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From in vitro to in vivo: intracellular determination of imatinib and nilotinib may be related with clinical outcome

Leukemia volume 27, pages 1757–1759 (2013)Cite this article

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Imatinib (Glivec or Gleevec) is an inhibitor of BCR-ABL that has been used in the first-line treatment of chronic myeloid leukemia (CML) over the past decade. Following imatinib marketing, nilotinib (Tasigna) was initially introduced as second-line treatment, and has recently received first-line indication. Despite good efficacy, 30–40% of the patients remain in treatment failure (suboptimal response or resistance) after 5 years of imatinib.1 It has been reported that there is a large interpatient variability with regards to plasma concentration of imatinib, and this led to the determination of a threshold close to 1000 ng/ml significantly associated with better cytogenetic and molecular responses in imatinib treatment.2 This factor is one aspect of the potential mechanisms for resistance to imatinib,3 which also includes intracellular incorporation of the drug, mediated by influx or efflux transport-proteins. Multidrug resistance 1 (MDR1) (=ABCB1)-mediated efflux has been reported to be involved in imatinib and nilotinib resistance,4, 5 and these molecules are also substrates of BCRP2(=ABCG2).6, 7 However, with regards to influx, it is of note that imatinib, but not nilotinib is mediated by organic cationic transporter-1 (OCT1) (=SLC22A1).8 Mutations or differences in the expression of these transporters could modify the intracellular concentration of tyrosine kinase inhibitors (TKIs), and lead to interpatient variability similar to that found for plasma concentration. Therefore, the current study was performed to further investigate the transporters involved in cellular intake of imatinib and nilotinib, and the potential for intracellular therapeutic drug monitoring .

The same experiments using nilotinib found no difference between cell lines, with or without inhibitors, suggesting that intracellular levels were not influenced by either MDR1, BCRP2 or OCT1 (Figures 1c and d), which is in accordance (at least for MDR1 and OCT1) with that reported by White et al.8 However, nilotinib has been reported to be a substrate of both MDR1 and BCRP2 transporters,5, 7 but, as suggested by Hegedus et al.,7 these diverging results are probably due to differences in the concentration of nilotinib studied in previous reports, cells were incubated with less than 100 nM, whereas in this report a concentration of 1 μM was used, which is closer to the concentration found in patient blood, and which could have saturated the transporters investigated.

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Figure 1
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Authors and Affiliations

  1. Univ. de Bordeaux, Bordeaux, France

    S Bouchet, S Dulucq, J-M Pasquet, V Lagarde, M Molimard & F-X Mahon

  2. CHU de Bordeaux, Bordeaux, France

    S Bouchet, S Dulucq, M Molimard & F-X Mahon

  3. INSERM, U657, Bordeaux, France

    S Bouchet & M Molimard

  4. INSERM, U1035, Bordeaux, France

    S Dulucq, J-M Pasquet, V Lagarde & F-X Mahon

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  1. S Bouchet
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Correspondence to S Bouchet.

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Bouchet, S., Dulucq, S., Pasquet, JM. et al. From in vitro to in vivo: intracellular determination of imatinib and nilotinib may be related with clinical outcome. Leukemia 27, 1757–1759 (2013). https://doi.org/10.1038/leu.2013.13

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