RT Journal Article SR Electronic T1 Sunitinib (Sutent, SU11248), a Small-Molecule Receptor Tyrosine Kinase Inhibitor, Blocks Function of the ATP-Binding Cassette (ABC) Transporters P-Glycoprotein (ABCB1) and ABCG2 JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 359 OP 365 DO 10.1124/dmd.108.024612 VO 37 IS 2 A1 Suneet Shukla A1 Robert W. Robey A1 Susan E. Bates A1 Suresh V. Ambudkar YR 2009 UL http://dmd.aspetjournals.org/content/37/2/359.abstract AB Sunitinib malate (Sutent, SU11248) is a small-molecule receptor tyrosine kinase inhibitor that inhibits cellular signaling of multiple targets such as the platelet-derived growth factor receptors and the vascular endothelial growth factor receptors and is used in the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. Because tyrosine kinase inhibitors are known to increase the p.o. bioavailability and brain penetration of chemotherapy drugs in animal models, we sought to examine the effect of sunitinib on the ATP-binding cassette (ABC) drug transporters P-glycoprotein (P-gp, ABCB1), the multidrug resistance-associated protein 1 (ABCC1), and ABCG2, which are known to transport a wide variety of anticancer drugs. In this study, we show that sunitinib inhibits P-gp- and ABCG2-mediated efflux of fluorescent substrates in cells overexpressing these transporters. In 4-day cytotoxicity assays, at a nontoxic concentration (2 μM) sunitinib was able to partially reverse drug resistance mediated by P-gp and completely reverse resistance mediated by ABCG2. We further show a direct interaction of sunitinib with the substrate binding pocket of these transporters as it inhibited binding of the photoaffinity substrate [125I]iodoarylazidoprazosin to P-gp (IC50 = 14.2 μM) and ABCG2 (IC50 = 1.33 μM). Sunitinib stimulated the ATP hydrolysis by both transporters in a concentration-dependent manner. Conformation-sensitive antibody binding assays with the P-gp- and ABCG2-specific antibodies, UIC2 and 5D3, respectively, also confirmed the interaction of sunitinib with these transporters. Taken together, this is the first report showing that sunitinib inhibits transport mediated by ABC drug transporters, which may affect the bioavailability of drugs coadministered with sunitinib. U.S. Government work not protected by U.S. copyright.