Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors.
Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors.
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DOI：
10.1111/j.1365-2125.2011.03911.x
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发表时间：
2011-06
影响因子：
3.4
通讯作者：
Yong Liu;J. Ramírez;M. Ratain
中科院分区：
文献类型：
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作者：
Yong Liu;J. Ramírez;M. Ratain
临床病例报告，当扑热息痛（对乙酰氨基酚）与某些酪氨酸激酶抑制剂（TKI）联合给药时，发生了致命的急性肝功能衰竭。UDP-葡萄糖醛酸基转移酶活性的直接抑制已被确定为对乙酰氨基酚肝毒性增强的机制。然而，TKI对对乙酰氨基酚葡萄糖醛酸化的影响尚不清楚。本研究补充内容·TKI、索拉非尼、达沙替尼和伊马替尼在合并的人肝微粒体中对扑热息痛葡萄糖醛酸化表现出强效混合抑制作用，这意味着当它们与扑热息痛联合给药时，扑热息痛肝毒性可能增加。目的研究酪氨酸激酶抑制剂（TKI）对扑热息痛（对乙酰氨基酚）葡萄糖醛酸化的影响。方法在人肝微粒体（HLM）和重组人UDP-葡萄糖醛酸转移酶（UGT）中研究9种小分子TKI对对扑热息痛葡萄糖醛酸化的抑制作用。结果索拉非尼、达沙替尼和伊马替尼对合并HLM中的对乙酰氨基酚葡萄糖醛酸化表现出混合抑制作用，对UGT 1A 9和UGT 2B 15表现出强效抑制作用。达沙替尼和伊马替尼也抑制UGT 1A 1介导的对乙酰氨基酚葡萄糖醛酸化。阿昔替尼、厄洛替尼、吉非替尼、拉帕替尼、尼洛替尼和凡德他尼对HLM中对乙酰氨基酚葡萄糖醛酸化活性的抑制作用较弱。结论：TKI对对扑热息痛葡萄糖醛酸化的抑制作用可能是合并给药时特别关注的问题。
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.