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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    • "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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    ABSTRACT: Doxorubicin (DOX) is a potent chemotherapy drug with a narrow therapeutic window. Nilotinib, a small-molecule Bcr-Abl tyrosine kinase inhibitor, was reported to reverse multidrug resistance (MDR) mediated by P-Glycoprotein (P-gp) transmembrane transporters. The present study aimed to investigate nilotinib's affection on the steady-state pharmacokinetics, disposition and cardiotoxicity of DOX. A total of 24 male Sprague-Dawley rats were randomized into four groups (6 in each) and received the following regimens: saline, intravenous DOX (5mg/kg) alone, DOX co-administrated with either 20 or 40 mg/kg nilotinib. Blood was withdrawn at 12 time points till 72 h after DOX injection and the concentrations of DOX and its metabolite doxorubicinol (DOXol) in serum and cardiac tissue were assayed by LC-MS-MS method. To determine the cardiotoxicity, the following parameters were investigated: creatine kinase, lactate dehydrogenase, malondialdehyde, and superoxide dismutase. Histopathological examination of heart section were carried to evaluate the extent of cardiotoxicity after treatments. The results showed that pretreatment of 40 mg/kg nilotinib increased the AUC0-t and Cmax of DOX and DOXol. However, their accumulation in cardiac tissue was significantly decreased when compared with the group that received DOX alone. In addition, biochemical and histopathological results showed that 40 mg/kg nilotinib reduced the cardiotoxicity induced by DOX administration. In conclusion, co-administration of nilotinib increased the serum exposure, but significantly decreased cardiac tissue accumulation of DOX. Consistent with in vitro profile, oral dose of 40mg/kg nilotinib significantly decreased the cardiotoxicity of DOX in rat by enhancing the P-gp activity in heart.
    Toxicology and Applied Pharmacology 06/2013; 272(1). DOI:10.1016/j.taap.2013.06.002 · 3.71 Impact Factor
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    • "Our results highlight that THC is a dual substrate for P-gp and Bcrp which is not surprising given the considerable overlap in the substrate specificities of P-gp and Bcrp and that many drugs are transported by both these efflux proteins [17], [18], [19], [32]. THC appears a better substrate for Bcrp than P-gp because Abcg2 (−/−) mice retained higher levels of THC than Abcb1a/b (−/−) mice in the brain at 3 h post-administration. "
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    ABSTRACT: The ABC transporters P-glycoprotein (P-gp, Abcb1) and breast cancer resistance protein (Bcrp, Abcg2) regulate the CNS disposition of many drugs. The main psychoactive constituent of cannabis Δ(9)-tetrahydrocannabinol (THC) has affinity for P-gp and Bcrp, however it is unknown whether these transporters modulate the brain accumulation of THC and its functional effects on the CNS. Here we aim to show that mice devoid of Abcb1 and Abcg2 retain higher brain THC levels and are more sensitive to cannabinoid-induced hypothermia than wild-type (WT) mice. Abcb1a/b (-/-), Abcg2 (-/-) and wild-type (WT) mice were injected with THC before brain and blood were collected and THC concentrations determined. Another cohort of mice was examined for THC-induced hypothermia by measuring rectal body temperature. Brain THC concentrations were higher in both Abcb1a/b (-/-) and Abcg2 (-/-) mice than WT mice. ABC transporter knockout mice exhibited delayed elimination of THC from the brain with the effect being more prominent in Abcg2 (-/-) mice. ABC transporter knockout mice were more sensitive to THC-induced hypothermia compared to WT mice. These results show P-gp and Bcrp prolong the brain disposition and hypothermic effects of THC and offer a novel mechanism for both genetic vulnerability to the psychoactive effects of cannabis and drug interactions between CNS therapies and cannabis.
    PLoS ONE 04/2012; 7(4):e35937. DOI:10.1371/journal.pone.0035937 · 3.23 Impact Factor
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    • "In addition, insufficient drug penetration in the brain and in some part of the tumor may explain these disappointing results. Enhanced delivery would then need either blood to brain barrier opening [74] or P-gp and ABCG2 inhibition [75]. In this respect the DIPG orthotopic models newly described [63], [64] will be valuable tools to study the appropriate way to deliver these drugs in addition to help our understanding of the disease. "
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    PLoS ONE 02/2012; 7(2):e30313. DOI:10.1371/journal.pone.0030313 · 3.23 Impact Factor
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