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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Mechanism of Pluronic Effect on P-Glycoprotein Efflux System in Blood-Brain Barrier: Contributions of Energy Depletion and Membrane Fluidization

Elena V. Batrakova, Shu Li, Sergey V. Vinogradov, Valery Yu Alakhov, Donald W. Miller and Alexander V. Kabanov
Journal of Pharmacology and Experimental Therapeutics November 2001, 299 (2) 483-493;
Elena V. Batrakova
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Shu Li
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Sergey V. Vinogradov
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Valery Yu Alakhov
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Donald W. Miller
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Alexander V. Kabanov
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Abstract

Pluronic block copolymer, P85, inhibits the P-glycoprotein (Pgp) drug efflux system and increases the permeability of a broad spectrum of drugs in the blood-brain barrier (BBB). This study examines the mechanisms by which P85 inhibits Pgp using bovine brain microvessel endothelial cells (BBMEC) as an in vitro model of the BBB. The hypothesis was that simultaneous alterations in intracellular ATP levels and membrane fluidization in BBMEC monolayers by P85 results in inhibition of the drug efflux system. The methods included the use of 1) standard Pgp substrate rhodamine 123 to assay the Pgp efflux system in BBMEC, 2) luciferin/luciferase assay for ATP intracellular levels, and 3) 1,6-diphenyl-1,3,5-hexatriene for membrane microviscosity. Using3H-labeled P85 and fluorescein-labeled P85 for confocal microscopy, this study suggests that P85 accumulates in the cells and intracellular organelles such as the mitochondria where it can interfere with metabolic processes. Following exposure of BBMEC to P85, the ATP levels were depleted, and microviscosity of the cell membranes was decreased. Furthermore, P85 treatment decreased Pgp ATPase activity in membranes expressing human Pgp. A combination of experiments examining the kinetics, concentration dependence, and directionality of P85 effects on Pgp-mediated efflux in BBMEC monolayers suggests that both energy depletion (decreasing ATP pool available for Pgp) and membrane fluidization (inhibiting Pgp ATPase activity) are critical factors contributing to the activity of the block copolymer in the BBB.

Footnotes

  • This study was supported by National Institutes of Health Grant RO1 NS366229-01-A1 (A.V.K.) and RO3 A617294-01 (D.W.M.).

  • Abbreviations:
    BBB
    blood-brain barrier
    Pgp
    P-glycoprotein
    BBMEC
    bovine brain microvessel endothelial cells
    P85
    Pluronic P85
    FITC
    fluorescein isothiocyanate
    PBS
    phosphate-buffered saline
    R123
    rhodamine 123
    MES
    4-morpholineethanesulfonic acid
    DPH
    1,6-diphenyl-1,3,5-hexatriene
    AP
    apical
    BL
    basolateral
    CMC
    critical micelle concentration
    • Received May 31, 2001.
    • Accepted July 26, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 2
1 Nov 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Mechanism of Pluronic Effect on P-Glycoprotein Efflux System in Blood-Brain Barrier: Contributions of Energy Depletion and Membrane Fluidization

Elena V. Batrakova, Shu Li, Sergey V. Vinogradov, Valery Yu Alakhov, Donald W. Miller and Alexander V. Kabanov
Journal of Pharmacology and Experimental Therapeutics November 1, 2001, 299 (2) 483-493;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Mechanism of Pluronic Effect on P-Glycoprotein Efflux System in Blood-Brain Barrier: Contributions of Energy Depletion and Membrane Fluidization

Elena V. Batrakova, Shu Li, Sergey V. Vinogradov, Valery Yu Alakhov, Donald W. Miller and Alexander V. Kabanov
Journal of Pharmacology and Experimental Therapeutics November 1, 2001, 299 (2) 483-493;
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