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Type: Journal article
Title: Degree of kinase inhibition achieved in vitro by imatinib and nilotinib is decreased by high levels of ABCB1 but not ABCG2
Author: Eadie, L.
Saunders, V.
Hughes, T.
White, D.
Citation: Leukemia & Lymphoma, 2013; 54(3):569-578
Publisher: Taylor & Francis Ltd
Issue Date: 2013
ISSN: 1042-8194
Statement of
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.
RMID: 0020124710
DOI: 10.3109/10428194.2012.715345
Appears in Collections:Medicine publications

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