Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity

Article date: July 2019

By: Qi Zhao, Ting Zhang, Xue‐Rong Xiao, Jian‐Feng Huang, Yan Wang, Frank J. Gonzalez, Fei Li in Volume 176, Issue 13, pages 2162-2178

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.

DOI: 10.1111/bph.14664

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