摘要
药物代谢研究在药物的发现和开发过程中是一个重要的组成部分。随着药物代谢学科的发展,我国的药物代谢研究水平也在努力与国际接轨。本文综述了由中国自主研发、已经上市或处于临床研究阶段的酪氨酸激酶抑制剂在人或动物体内的代谢研究。其中,埃克替尼和阿帕替尼已经上市,法米替尼、氟马替尼、艾力替尼、呋喹替尼和塞拉替尼目前处于临床试验阶段。多数药物以CYP3A4为主要代谢酶,活性代谢位点主要在结构改造部分。代谢活化方面,埃克替尼形成冠醚氧化开环的醛中间体;法米替尼的二氢亚吲哚环氧化脱氟重排为醌亚胺中间体;艾力替尼的α,β-不饱和羰基双键氧化形成环氧化物中间体。与国际上研究代谢的方法相比,多数药物没有进行人体放射性标记试验,缺少临床药物-药物相互作用和转运体研究方面的数据。
Drug metabolism research plays an essential role in drug discovery and development. Great efforts have been made domestically to be line with the international standardized research on drug metabolism. In this article, we will review new-generation of tyrosine kinase inhibitors（TKIs）, these TKIs include icotinib, apatinib, famitinib, flumatinb, allitinib, fruquintinib, and selatinib, among which icotinib and apatinib have been approved by China food and drug administration（CFDA） to reach the market, while others are in clinical trials. For these TKIs, the structural modified sites are active metabolic centers and CYP3A4 is identified as the primary metabolic enzyme. Considering the active intermediates, the crown ether ring of icotinib is oxidated to open to form an aldehyde; the indolylidene ring of famitinib is oxidated followed by rearrangement to form a quinone- imine; the α, β-unsaturated carbonyl group of allitinib is oxidated to form an epoxide, these intermediates are capable of covalently binding biomolecules and generating toxicity. In addition, human 14 C radioactive trials of most of these TKIs have not been conducted, and the data of drug-drug interactions in clinic are also absent, which indicate our deficiency compared to the international regular approaches in metabolic research.
出处
《药学学报》
CAS
CSCD
北大核心
2016年第2期248-256,共9页
Acta Pharmaceutica Sinica
基金
重大新药创制科技重大专项(2014ZX09304002-008-001)
中国科学院上海药物研究所新药研究国家重点实验室项目(SIMM1501ZZ-02)
