P-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinib.
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)-alpha-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride (zosuquidar; LY335979) and 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12alpha-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.
Chen
Ying
Y
Department of Pharmaceutics, University of Minnesota, 308 Harvard St. SE, Minneapolis, MN 55455, USA.
Agarwal
Sagar
S
Shaik
Naveed M
NM
Chen
Cliff
C
Yang
Zheng
Z
Elmquist
William F
WF
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000493:pharmacokinetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D002463:Cell Membrane Permeability; D000069439:Dasatinib; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004285:Dogs; D019008:Drug Resistance, Neoplasm; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D011804:Quinolines / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics; D013844:Thiazoles / Q000493:pharmacokinetics*; D014747:Vinblastine / Q000493:pharmacokinetics
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000166:Acridines; D000972:Antineoplastic Agents, Phytogenic; D003986:Dibenzocycloheptenes; D007202:Indicators and Reagents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D044005:Tetrahydroisoquinolines; D013844:Thiazoles; D014747:Vinblastine; C095179:zosuquidar trihydrochloride; C095122:multidrug resistance protein 3; C083501:Elacridar; D000069439:Dasatinib