癌症治疗中激酶抑制剂的代谢考虑因素。
Metabolism considerations for kinase inhibitors in cancer treatment.
机构信息
Scripps Florida, The Scripps Research Institute, Department of Molecular Therapeutics, 130 Scripps Way, Jupiter, FL 33458, USA.
出版信息
Expert Opin Drug Metab Toxicol. 2010 Oct;6(10):1175-93. doi: 10.1517/17425255.2010.506873.
IMPORTANCE OF THE FIELD
A concerted effort by the pharmaceutical industry over the last decade has led to the successful clinical development of protein kinase inhibitors as effective targeted therapies for certain cancers.
AREAS COVERED IN THIS REVIEW
This review details eight small molecule kinase inhibitors that have been approved for the treatment of cancer in either the US or Europe as of March 2010: imatinib, sorafenib, gefitinib, erlotinib, dasatinib, lapatinib, sunitinib and nilotinib. These eight compounds vary from the relatively specific inhibitor lapatinib to the more promiscuous kinase inhibitors dasatinib and sunitinib.
WHAT THE READER WILL GAIN
A brief discussion on the biology of each inhibitor, selectivity over other kinases and toxicity is provided. A more detailed discussion on the metabolism, drug transporters, drug-drug interactions and possible roles of metabolism in compound toxicity is provided for each compound.
TAKE HOME MESSAGE
The majority of the currently approved kinase inhibitors is heavily influenced by drug transporters and significantly affected by CYP3A4 inhibitors/inducers. At least three, gefitinib, erlotinib and dasatinib, are metabolized to form reactive metabolites capable of covalently-binding biomolecules.
重要性领域
在过去十年中，制药行业的共同努力使得蛋白激酶抑制剂作为某些癌症的有效靶向治疗药物成功地进行了临床开发。
本篇综述涵盖内容
本文详细介绍了截至 2010 年 3 月在美国或欧洲获准用于癌症治疗的八种小分子激酶抑制剂：伊马替尼、索拉非尼、吉非替尼、厄洛替尼、达沙替尼、拉帕替尼、舒尼替尼和尼洛替尼。这八种化合物从相对特异性抑制剂拉帕替尼到更具混杂性的激酶抑制剂达沙替尼和舒尼替尼不等。
读者将获得什么
对每种抑制剂的生物学、对其他激酶的选择性和毒性进行了简要讨论。对每种化合物的代谢、药物转运蛋白、药物相互作用以及代谢在化合物毒性中的可能作用进行了更详细的讨论。
需要牢记的要点
目前批准的大多数激酶抑制剂受药物转运蛋白的强烈影响，并受到 CYP3A4 抑制剂/诱导剂的显著影响。至少有三种，吉非替尼、厄洛替尼和达沙替尼，被代谢形成能够与生物分子共价结合的反应性代谢物。
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