The small-molecule tyrosine kinase inhibitor nilotinib is a potent noncompetitive inhibitor of the SN-38 glucuronidation by human UGT1A1

Purpose Inhibition of the UDP-glucuronosyltransferase (UGT) 1A1 by nilotinib was examined in vitro with SN-38 as a substrate, to estimate the possibility of drug-drug interaction of nilotinib with other medicines predominantly detoxified by UGT1A1. Methods Inhibition of UGT1A1-catalyzed SN-38 glucuronidation by nilotinib was examined with human liver microsomes (HLM) and recombinant human UGT1A1 as enzyme sources. Inhibition constants (Ki) were estimated with kinetic analysis. Results Nilotinib potently inhibited the SN-38 glucuronidation by human liver microsomal UGT1A1 and recombinant UGT1A1 in a noncompetitive manner, with Ki values of 0.286 +/- 0.0094 and 0.079 +/- 0.0029 mu M, respectively. If a drug that serves as a substrate of UGT1A1 is administered with nilotinib, the area under the plasma concentration-time curve of a drug estimated by using these Ki values would be two times or higher than that without nilotinib, suggesting drug-drug interactions involving UGT1A1. These in vitro data and the prediction of drug-drug interaction are helpful for the clinical management of the nilotinib use. Conclusion We found that nilotinib is a potent noncompetitive inhibitor of human UGT1A1 activity.