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Trends Pharmacol Sci. 2016 Nov;37(11):904-932. doi: 10.1016/ Epub 2016 Sep 19.

Impact of Membrane Drug Transporters on Resistance to Small-Molecule Tyrosine Kinase Inhibitors.

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Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany.
Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH, USA.
Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen, Germany.
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany; Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tübingen, Germany; Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany. Electronic address:


Small-molecule inhibitors of tyrosine kinases (TKIs) are the mainstay of treatment for many malignancies and represent novel treatment options for other diseases such as idiopathic pulmonary fibrosis. Twenty-five TKIs are currently FDA-approved and >130 are being evaluated in clinical trials. Increasing evidence suggests that drug exposure of TKIs may significantly contribute to drug resistance, independently from somatic variation of TKI target genes. Membrane transport proteins may limit the amount of TKI reaching the target cells. This review highlights current knowledge on the basic and clinical pharmacology of membrane transporters involved in TKI disposition and their contribution to drug efficacy and adverse drug effects. In addition to non-genetic and epigenetic factors, genetic variants, particularly rare ones, in transporter genes are promising novel factors to explain interindividual variability in the response to TKI therapy.


ABC transporters; SLC transporters; clinical trials; drug resistance; interindividual variability; pharmacogenomics; tyrosine kinase inhibitors

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