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The degree of kinase inhibition achieved in vitro by imatinib and nilotinib is decreased by high levels of ABCB1 but not ABCG2.

Leuk Lymphoma. 2012 Jul 31;

Authors: Eadie LN, Saunders VA, Hughes TP, White DL


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 impact of ABCB1/ABCG2 over-expression on imatinib and nilotinib transport. High levels of ABCB1 protein in K562-Dox cells resulted in significantly increased IC50 compared with parental K562 cells for imatinib (IC50(IM); 9μM to 19μM, P=0.002) and nilotinib (IC50(NIL); 345nM to 620nM, P=0.013). This difference was abrogated by ABCB1 inhibitors. However, over-expression of ABCG2 did not significantly increase IC50(IM) or IC50(NIL) nor significantly decrease IC50 upon ABCG2 inhibition. Inhibition of ABCB1 but not ABCG2 resulted in a substantial increase in intracellular nilotinib when used at 150nM but no increase when used at 2μM. 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.

PMID: 22845311 [PubMed - as supplied by publisher]