Metabolism considerations for kinase inhibitors in cancer treatment

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.