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.