Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity

Br J Pharmacol. 2019 Jul;176(13):2162-2178. doi: 10.1111/bph.14664. Epub 2019 May 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / urine
  • Bile Acids and Salts / metabolism
  • Chemical and Drug Induced Liver Injury / etiology*
  • Fatty Acids / metabolism
  • Feces / chemistry
  • Liver / metabolism
  • Male
  • Metabolic Diseases / chemically induced*
  • Mice, Inbred C57BL
  • Protein Kinase Inhibitors / adverse effects*
  • Protein Kinase Inhibitors / blood
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein Kinase Inhibitors / urine
  • Sunitinib / adverse effects*
  • Sunitinib / blood
  • Sunitinib / pharmacokinetics*
  • Sunitinib / urine

Substances

  • Antineoplastic Agents
  • Bile Acids and Salts
  • Fatty Acids
  • Protein Kinase Inhibitors
  • Sunitinib