Liver toxicity associated with the use of pazopanib in renal cancer patients: UK teaching hospital experience.

Jain, Ankit; Canipari, Cinzia; Haque, Farzana; Solanki, Heena; Kumar, Abhishek; Porfiri, Emilio

doi:10.1200/jco.2015.33.15_suppl.e15610

Cited by 1 publication

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“…However, adverse effects were frequently reported, including increased liver injury, hypertension and lupus erythematosus (Casado-Verrier et al, 2014). For example, meta-analyses of clinical trials reported that pazopanib is associated with increased risk of liver toxicity (Lim et al, 2013; Rickmann et al, 2013; Jain et al, 2015; Vlenterie et al, 2015; Shantakumar et al, 2016; Choudhury et al, 2017). In vitro screening of 31 small-molecule kinase inhibitors approved by the US FDA revealed that pazopanib is associated with significant liver toxicity involving mitochondria damage (Zhang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice

Wang

Yang

Liang³

et al. 2018

Xenobiotica

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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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