药学学报, 2019, 54(3): 432-439
引用本文:
刘晓云, 陈笑艳, 钟大放. 共价酪氨酸激酶抑制剂的代谢和药动学[J]. 药学学报, 2019, 54(3): 432-439.
LIU Xiao-yun, CHEN Xiao-yan, ZHONG Da-fang. Metabolism and pharmacokinetics of covalent tyrosine kinase inhibitors[J]. Acta Pharmaceutica Sinica, 2019, 54(3): 432-439.

共价酪氨酸激酶抑制剂的代谢和药动学
刘晓云, 陈笑艳, 钟大放
中国科学院上海药物研究所, 上海 201203
摘要:
共价酪氨酸激酶抑制剂通过与靶蛋白中的半胱氨酸形成共价键,抑制肿瘤细胞的信号通路转导,具有高效能和持续时间长、克服耐药性的优点。本文综述了已经上市的共价酪氨酸激酶抑制剂的代谢和药动学。目前FDA批准上市的共价酪氨酸激酶抑制剂有阿法替尼、来那替尼、达克替尼、奥希替尼、依鲁替尼和阿可替尼。吡咯替尼是由中国自主研发,最近获批上市的抗肿瘤新药。共价酪氨酸激酶抑制剂能够与血浆蛋白,尤其是人血清白蛋白发生共价结合,从而影响这类药物的药动学。
关键词:    共价酪氨酸激酶抑制剂      代谢      药动学      人血清白蛋白      共价结合     
Metabolism and pharmacokinetics of covalent tyrosine kinase inhibitors
LIU Xiao-yun, CHEN Xiao-yan, ZHONG Da-fang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Abstract:
Covalent tyrosine kinase inhibitors (TKIs) can inhibit the signaling pathway of tumor cells by covalent binding with cysteine residues of target proteins, which has the advantages of high potency, extended duration of action and overcoming drug resistance. In this article, we will review the metabolism and pharmacokinetics of some covalent TKIs. Currently, the covalent TKIs approved by US food and drug administration (FDA) are afatinib, neratinib, dacomitinib, osimertinib, ibrutinib and acalabrutinib. Pyrotinib have been approved by National Medical Products Administration (NMPA) to reach the market recently. Covalent TKIs can covalently bind with plasma proteins, especially human serum albumin, thus effected the pharmacokinetics of these drugs.
Key words:    covalent tyrosine kinase inhibitor    metabolism    pharmacokinetics    human serum albumin    covalently binding   
收稿日期: 2018-09-11
DOI: 10.16438/j.0513-4870.2018-0834
基金项目: 国家自然科学基金资助项目(81521005);中国科学院个性化药物战略性先导科技专项(XDA12050306).
通讯作者: 钟大放
Email: dfzhong@simm.ac.cn
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