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|Title:||Degree of kinase inhibition achieved in vitro by imatinib and nilotinib is decreased by high levels of ABCB1 but not ABCG2|
|Citation:||Leukemia & Lymphoma, 2013; 54(3):569-578|
|Publisher:||Taylor & Francis Ltd|
|Laura N. Eadie, Verity A. Saunders, Timothy P. Hughes & Deborah L. White|
|Abstract:||Imatinib and nilotinib interact with ABCB1 and ABCG2. However, whether they are substrates or inhibitors is a source of conjecture. Here, in vitro, Bcr–Abl kinase inhibition was used to elucidate the impact of ABCB1/ABCG2 overexpression on imatinib and nilotinib transport. High levels of ABCB1 protein in K562-Dox cells resulted in a significantly increased 50% inhibitory concentration (IC₅₀) compared with parental K562 cells for imatinib (IC₅₀(IM); 9 µM to 19 µM, p = 0.002) and nilotinib (IC₅₀(NIL); 345 nM to 620 nM, p = 0.013). This difference was abrogated by ABCB1 inhibitors. However, overexpression of ABCG2 did not significantly increase IC₅₀(IM) or IC₅₀(NIL) or significantly decrease IC₅₀ upon ABCG2 inhibition. Inhibition of ABCB1 but not ABCG2 resulted in a substantial increase in intracellular nilotinib when used at 150 nM but no increase when used at 2 µM. Imatinib and nilotinib appear to be transported by ABCB1 but do not interact strongly with ABCG2. Furthermore, ABCB1 efflux of nilotinib may be concentration-dependent with transport occurring at clinically relevant concentrations.|
|Keywords:||CML; nilotinib; imatinib; ABC transporters|
|Rights:||© 2013 Informa UK, Ltd.|
|Appears in Collections:||Medicine publications|
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