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Research ArticleMetabolism, Transport, and Pharmacogenomics

Impact of P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) on the Brain Distribution of a Novel BRAF Inhibitor: Vemurafenib (PLX4032)

Rajendar K. Mittapalli, Shruthi Vaidhyanathan, Ramola Sane and William F. Elmquist
Journal of Pharmacology and Experimental Therapeutics July 2012, 342 (1) 33-40; DOI: https://doi.org/10.1124/jpet.112.192195
Rajendar K. Mittapalli
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Shruthi Vaidhyanathan
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Ramola Sane
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William F. Elmquist
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Abstract

Vemurafenib [N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide(PLX4032)] is a novel small-molecule BRAF inhibitor, recently approved by the Food and Drug Administration for the treatment of patients with metastatic melanoma with a BRAFV600E mutation. The objective of this study was to investigate the role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in the distribution of vemurafenib to the central nervous system. In vitro studies conducted in transfected Madin-Darby canine kidney II cells show that the intracellular accumulation of vemurafenib is significantly restricted because of active efflux by P-gp and BCRP. Bidirectional flux studies indicated greater transport in the basolateral-to-apical direction than the apical-to-basolateral direction because of active efflux by P-gp and BCRP. The selective P-gp and BCRP inhibitors zosuquidar and (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 (Ko143) were able to restore the intracellular accumulation and bidirectional net flux of vemurafenib. The in vivo studies revealed that the brain distribution coefficient (area under the concentration time profile of brain/area under the concentration time profile of plasma) of vemurafenib was 0.004 in wild-type mice. The steady-state brain-to-plasma ratio of vemurafenib was 0.035 ± 0.009 in Mdr1a/b(−/−) mice, 0.009 ± 0.006 in Bcrp1(−/−) mice, and 1.00 ± 0.19 in Mdr1a/b(−/−)Bcrp1(−/−) mice compared with 0.012 ± 0.004 in wild-type mice. These data indicate that the brain distribution of vemurafenib is severely restricted at the blood-brain barrier because of active efflux by both P-gp and BCRP. This finding has important clinical significance given the ongoing trials examining the efficacy of vemurafenib in brain metastases of melanoma.

Footnotes

  • This work was supported in part by the National Institutes of Health National Cancer Institute [Grant CA138437]. Financial support for R.S. was provided by 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.

    http://dx.doi.org/10.1124/jpet.112.192195.

  • ABBREVIATIONS:

    CNS
    central nervous system
    BBB
    blood-brain barrier
    P-gp
    P-glycoprotein
    BCRP
    breast cancer resistance protein
    ABC
    ATP-binding cassette
    MDCKII
    Madin-Darby canine kidney II
    A to B
    apical to basolateral
    B to A
    basolateral to apical
    LY335979
    (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
    PLX4032
    N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide
    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
    PLX4720
    propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]amide
    Papp
    apparent permeability
    FVB
    Friend leukemia virus strain B
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    B/P
    brain to plasma
    AUC
    area under the curve
    WT
    wild type.

  • Received January 17, 2012.
  • Accepted March 26, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 1
1 Jul 2012
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Research ArticleMetabolism, Transport, and Pharmacogenomics

P-gp and Bcrp Restrict Brain Distribution of Vemurafenib

Rajendar K. Mittapalli, Shruthi Vaidhyanathan, Ramola Sane and William F. Elmquist
Journal of Pharmacology and Experimental Therapeutics July 1, 2012, 342 (1) 33-40; DOI: https://doi.org/10.1124/jpet.112.192195

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Research ArticleMetabolism, Transport, and Pharmacogenomics

P-gp and Bcrp Restrict Brain Distribution of Vemurafenib

Rajendar K. Mittapalli, Shruthi Vaidhyanathan, Ramola Sane and William F. Elmquist
Journal of Pharmacology and Experimental Therapeutics July 1, 2012, 342 (1) 33-40; DOI: https://doi.org/10.1124/jpet.112.192195
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