Selectivity for inhibition of nilotinib on the catalytic activity of human UDP-glucuronosyltransferases

Abstract

1. Nilotinib, a tyrosine kinase inhibitor, could potently inhibit SN-38 glucuronidation mainly catalyzed by UDP-glucuronosyltransferase (UGT) 1A1. This study was designed to investigate whether nilotinib can be used as a selective inhibitor of UGT1A1 in human liver.

2. Assays with recombinant UGTs indicated that nilotinib could strongly inhibit the activity of UGT1A1 and decreased the activity of extra-hepatic UGT1A7 to a much lesser extent. The inhibition on 4-methylumbelliferone (4Mu) glucuronidation by recombinant UGT1A1 obeyed competitive inhibition mechanism, with a kinetic constants (K_i) value of 0.17 μM. Assays with human liver microsomes (HLM) demonstrated that nilotinib could selectively inhibit estradiol-3-O-glucuronidation (E2-3-O-glucuronidation), a probe reaction of UGT1A1. Kinetic studies displayed that the inhibition on E2-3-O-glucuronidation followed non-competitive inhibition model, different from the inhibition on 4Mu glucuronidation. The K_i values were calculated to be 0.14 and 0.53 μM, depending on the enzyme sources of recombinant UGT1A1 or HLM, respectively.

3. Given that UGT1A7 is an extra-hepatic enzyme, this study indicates that nilotinib can be used as a selective inhibitor of UGT1A1 in human liver.

• Niloinib
• the selective inhibitor
• UDP-glucuronosyltransferase 1A1