Brain Accumulation of Dasatinib Is Restricted by P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) and Can Be Enhanced by Elacridar Treatment
ABSTRACT 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.
- SourceAvailable from: Yong-Long Han
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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). "
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; DOI:10.1016/j.taap.2013.06.002 · 3.63 Impact Factor
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- "Along these lines, pre-clinical studies and clinical trials are currently ongoing to evaluate the combination of anticancer drugs with EGFR TKIs to improve therapeutic outcome in cancer patients (Milano et al., 2008). It should also be mentioned that several studies have shown that the brain concentrations of TKIs such as imatinib (Breedveld et al., 2005, 2006; Kun-Eek et al., 2007), gefitinib (Heimberger et al., 2002), and lapatinib (Lagas et al., 2009; Polli et al., 2008) were relatively low. This could now be explained by the fact that these are substrates of P-gp and ABCG2, which are present abundantly at the BBB. "
ABSTRACT: Tyrosine kinases (TKs) are involved in key signaling events/pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Deregulated activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to inhibit specific kinases whose constitutive activity results in specific cancer types. These TKIs have been found to demonstrate effective anticancer activity and some of them have been approved by the Food and Drug Administration for clinical use or are in clinical trials. However, these targeted therapeutic agents are also transported by ATP-binding cassette (ABC) transporters, resulting in altered pharmacokinetics or development of resistance to these drugs in cancer patients. This review covers the recent findings on the interactions of clinically important TKIs with ABC drug transporters. Future research efforts in the development of novel TKIs with specific targets, seeking improved activity, should consider these underlying causes of resistance to TKIs in cancer cells.Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 02/2012; 15(1-2):70-80. DOI:10.1016/j.drup.2012.01.005 · 8.82 Impact Factor
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- "Moreover, dasatinib brain concentrations were considerably higher in P-glycoproteindeficient Abcb1a/1b knockout mice, but not in Bcrpdeficient mice compared with wild-type mice (Chen et al., 2009; Lagas et al., 2009). Interestingly, Abcb1a/1b Abcg2 knockout mice accumulated considerably more dasatinib in the brain compared with Abcb1a/1b knockout mice, indicating that Bcrp can partly take over P-glycoprotein function in the absence of P-glycoprotein (Chen et al., 2009; Lagas et al., 2009). "
ABSTRACT: Multiple new small molecules such as tyrosine kinase, mammalian target of rapamycin (mTOR) and proteasome inhibitors have been approved in the last decade and are a considerable progress for cancer therapy. Drug transporters are important determinants of drug concentrations in the systemic circulation. Moreover, expression of drug transporters in blood-tissue barriers (e.g. blood-brain barrier) can limit access of small molecules to the tumour (e.g. brain tumour). Finally, transporter expression and (up)regulation in the tumour itself is known to affect local drug concentrations in the tumour tissue contributing to multidrug resistance observed for multiple anticancer agents. This review summarizes the current knowledge on: (i) small molecules as substrates of uptake and efflux transporters; (ii) the impact of transporter deficiency in knockout mouse models on plasma and tissue concentrations; (iii) small molecules as inhibitors of uptake and efflux transporters with possible consequences for drug-drug interactions and the reversal of multidrug resistance; and (iv) on clinical studies investigating the association of polymorphisms in genes encoding drug transporters with pharmacokinetics, outcome and toxicity during treatment with the small molecules.British Journal of Pharmacology 08/2011; 165(2):345-62. DOI:10.1111/j.1476-5381.2011.01618.x · 4.99 Impact Factor