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Metabolic profiling of the anti-tumor drug regorafenib in mice
Wang, Yi-Kun1,2; Xiao, Xue-Rong1; Xu, Kang-Ping3; Li, Fei1
2018-09-10
发表期刊JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
ISSN0731-7085
卷号159页码:524-535
摘要Regorafenib is a novel tyrosine kinase inhibitor, which has been approved by the United States Food and DrugAdministration for the treatment of various tumors. The purpose of the present study was to describe the metabolic map of regorafenib, and investigate its effect on liver function. Mass spectrometry-based metabolomics approach integrated with multiple mass defect filter was used to determine the metabolites of regorafenib in vitro incubation mixtures (human liver microsomes and mouse liver microsomes), serum, urine and feces samples from mice treated with 80 mg/kg regorafenib. Eleven metabolites including four novel metabolites were identified in the present investigation. As halogen substituted drug, reductive defluorination and oxidative dechlorination metabolites of regorafenib were firstly report in present study. By screening using recombinant cytochrome P450 s (CYPs), CYP3A4 was found to be the principal isoforms involved in regorafenib metabolism. The predication with a molecular docking model confirmed that regorafenib had potential to interact with the active sites of CYP3A4, CYP3A5 and CYP2D6. Serum chemistry analysis revealed no evidence of hepatic damage from regorafenib exposure. This study provided a global view of regorafenib metabolism and its potential side-effects. (C) 2018 Elsevier B.V. All rights reserved.
关键词Regorafenib Metabolomics Multiple mass defect filters Molecular docking
资助信息National Key Research and Development Program of China; Kunming Institute of Botany; Thousand Young Talents Program of China
DOI10.1016/j.jpba.2018.07.039
语种英语
资助项目National Key Research and Development Program of China[2017YFC0906903] ; Kunming Institute of Botany[Y4662211K1] ; Thousand Young Talents Program of China
WOS研究方向Chemistry ; Pharmacology & Pharmacy
WOS类目Chemistry, Analytical ; Pharmacology & Pharmacy
WOS记录号WOS:000442699900058
出版者ELSEVIER SCIENCE BV
引用统计
文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/62224
专题中国科学院昆明植物研究所
通讯作者Li, Fei
作者单位1.Chinese Acad Sci, Kunming Inst Bot, States Key Lab Phytochem & Plant Resources West C, Kunming 650201, Yunnan, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Cent S Univ, Xiangya Sch Pharmaceut Sci, Changsha 410013, Hunan, Peoples R China
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Wang, Yi-Kun,Xiao, Xue-Rong,Xu, Kang-Ping,et al. Metabolic profiling of the anti-tumor drug regorafenib in mice[J]. JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,2018,159:524-535.
APA Wang, Yi-Kun,Xiao, Xue-Rong,Xu, Kang-Ping,&Li, Fei.(2018).Metabolic profiling of the anti-tumor drug regorafenib in mice.JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,159,524-535.
MLA Wang, Yi-Kun,et al."Metabolic profiling of the anti-tumor drug regorafenib in mice".JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS 159(2018):524-535.
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