Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors

Abstract

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. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.