Enzyme- and transporter-mediated drug interactions with small molecule tyrosine kinase inhibitors

J Pharm Sci. 2014 Dec;103(12):3810-3833. doi: 10.1002/jps.24113. Epub 2014 Oct 10.

Abstract

Among the novel and target-specific classes of anticancer drugs, small molecule tyrosine kinase inhibitors (TKIs) represent an extremely promising and rapidly expanding group. TKIs attack cancer-specific targets and therefore have a favorable safety profile. However, as TKIs are taken orally along with other medications on a daily basis, there is an elevated risk of potentially significant drug-drug interactions. Most TKIs are metabolized primarily through CYP3A4. In addition, many TKIs are also CYP3A4 inhibitors at the same time. In addition to drug metabolizing enzymes (DMEs), another determinant of TKI disposition are drug transporters. There is accumulating evidence showing that the majority of currently marketed TKIs interact with ATP-binding cassette transporters, particularly P-glycoprotein as well as Breast Cancer Resistance Protein and serve as both substrates and inhibitors. Considering the dual roles of TKIs on both DMEs and drug transporters, and the importance of these enzyme and transporters in drug disposition, the potential for enzyme- and transporter-mediated TKI-drug interactions in patients with cancer is an important consideration. This review provides a comprehensive overview of drug interactions with small molecule TKIs mediated by DMEs and drug transporters. The TKI-drug interactions with TKIs being victims and/or perpetrators are summarized.

Keywords: ADME; cancer chemotherapy; clinical pharmacokinetics; drug interactions; drug metabolizing enzymes; membrane transporter.

Publication types

  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Drug Interactions / physiology*
  • Humans
  • Membrane Transport Proteins / metabolism*
  • Protein Kinase Inhibitors / metabolism*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism*

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP-Binding Cassette Transporters
  • Membrane Transport Proteins
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases