Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1.
10.1016/j.apsb.2017.07.004
- Author:
Xuewei CHENG
1
;
Xia LV
2
;
Hengyan QU
1
;
Dandan LI
1
;
Mengmeng HU
1
;
Wenzhi GUO
3
;
Guangbo GE
4
;
Ruihua DONG
1
Author Information
1. Clinical Pharmacology Laboratory, Military Academy of Medical Science Hospital, Beijing 100071, China.
2. College of Life Science, Dalian Nationalities University, Dalian 116600, China.
3. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China.
4. Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
- Publication Type:Journal Article
- Keywords:
Drug–drug interactions (DDIs);
Erlotinib;
Icotinib;
Inhibitory effects;
UGT1A1
- From:
Acta Pharmaceutica Sinica B
2017;7(6):657-664
- CountryChina
- Language:English
-
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 risksUGT1A1 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 ICvalues of icotinib and erlotinib against UGT1A1-mediated NCHN--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 thevalues of 8.55 and 1.23 μmol/L, respectively. Furthermore, their potential DDI risksUGT1A1 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 risksUGT1A1 inhibition.
