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 (Ki) 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 Ki 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.

Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib for Patients with Chronic Myeloid Leukemia

“…An effective transient dasatinib concentration of 100 nM (approximately 50 ng/mL) is sufficient to inhibit in vitro proliferation of most cell lines expressing imatinib-resistant BCR-ABL mutations, with the exception of T315I. 72) In addition, Vainstein et al have reported that a higher inhibitory potential at maximum concentration based on the IC 50 and C max of dasatinib correlated with improved CCyR rates in CML patients treated with dasatinib. 73) Although continuous dasatinib exposure for 24 h is not needed, a higher C max of dasatinib is necessary (Fig.…”

“…47) In particular, bilirubin is glucuronidated by UGT1A1 48) ; however, nilotinib inhibits bilirubin metabolism via UGT1A1, thereby increasing bilirubin levels. 49,50) In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients (ENESTnd) study, a higher nilotinib exposure was reported to be significantly correlated with greater incidence of all-grade bilirubin elevation.…”

Tissue and species differences in the glucuronidation of glabridin with UDP-glucuronosyltransferases

“…Nilotinib, magnolol and fluconazole were reported to be selective inhibitors of UGT1A1, 1A9 and 2B7, respectively [1,26,28]). Mycophenolic acid was reported to be a high affinity substrate of UGT1A8 [20].…”

Metabolic Drug-Drug Interaction Potential of Macrolactin A and 7- O -Succinyl Macrolactin A Assessed by Evaluating Cytochrome P450 Inhibition and Induction and UDP-Glucuronosyltransferase Inhibition In Vitro

“…On the basis of the observed potency, experiments to determine the K i values of MA and SMA for UGT1A1 were conducted. Briefly, ␤-estradiol (a UGT1A1 substrate) was incubated with MA (0 to 200 M), SMA (0 to 200 M), or nilotinib (0 to 5 M), a well-known inhibitor (29). Other procedures were similar to those for the reversible inhibition studies.…”

“…Nilotinib, hecogenin, 1-naphthol, niflumic acid, and efavirenz were used as well-known inhibitors for UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7, respectively. All substrates and inhibitors used as positive controls were selected according to published reports (24)(25)(26)(27)(28)(29). On the basis of the observed potency, experiments to determine the K i values of MA and SMA for UGT1A1 were conducted.…”