Mechanistic and pharmacological insights into modulation of ABC drug transporters by tyrosine kinase inhibitors

Abstract

ATP-binding cassette (ABC) drug transporters have both physiological and pharmacological importance in humans. They not only protect the cells from xenobiotics, but also alter the pharmacokinetics and toxicity of drugs that are substrates for these transporters. P-glycoprotein (P-gp) was the first human ABC transporter to be discovered, almost four decades ago. Drug transport using the energy harvested by ATP hydrolysis is a hallmark of ABC drug transporters and has been extensively studied to determine its mechanism of substrate specificity and transport activity. Structural information from a number of human P-gp homologs highlights the existence of multiple drug-binding sites that can interact with a diverse set of chemically or structurally unrelated compounds. Tyrosine kinase inhibitors (TKIs) comprise a class of drugs that interact with ABC transporters with high affinity and are reported to be transport substrates of several ABC transporters. A number of preclinical and clinical studies have shown that ABC transporters influence the disposition of several TKIs that include altered pharmacokinetics and safety profiles and have a role in the development of resistance to this class of therapeutics. Structural details regarding the TKIs’ effect on ABC transporters have not been thoroughly explored. This review summarizes preclinical and clinical observations on the interaction of TKIs with ABC drug transporters. In addition, we provide structural information on the interaction of two TKIs, nilotinib and imatinib, at the drug-binding regions within P-gp and ABCG2. This information could help to generate a novel scaffold that would be an ideal TKI with potent inhibition of kinases, but minimal interactions with ABC drug transporters.