Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1

Abstract

UDP-glucuronosyltransferase 1A1 (UGT1A1) plays a key role in detoxification of many potentially harmful compounds and drugs. UGT1A1 inhibition may bring risks of drug–drug interactions (DDIs), hyperbilirubinemia and drug-induced liver injury. This study aimed to investigate and compare the inhibitory effects of icotinib and erlotinib against UGT1A1, as well as to evaluate their potential DDI risks via UGT1A1 inhibition. The results demonstrated that both icotinib and erlotinib are UGT1A1 inhibitors, but the inhibitory effect of icotinib on UGT1A1 is weaker than that of erlotinib. The IC50 values of icotinib and erlotinib against UGT1A1-mediated NCHN-O-glucuronidation in human liver microsomes (HLMs) were 5.15 and 0.68 μmol/L, respectively. Inhibition kinetic analyses demonstrated that both icotinib and erlotinib were non-competitive inhibitors against UGT1A1-mediated glucuronidation of NCHN in HLMs, with the Ki values of 8.55 and 1.23 μmol/L, respectively. Furthermore, their potential DDI risks via UGT1A1 inhibition were quantitatively predicted by the ratio of the areas under the concentration–time curve (AUC) of NCHN. These findings are helpful for the medicinal chemists to design and develop next generation tyrosine kinase inhibitors with improved safety, as well as to guide reasonable applications of icotinib and erlotinib in clinic, especially for avoiding their potential DDI risks via UGT1A1 inhibition.

Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species

“…Since UGT1A1-mediated hepatic glucuronidation plays a key role in clearance of bilirubin from the systemic circulation, deficiency of this enzyme results in elevated serum level of total bilirubin [30,31] . Due to growing recognition of the importance of drug-bilirubin interactions, many tyrosine kinase inhibitors were assessed with respect to their inhibition of UGT1A1 activity [32][33][34][35][36] . Anlotinib inhibited UGT1A1-mediated β-estradiol glucuronidation, a surrogate for UGT1A1-mediated bilirubin glucuronidation, with an IC 50 of 4.0 µmol/L; the UGT1A1 inhibition by anlotinib appeared less potent than those by erlotinib (IC 50 , 0.7 µmol/L, against N-3-carboxy propyl-4-hydroxy-1,8-naphthalimide glucuronidation) [36] and sorafenib (0.1 µmol/L, against 4-methylumbelliferone glucuronidation) [35] .…”

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

“…Sorafenib, imatinib, and dasatinib were reported to inhibit UGT1A9‐mediated paracetamol glucuronidation in vitro, inhibitions being also predicted to occur in vivo for sorafenib and imatinib . Erlotinib was reported as a potent competitive and selective UGT1A1 inhibitor using 4‐methylumbelliferone (4‐Mu) or bilirubin as substrates in rUGT or HLM, respectively whereas it appeared as a noncompetitive inhibitor with a fluorescent probe substrate . With a broader inhibition profile in rUGT, gefitinib exhibited only a weak effect against bilirubin glucuronidation in HLM .…”

“…146 Erlotinib was reported as a potent competitive and selective UGT1A1 inhibitor using 4-methylumbelliferone (4-Mu) or bilirubin as substrates in rUGT or HLM, respectively 147 whereas it appeared as a noncompetitive inhibitor with a fluorescent probe substrate. 148 With a broader inhibition profile in rUGT, gefitinib exhibited only a weak effect against bilirubin glucuronidation in PALUDETTO ET AL.…”

Discovery of dihydrooxazolo[2,3-a]isoquinoliniums as highly specific inhibitors of hCE2

“…The HepG2 cells were cultured in Modied Eagle's Medium (MEM) with 5% CO 2 and 0.1% antibiotic-antimycoticmix antibiotic at 37 C, supplemented with 10% fetal bovine serum (FBS) and used NCEN as substrate probe to assay the 23o inhibition potential toward hCE2. NCEN, 43 another specic optical probe substrate for hCE2, the structure and hydrolytic site were shown in Fig. S2(A).…”