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, 71 (6), 917-20

Inhibition of Paracetamol Glucuronidation by Tyrosine Kinase Inhibitors

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Inhibition of Paracetamol Glucuronidation by Tyrosine Kinase Inhibitors

Yong Liu et al. Br J Clin Pharmacol.

Abstract

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.

Figures

Figure 1
Figure 1
Representative Eadie–Hofstee plot for paracetamol glucuronidation (A) and Dixon plots of the effects of sorafenib (B), dasatinib (C) and imatinib (D) on paracetamol glucuronidation in pooled human liver microsomes. Reactions were performed as described in Methods. All data points shown represent the mean of duplicate measurements. 2 mm paracetamol (formula image); 5 mm paracetamol (formula image); 10 mm paracetamol (formula image); 15 mm paracetamol (formula image)

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