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.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 10 to 12 per 100 000 people worldwide.^1,2 Currently, 5 tyrosine kinase inhibitors (TKIs) targeting the activated BCR-ABL1 oncoprotein have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with CML.

Due to their association with type 2 diabetes mellitus treatment, α-glucosidase inhibitors have attracted increasing attention of researchers. In this study, we systemically investigated the kinetics and inhibition mechanism of piceatannol on α-glucosidase. Enzyme kinetics analyses showed that piceatannol exhibited strong inhibition on α-glucosidase in a non-competitive manner. Spectroscopy analyses indicated that piceatannol could bind with α-glucosidase to form complexes via high affinity. Further, computational molecular dynamics and molecular docking studies validated that the binding of piceatannol was outside the catalytic site of α-glucosidase, which would induce conformational changes of α-glucosidase and block the entrance of substrate, causing declines in α-glucosidase activities. Our results provide useful information not only for the inhibition mechanism of piceatannol against α-glucosidase but also for a novel target site for developing novel α-glucosidase inhibitors as potential therapeutic agents in the treatment of type 2 diabetes mellitus.