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

doi:10.1016/j.apsb.2017.07.004

	Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1
	Cheng, Xuewei 2,4; Lv, Xia 3,4; Qu, Hengyan 2; Li, Dandan 2; Hu, Mengmeng 2; Guo, Wenzhi 1; Ge, Guangbo 4,5; Dong, Ruihua 2
刊名	ACTA PHARMACEUTICA SINICA B
	2017-11-01
卷号	7 期号:6 页码:657-664
关键词	Icotinib Erlotinib Ugt1a1 Inhibitory Effects Drug-drug Interacts (Ddis)
ISSN号	2211-3835
DOI	10.1016/j.apsb.2017.07.004
文献子类	Article
英文摘要	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 fimol/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 K-1 values of 8.55 and 1.23 fimol/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. (C) 2017 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND.
WOS关键词	CELL LUNG-CANCER ; TYROSINE KINASE INHIBITORS ; GLUCURONIDATION ; LICOCHALCONE ; SELECTIVITY ; METABOLISM ; THERAPY ; ENZYMES ; TUMORS ; DRUGS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号	WOS:000417191200006
内容类型	期刊论文
源URL	[http://cas-ir.dicp.ac.cn/handle/321008/168426]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
通讯作者	Ge, Guangbo; Dong, Ruihua
作者单位	1.Zhengzhou Univ, Affiliated Hosp 1, Dept Hepatobiliary & Pancreat Surg, Zhengzhou 450001, Henan, Peoples R China 2.Mil Acad Med Sci Hosp, Clin Pharmacol Lab, Beijing 100071, Peoples R China 3.Dalian Nationalities Univ, Coll Life Sci, Dalian 116600, Peoples R China 4.Chinese Acad Sci, Dalian Inst Chem Phys, Dalian 116023, Peoples R China 5.Shanghai Univ Tradit Med, Inst Interdisciplinary Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Cheng, Xuewei,Lv, Xia,Qu, Hengyan,et al. Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1[J]. ACTA PHARMACEUTICA SINICA B,2017,7(6):657-664.
APA	Cheng, Xuewei.,Lv, Xia.,Qu, Hengyan.,Li, Dandan.,Hu, Mengmeng.,...&Dong, Ruihua.(2017).Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1.ACTA PHARMACEUTICA SINICA B,7(6),657-664.
MLA	Cheng, Xuewei,et al."Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1".ACTA PHARMACEUTICA SINICA B 7.6(2017):657-664.