title: Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors.
abstract: BACKGROUND
  • Clinical cases reported that fatal acute liver failure occurred when paracetamol (acetaminophen) was co-administrated with some tyrosine kinase inhibitors (TKIs). The direct inhibition of UDP-glucuronosyltransferase activities has been identified as a mechanism of potentiation of paracetamol hepatotoxicity. However, the effects of TKIs on paracetamol glucuronidation are not known.
  
  
  CONCLUSIONS
  • The TKIs, sorafenib, dasatinib and imatinib exhibited potent mixed inhibition against paracetamol glucuronidation in pooled human liver microsomes, implying a possible increase in paracetamol hepatotoxicity when they are co-administrated with paracetamol. AIMS We aimed to investigate the effects of tyrosine kinase inhibitors (TKIs) on paracetamol (acetaminophen) glucuronidation.
  
  
  METHODS
  The inhibition of nine small molecule TKIs on paracetamol glucuronidation was investigated in human liver microsomes (HLMs) and recombinant human UDP-glucuronosyltransferases (UGTs).
  
  
  RESULTS
  Sorafenib, dasatinib and imatinib exhibited mixed inhibition against paracetamol glucuronidation in pooled HLMs, and potent inhibition in UGT1A9 and UGT2B15. Dasatinib and imatinib also inhibited UGT1A1-mediated paracetamol glucuronidation. Axitinib, erlotinib, gefitinib, lapatinib, nilotinib and vandetanib exhibited weak inhibition of paracetamol glucuronidation activity in HLMs.
  
  
  CONCLUSIONS
  The inhibition of paracetamol glucuronidation by TKIs might be of particular concern when they are co-administered.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramírez
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D004347:Drug Interactions; D020719:Glucuronides / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D018712:Analgesics, Non-Narcotic; D020719:Glucuronides; D047428:Protein Kinase Inhibitors; D000082:Acetaminophen; D014453:Glucuronosyltransferase; D011505:Protein-Tyrosine Kinases