Metabolic profiling of tyrosine kinase inhibitor nintedanib using metabolomics
Zhou, Zi-Meng1,2; Wang, Yi-Kun2,3; Yan, Dong-Mei1; Fang, Jian-He1; Xiao, Xue-Rong2; Zhang, Ting2,3; Cheng, Yan2; Xu, Kang-Ping4; Li, Fei2
Corresponding AuthorCheng, Yan( ; Li, Fei(
AbstractNintedanib is a promising tyrosine kinase inhibitor for clinically treating idiopathic pulmonary fibrosis (IPF). Some clinical cases reported that nintedanib treatment can cause hepatotoxicity and myocardial toxicity. U. S. FDA warns the potential drug-drug interaction when it is co-administrated with other drugs. In order to understand the potential toxicity of nintedanib and avoid drug-drug interaction, the metabolism of nintedanib was systematically investigated in human liver microsomes and mice using metabolomics approach, and the toxicity of metabolites was predicted by ADMET lab. Nineteen metabolites were detected in vivo and in vitro metabolism, and 8 of them were undescribed. Calculated partition coefficients (Clog P) were used to distinguish the isomers of nintedanib metabolites in this study. The major metabolic pathways of nintedanib majorly included hydroxylation, demethylation, glucuronidation, and acetylation reactions. The ADMET prediction indicated that nintedanib was a substrate of the cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). And nintedanib and most of its metabolites might possess potential hepatotoxicity and cardiotoxicity. This study provided a global view of nintedanib metabolism, which could be used to understand the mechanism of adverse effects related to nintedanib and its potential drug-drug interaction. (C) 2019 Elsevier B.V. All rights reserved.
KeywordNintedanib Metabolism Metabolomics ADMET prediction UPLC-ESI-QTOF-MS
Indexed BySCI ; SCI
WOS Research AreaChemistry ; Pharmacology & Pharmacy
WOS SubjectChemistry, Analytical ; Pharmacology & Pharmacy
WOS IDWOS:000514256500011
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Document Type期刊论文
Corresponding AuthorCheng, Yan; Li, Fei
Affiliation1.Jiangxi Univ Tradit Chinese Med, Coll Pharm, Nanchang 330004, Jiangxi, Peoples R China
2.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Cent South Univ, Xiangya Sch Pharmaceut Sci, Changsha 410013, Peoples R China
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Zhou, Zi-Meng,Wang, Yi-Kun,Yan, Dong-Mei,et al. Metabolic profiling of tyrosine kinase inhibitor nintedanib using metabolomics[J]. JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,2020,180:13.
APA Zhou, Zi-Meng.,Wang, Yi-Kun.,Yan, Dong-Mei.,Fang, Jian-He.,Xiao, Xue-Rong.,...&Li, Fei.(2020).Metabolic profiling of tyrosine kinase inhibitor nintedanib using metabolomics.JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,180,13.
MLA Zhou, Zi-Meng,et al."Metabolic profiling of tyrosine kinase inhibitor nintedanib using metabolomics".JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS 180(2020):13.
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