Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1
Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1
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埃克替尼和厄洛替尼对人UDP-葡萄糖醛酸基转移酶1A1抑制潜力的比较
DOI：
10.1016/j.apsb.2017.07.004
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发表时间：
2017-11-01
影响因子：
14.5
通讯作者：
Dong, Ruihua
中科院分区：
文献类型：
--
作者：
Cheng, Xuewei;Lv, Xia;Dong, Ruihua
UDP-葡萄糖醛酸基转移酶 1A1 (UGT1A1) 在许多潜在有害化合物和药物的解毒中发挥着关键作用。 UGT1A1抑制可能带来药物相互作用（DDI）、高胆红素血症和药物性肝损伤的风险。本研究旨在调查和比较埃克替尼和厄洛替尼对 UGT1A1 的抑制作用，并通过抑制 UGT1A1 评估其潜在的 DDI 风险。结果表明，埃克替尼和厄洛替尼都是UGT1A1抑制剂，但埃克替尼对UGT1A1的抑制作用弱于厄洛替尼。埃克替尼和厄洛替尼在人肝微粒体（HLM）中对抗 UGT1A1 介导的 NCHN-O-葡萄糖醛酸化的 IC50 值分别为 5.15 和 0.68 fimol/L。抑制动力学分析表明，埃克替尼和厄洛替尼都是 HLM 中 UGT1A1 介导的 NCHN 葡萄糖醛酸化的非竞争性抑制剂，K-1 值分别为 8.55 和 1.23 fimol/L。此外，通过 NCHN 浓度时间曲线下面积 (AUC) 的比率定量预测了它们通过 UGT1A1 抑制而产生的潜在 DDI 风险。这些发现有助于药物化学家设计和开发安全性更高的下一代酪氨酸激酶抑制剂，并指导埃克替尼和厄洛替尼在临床上的合理应用，特别是通过抑制UGT1A1来避免其潜在的DDI风险。 (C) 2017 中国药学会、中国医学科学院药物研究所。由 Elsevier B.V. 制作和托管。这是一篇 CC BY-NC-ND 下的开放获取文章。
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.