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Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity

Authors :
Qi Zhao
Yan Wang
Fei Li
Xue-Rong Xiao
Ting Zhang
Frank J. Gonzalez
Jian-Feng Huang
Source :
Br J Pharmacol
Publication Year :
2018

Abstract

Background and purpose Sunitinib is a small-molecule TK inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear. Experimental approach In the present study, mice were treated with 60, 150, and 450 mg·kg-1 sunitinib to evaluate sunitinib hepatotoxicity. Sunitinib metabolites and endogenous metabolites in liver, serum, faeces, and urine were analysed using ultra-performance LC electrospray ionization quadrupole time-of-flight MS-based metabolomics. Key results Four reactive metabolites and impaired clearance of sunitinib in liver played a dominant role in sunitinib-induced hepatotoxicity. Using a non-targeted metabolomics approach, various metabolic pathways, including mitochondrial fatty acid β-oxidation (β-FAO), bile acids, lipids, amino acids, nucleotides, and tricarboxylic acid cycle intermediates, were disrupted after sunitinib treatment. Conclusions and implications These studies identified significant alterations in mitochondrial β-FAO and bile acid homeostasis. Activation of PPARα and inhibition of xenobiotic metabolism may be of value in attenuating sunitinib hepatotoxicity.

Details

ISSN :
14765381
Volume :
176
Issue :
13
Database :
OpenAIRE
Journal :
British journal of pharmacology
Accession number :
edsair.doi.dedup.....e12742cfd89a09bd10d9c0d986fd9d2b