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Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors
Author(s) -
Liu Yong,
Ramírez Jacqueline,
Ratain Mark J.
Publication year - 2011
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2011.03911.x
Subject(s) - glucuronidation , pharmacology , dasatinib , chemistry , acetaminophen , tyrosine kinase inhibitor , glucuronosyltransferase , drug interaction , tyrosine kinase , medicine , imatinib , microsome , myeloid leukemia , drug , biochemistry , cancer , enzyme , signal transduction
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • 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. WHAT THIS STUDY ADDS • 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.