhibition towards the activity of almost all the tested UGT isoforms. Furthermore, based on reversible inhibition, the co‐administration of midostaurin at the clinical available dose was predicted to increase the plasma exposure to sensitive UGT1A3, 1A7, and 1A8 substrates by at least 61.4%, 25.6%, and 651%, respectively. In summary, our data identify that midostaurin is a potent inhibitor of the majority of human UGTs and may bring a potential risk of DDI via inhibition against UGT1A3, 1A7, and 1A8, while ruxolitinib cannot trigger UGT‐mediated DDI due to its weak inhibition towards UGTs.