title: Drug-Drug Interaction Potentials of Tyrosine Kinase Inhibitors via Inhibition of UDP-Glucuronosyltransferases.
abstract: Tyrosine kinase inhibitors (TKIs) are anticancer drugs that may be co-administered with other drugs. The aims of this study are to investigate the inhibitory effects of TKIs on UDP-glucuronosyltransferase (UGT) activities, and to quantitatively evaluate their potential to cause drug-drug interactions (DDIs). Inhibition kinetic profiles of a panel of UGT enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17) by four TKIs (axitinib, imatinib, lapatinib and vandetanib) were characterized by using hepatic microsomes and recombinant proteins. Lapatinib exhibited potent competitive inhibition against UGT1A1 activity with a Ki of 0.5 μM. Imatinib was found to exhibit broad inhibition on several UGTs, particularly potent competitive inhibition against UGT2B17 with a Ki of 0.4 μM. The TKIs also exerted intermediate inhibition against several UGTs (i.e., UGT1A7 by lapatinib; UGT1A1 by imatinib; UGT1A4, 1A7 and 1A9 by axitinib; and UGT1A9 by vandetanib). Results from modeling for the quantitative prediction of DDI risk indicated that the coadministration of lapatinib or imatinib at clinical doses could result in a significant increase in AUC of drugs primarily cleared by UGT1A1 or 2B17. Lapatinib and imatinib may cause clinically significant DDIs when co-administered UGT1A1 or 2B17 substrates.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: School of Life Science and Medicine, Dalian University of Technology, Panjin, LN 124221, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States.|Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States.
authors.forename: Hyunyoung
authors.initials: H
authors.lastname: Jeong
mesh_terms: D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D000077341:Lapatinib; D008862:Microsomes, Liver / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib; D014453:Glucuronosyltransferase; D011505:Protein-Tyrosine Kinases