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Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity
- 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.
- Subjects :
- 0301 basic medicine
Male
medicine.drug_class
Antineoplastic Agents
Pharmacology
urologic and male genital diseases
Bile Acids and Salts
03 medical and health sciences
Feces
0302 clinical medicine
Metabolomics
Metabolic Diseases
medicine
Sunitinib
Animals
Protein Kinase Inhibitors
Bile acid
Chemistry
Fatty Acids
Research Papers
female genital diseases and pregnancy complications
Citric acid cycle
Mice, Inbred C57BL
Metabolic pathway
030104 developmental biology
Liver
Toxicity
Chemical and Drug Induced Liver Injury
030217 neurology & neurosurgery
Homeostasis
Drug metabolism
medicine.drug
Subjects
Details
- ISSN :
- 14765381
- Volume :
- 176
- Issue :
- 13
- Database :
- OpenAIRE
- Journal :
- British journal of pharmacology
- Accession number :
- edsair.doi.dedup.....e12742cfd89a09bd10d9c0d986fd9d2b