个人信息Personal Information
教授
博士生导师
硕士生导师
性别:男
毕业院校:中科院大连化学物理研究所
学位:博士
所在单位:化工海洋与生命学院
学科:药理学. 生物医学工程. 生物化学与分子生物学
办公地点:盘锦校区F03-312B
联系方式:大连理工大学生命科学与药学学院 辽宁省盘锦市辽东湾新区大工路2号 邮编:124221 电话: 0427-2631433
电子邮箱:yliu@dlut.edu.cn
Drug-Drug Interaction Potentials of Tyrosine Kinase Inhibitors via Inhibition of UDP-Glucuronosyltransferases
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论文类型:期刊论文
发表时间:2015-12-08
发表刊物:SCIENTIFIC REPORTS
收录刊物:SCIE、PubMed、Scopus
卷号:5
页面范围:17778
ISSN号:2045-2322
摘要: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 mu M. Imatinib was found to exhibit broad inhibition on several UGTs, particularly potent competitive inhibition against UGT2B17 with a Ki of 0.4 mu M. 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.