Comparison of ATP-Binding Cassette Transporter Interactions with the Tyrosine Kinase Inhibitors Imatinib, Nilotinib, and Dasatinib

• DOI: 10.1124/dmd.109.031302
• Publication Date: 2010-04-28T00:45:41Z
• Authors: Marius Dohse; Christian Scharen...; Suneet Shukla; Robert W. Robey; Thorsten Volkmann; John F. Deeken; Cornelia Brendel; Suresh V. Ambudkar; Andreas Neubauer; Susan E. Bates
• Keywords: Abcg2

Although the development of tyrosine kinase inhibitors (TKIs) to control unregulated activity BCR-ABL revolutionized therapy chronic myeloid leukemia, resistance TKIs is a clinical reality. Among postulated mechanisms overexpression ATP-binding cassette (ABC) transporters, such as P-glycoprotein (ABCB1) and breast cancer protein (ABCG2), which mediate reduced intracellular drug accumulation. We compared interactions imatinib, nilotinib, dasatinib with ABCB1 ABCG2 in ex vivo vitro systems. The inhibited rhodamine 123 Hoechst 33342 efflux mediated by endogenous expression transporters murine human hematopoietic stem cells potency order nilotinib ≫ imatinib dasatinib. Studies <i>ABCB1</i>-, <i>ABCG2</i>-, <i>ABCC1</i>-transfected embryonic kidney 293 verified that was most potent inhibitor ABCG2. Cytotoxicity assays stably transduced K562-ABCG2 K562-ABCB1 confirmed were also substrates for two transporters. Like both decreased surface cells. Finally, we found all able compete labeling photo-cross-linkable prazosin analog [¹²⁵I]iodoarylazidoprazosin, suggesting interaction at prazosin-binding site proteins. Our experiments support hypothesis three are ABC that, higher concentrations, overcome transporter function. Taken together, results suggest therapeutic doses may diminish potential limit oral absorption or confer resistance. Clinical data required definitively answer latter question.