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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Distribution of Gefitinib to the Brain Is Limited by P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2)-Mediated Active Efflux

Sagar Agarwal, Ramola Sane, Jose L. Gallardo, John R. Ohlfest and William F. Elmquist
Journal of Pharmacology and Experimental Therapeutics July 2010, 334 (1) 147-155; DOI: https://doi.org/10.1124/jpet.110.167601
Sagar Agarwal
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Ramola Sane
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Jose L. Gallardo
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John R. Ohlfest
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William F. Elmquist
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Abstract

Gefitinib is an orally active inhibitor of the epidermal growth factor receptor approved for use in patients with locally advanced or metastatic non–small cell lung cancer. It has also been evaluated in several clinical trials for treatment of brain tumors such as high-grade glioma. In this study, we investigated the influence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) on distribution of gefitinib to the central nervous system. In vitro studies conducted in Madin-Darby canine kidney II cells indicate that both P-gp and BCRP effectively transport gefitinib, limiting its intracellular accumulation. In vivo studies demonstrated that transport of gefitinib across the blood-brain barrier (BBB) is significantly limited. Steady-state brain-to-plasma (B/P) concentration ratios were 70-fold higher in the Mdr1a/b(−/−) Bcrp1(−/−) mice (ratio of approximately 7) compared with wild-type mice (ratio of approximately 0.1). The B/P ratio after oral administration increased significantly when gefitinib was coadministered with the dual P-gp and BCRP inhibitor elacridar. We investigated the integrity of tight junctions in the Mdr1a/b(−/−) Bcrp1(−/−) mice and found no difference in the brain inulin and sucrose space between the wild-type and Mdr1a/b(−/−) Bcrp1(−/−) mice. This suggested that the dramatic enhancement in the brain distribution of gefitinib is not due to a leakier BBB in these mice. These results show that brain distribution of gefitinib is restricted due to active efflux by P-gp and BCRP. This finding is of clinical significance for therapy in brain tumors such as glioma, where concurrent administration of a dual inhibitor such as elacridar can increase delivery and thus enhance efficacy of gefitinib.

Footnotes

  • This work was supported in part by National Institutes of Health National Cancer Institute [Grant CA138437] (to W.F.E. and J.R.O.) and the Children's Cancer Research Fund at the University of Minnesota (to W.F.E, J.R.O). Financial support for S.A. was provided by the Edward G. Rippie Fellowship and the Ronald J. Sawchuk Fellowship in Pharmacokinetics from the Department of Pharmaceutics, University of Minnesota.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.167601.

  • ABBREVIATIONS:

    CNS
    central nervous system
    BBB
    blood-brain-barrier
    MDR1
    multi-drug resistance protein 1
    P-gp
    P-glycoprotein
    BCRP
    breast cancer resistance protein
    A-to-B
    apical-to-basolateral
    B-to-A
    basolateral-to-apical
    Peff
    effective permeability
    B/P
    brain-to-plasma
    ER
    efflux ratio
    GBM
    glioblastoma multiforme
    EGFR
    epidermal growth factor receptor
    EGFRvIII
    epidermal growth factor receptor mutant vIII
    Mdr1
    gene encoding the murine P-glycoprotein
    MDR1
    gene encoding the human P-glycoprotein
    Bcrp1
    gene encoding the murine breast cancer resistance protein
    MS
    mass spectrometry
    ZD1839
    gefitinib
    ABC
    ATP-binding cassette
    GF120918 (elacridar)
    N-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide]
    MDCKII
    Madin-Darby canine kidney II
    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-piperazine ethanol, trihydrochloride
    Ko143
    (3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino(1',2':1,6) pyrido(3,4-b)indole-3-propanoic acid 1,1-dimethylethyl ester
    WT
    wild type
    DMSO
    dimethyl sulfoxide
    FVB
    Friend Leukemia Virus Strain B.

  • Received February 23, 2010.
  • Accepted April 23, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Distribution of Gefitinib to the Brain Is Limited by P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2)-Mediated Active Efflux

Sagar Agarwal, Ramola Sane, Jose L. Gallardo, John R. Ohlfest and William F. Elmquist
Journal of Pharmacology and Experimental Therapeutics July 1, 2010, 334 (1) 147-155; DOI: https://doi.org/10.1124/jpet.110.167601

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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Distribution of Gefitinib to the Brain Is Limited by P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2)-Mediated Active Efflux

Sagar Agarwal, Ramola Sane, Jose L. Gallardo, John R. Ohlfest and William F. Elmquist
Journal of Pharmacology and Experimental Therapeutics July 1, 2010, 334 (1) 147-155; DOI: https://doi.org/10.1124/jpet.110.167601
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