Metabolic research of domestically developed small molecule tyrosine kinase inhibitors
10.16438/j.0513-4870.2015-0998
- VernacularTitle:我国研发的小分子酪氨酸激酶抑制剂的药物代谢研究
- Author:
Jin-fang JIANG
1
;
Xiao-yan CHEN
1
;
Da-fang ZHONG
1
Author Information
1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Publication Type:REVIEWS
- Keywords:
tyrosine kinase inhibitor;
in vivo metabolism;
metabolic approach
- From:
Acta Pharmaceutica Sinica
2016;51(2):248-
- CountryChina
- Language:Chinese
-
Abstract:
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 14C 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.
