Brain Accumulation of Dasatinib Is Restricted by P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) and Can Be Enhanced by Elacridar Treatment

Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Clinical Cancer Research (Impact Factor: 8.72). 05/2009; 15(7):2344-51. DOI: 10.1158/1078-0432.CCR-08-2253
Source: PubMed


Imatinib, a BCR-ABL tyrosine kinase inhibitor, is a substrate of the efflux transporters P-glycoprotein (P-gp; ABCB1) and ABCG2 (breast cancer resistance protein), and its brain accumulation is restricted by both transporters. For dasatinib, an inhibitor of SCR/BCR-ABL kinases, in vivo interactions with P-gp and ABCG2 are not fully established yet.
We used Abcb1a/1b(-/-), Abcg2(-/-), and Abcb1a/1b;Abcg2(-/-) mice to establish the roles of P-gp and ABCG2 in the pharmacokinetics and brain accumulation of dasatinib.
We found that oral uptake of dasatinib is limited by P-gp. Furthermore, relative brain accumulation, 6 hours after administration, was not affected by Abcg2 deficiency, but absence of P-gp resulted in a 3.6-fold increase after oral and 4.8-fold higher accumulation after i.p. administration. Abcb1a/1b;Abcg2(-/-) mice had the most pronounced increase in relative brain accumulation, which was 13.2-fold higher after oral and 22.7-fold increased after i.p. administration. Moreover, coadministration to wild-type mice of dasatinib with the dual P-gp and ABCG2 inhibitor elacridar resulted in a similar dasatinib brain accumulation as observed for Abcb1a/1b;Abcg2(-/-) mice.
Brain accumulation of dasatinib is primarily restricted by P-gp, but Abcg2 can partly take over this protective function at the blood-brain barrier. Consequently, when both transporters are absent or inhibited, brain uptake of dasatinib is highly increased. These findings might be clinically relevant for patients with central nervous system Philadelphia chromosome-positive leukemia, as coadministration of an inhibitor of P-gp and ABCG2 with dasatinib might result in better therapeutic responses in these patients.

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    • "Making use of various in vitro and in vivo models, several groups including ours have recently shown that many TKIs are transported substrates of Abcb1a/1b and/or Abcg2/ABCG2 and that their oral availability is limited by either or both of these systems (Table 2; Chuan et al., 2014; Durmus et al., 2012; Lagas, Vlaming, et al., 2009; Marchetti et al., 2008; Mittapalli, et al., 2013; Poller et al., 2011). Lagas, van Waterschoot, et al. (2009) found that Abcb1a/1b, but not Abcg2, limits oral uptake of dasatinib. "
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    • "P-gp in the blood–brain barrier protects the brain against the entry of toxic compounds. Its presence in the intestinal epithelium reduces the uptake of substrates from the intestinal lumen and mediates their direct excretion from the bloodstream (Lagas et al., 2009; van Waterschoot et al., 2009). "
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