Abstract
The novel tyrosine kinase inhibitor dasatinib (Sprycel; BMS-354825) is approved for use in imatinib (Gleevec; STI 571)-resistant or -intolerant chronic myelogenous leukemia and may be useful for other tumors in the central nervous system (CNS). The objective of this study was to investigate the role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in modulating the CNS penetration of dasatinib. Results from the in vitro studies indicate that cellular delivery of dasatinib is significantly limited by active efflux due to both P-gp and BCRP. Permeability studies indicated greater permeability in the basolateral-to-apical direction than in the apical-to-basolateral direction due to active efflux by P-gp or BCRP. Selective inhibitors of P-gp and BCRP, such as (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo-(a,e)cyclopropa(c) cycloheptan-6-yl)-α-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride (zosuquidar; LY335979) and 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12α-octahydropyrazino1′,2′: 1,6pryrido3,4-bindol-3-yl)-propionic acid tert-butyl ester (Ko143), were able to restore the intracellular accumulation and abolish the directionality in net flux of dasatinib. In vivo brain distribution studies showed that the CNS distribution of dasatinib is limited, with the brain-to-plasma concentration ratios less than 0.12 in wild-type mice, which increased approximately 8-fold in Mdr1a/b(-/-) Bcrp1(-/-) mice. Dasatinib brain distribution was significantly increased in Mdr1a/b(-/-) mice and when wild-type mice were pretreated with LY335979. Simultaneous inhibition of P-gp and BCRP by elacridar [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] (GF120918) resulted in a 5-fold increase in brain concentration. These in vitro and in vivo studies demonstrate that dasatinib is a substrate for the important efflux transporters p-glycoprotein and BCRP. These transport systems play a significant role in limiting the CNS delivery of dasatinib and may have direct implications in the treatment of primary and metastatic brain tumors.
Footnotes
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This work was supported by a grant from the Leukemia Research Fund to the University of Minnesota.
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This work was originally presented at the 15th North American Regional ISSX Meeting; October 12–16, 2008; San Diego, CA. Abstracts. Chen Y, Shaik NM, Yang Z, Chen C, and Elmquist WF (2008) ABCB1 and ABCG2 mediated transport and brain distribution of dasatinib. Drug Metab Rev 40 (Suppl 3): 1–308.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.109.154781.
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ABBREVIATIONS: CML, chronic myelogenous leukemia; TKI, tyrosine kinase inhibitor; BCR, breakpoint cluster region; ABL, Abelson; CNS, central nervous system; ALL, acute lymphoblastic leukemia; Ph, Philadelphia chromosome; BBB, blood-brain barrier; P-gp, P-glycoprotein; BCRP, breast cancer resistance protein; BMS-354825 (dasatinib), N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide; LY335979 (zosuquidar), (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo-(a,e)cyclopropa(c) cycloheptan-6-yl)-α-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride; Ko143, 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12α-octahydropyrazino1′,2′:1,6pryrido3,4-bindol-3-yl)-propionic acid tert-butyl ester; GF120918 (elacridar), N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; MDCK, Madin-Darby canine kidney; WT, wild type; A-to-B, apical-to-basolateral; B-to-A, basolateral-to-apical; Mdr, multidrug resistance protein; Peff, effective permeability; ER, efflux ratio; LC-MS/MS, liquid chromatography-tandem mass spectrometry; IS, internal standard; B/P, brain-to-plasma.
- Received April 7, 2009.
- Accepted June 1, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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