ArticleXenobiotica; the fate of foreign compounds in biological systems2019
A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice.
Article in Xenobiotica; the fate of foreign compounds in biological systems, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 27 citations in OpenAlex.
- The impact of pazopanib and extremity radiotherapy on transaminase elevations in soft tissue sarcoma.Acta oncologica (Stockholm, Sweden) · 2026Article
- Personalized Medicine Approach to Proteomics and Metabolomics of Cytochrome P450 Enzymes: A Narrative Review.European journal of drug metabolism and pharmacokinetics · 2024Review
- Systematic Evaluation of Tyrosine Kinase Inhibitors as OATP1B1 Substrates Using a Competitive Counterflow Screen.Cancer research communications · 2024Article
- Real-world data on the management of pazopanib-induced liver toxicity in routine care of renal cell cancer and soft tissue sarcoma patients.Cancer chemotherapy and pharmacology · 2024Observational
- Parabacteroides distasonis ameliorates hepatic fibrosis potentially via modulating intestinal bile acid metabolism and hepatocyte pyroptosis in male mice.Nature communications · 2023Article
- The assessment of the potential hepatotoxicity of new drugs byFrontiers in pharmacology · 2023Review
- Biological Role of Pazopanib and Sunitinib Aldehyde Derivatives in Drug-Induced Liver Injury.Metabolites · 2022Article
- Sunitinib versus Pazopanib Dilemma in Renal Cell Carcinoma: New Insights into the In Vitro Metabolic Impact, Efficacy, and Safety.International journal of molecular sciences · 2022Article
- Severe tyrosine-kinase inhibitor induced liver injury in metastatic renal cell carcinoma patients: two case reports assessed for causality using the updated RUCAM and review of the literature.BMC gastroenterology · 2022Review
- Protective effects of taxifolin on pazopanib-induced liver toxicity: an experimental rat model.Experimental animals · 2021Article
- Novel advances in biotransformation and bioactivation research-2019 year in reviewDrug metabolism reviews · 2020Review
- Role of Metabolic Activation in Elemicin-Induced Cellular Toxicity.Journal of agricultural and food chemistry · 2019Article
- Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity.British journal of pharmacology · 2019Article
- Interaction between phytotherapy and oral anticancer agents: prospective study and literature review.Medical oncology (Northwood, London, England) · 2019Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
To elucidate the metabolism of pazopanib, a metabolomics approach was performed based on ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry. A total of 22 pazopanib metabolites were identified in vitro and in vivo. Among these metabolites, 17 were novel, including several cysteine adducts and aldehyde derivatives. By screening using recombinant CYPs, CYP3A4 and CYP1A2 were found to be the main forms involved in the pazopanib hydroxylation. Formation of a cysteine conjugate (M3), an aldehyde derivative (M15) and two N-oxide metabolites (M18 and M20) from pazopanib could induce the oxidative stress that may be responsible in part for pazopanib-induced hepatotoxicity. Morphological observation of the liver suggested that pazopanib (300 mg/kg) could cause liver injury. The aspartate transaminase and alanine aminotransferase in serum significantly increased after pazopanib (150, 300 mg/kg) treatment; this liver injury could be partially reversed by the broad-spectrum CYP inhibitor 1-aminobenzotriazole (ABT). Metabolomics analysis revealed that pazopanib could significantly change the levels of L-carnitine, proline and lysophosphatidylcholine 18:1 in liver. Additionally, drug metabolism-related gene expression analysis revealed that hepatic Cyp2d22 and Abcb1a (P-gp) mRNAs were significantly lowered by pazopanib treatment. In conclusion, this study provides a global view of pazopanib metabolism and clues to its influence on hepatic function.
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