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Research ArticleArticle

Quantitative Investigation of the Impact of P-Glycoprotein Inhibition on Drug Transport across Blood-Brain Barrier in Rats

Hiroshi Sugimoto, Hideki Hirabayashi, Yoshiaki Kimura, Atsutoshi Furuta, Nobuyuki Amano and Toshiya Moriwaki
Drug Metabolism and Disposition January 2011, 39 (1) 8-14; DOI: https://doi.org/10.1124/dmd.110.035774
Hiroshi Sugimoto
Discovery Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan
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Hideki Hirabayashi
Discovery Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan
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Yoshiaki Kimura
Discovery Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan
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Atsutoshi Furuta
Discovery Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan
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Nobuyuki Amano
Discovery Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan
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Toshiya Moriwaki
Discovery Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan
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Abstract

The magnitude of P-glycoprotein [(P-gp)/multidrug resistance protein 1 (MDR1)]-mediated drug-drug interaction (DDI) at the blood-brain barrier (BBB) in rats was estimated by in vitro-in vivo correlation (IVIVC). In in vitro studies, rat Mdr1a-expressing LLC-PK1 cells were examined for the evaluation of P-gp inhibitory activity using digoxin as a P-gp probe substrate. The in vitro Ki value was calculated using a modified corrected flux ratio that reflects the P-gp function. In in vivo studies, digoxin with or without P-gp inhibitors was administered to rats by constant intravenous infusion to evaluate the effect of P-gp inhibition on digoxin transport to the brain under steady-state conditions. In the presence of elacridar, the brain-to-plasma concentration ratio (Kp,brain) of digoxin was approximately 14 times the control value. However, no significant change in the Kp,brain was observed in the presence of clinically used P-gp inhibitors, with the exception of cyclosporine A. A positive correlation was found between the in vivo Kp,brain of digoxin and [I,unbound/Ki] (where I,unbound is the unbound plasma concentration of P-gp inhibitors). Compounds with [I,unbound/Ki] values of >1 increased Kp,brain of digoxin in rats. In summary, we used a quantitative approach to evaluate the impact of P-gp-mediated DDI at the rat BBB. We successfully established the IVIVC, which indicated the potential DDI in the presence of potent P-gp inhibitors. On the basis of the IVIVC in rats and Ki values in human MDR1, we speculated that clinically used P-gp inhibitors do not cause DDI at the human BBB, because none of the compounds studied showed [I,unbound/Ki] values of >1 at therapeutic doses.

Footnotes

    • Received August 6, 2010.
    • Accepted October 20, 2010.
  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.035774.

  • ABBREVIATIONS:

    P-gp
    P-glycoprotein
    BBB
    blood-brain barrier
    DDI
    drug-drug interaction
    IVIVC
    in vitro-in vivo correlation
    CFR
    corrected flux ratio
    FR
    flux ratio
    MDR1
    multidrug resistance protein 1
    MCFR
    modified corrected flux ratio
    I,unbound
    unbound plasma concentration of P-gp inhibitors
    LY
    lucifer yellow
    UFLC
    ultrafast liquid chromatograph
    LC/MS/MS
    liquid chromatography with triple quad mass spectrometric detection
    MS/MS
    tandem mass spectrometry
    MS
    mass spectrometry
    Kp,brain
    brain-to-plasma concentration ratio
    OATP
    organic anion transport peptide.

  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (1)
Drug Metabolism and Disposition
Vol. 39, Issue 1
1 Jan 2011
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Research ArticleArticle

Quantitative Investigation of the Impact of P-Glycoprotein Inhibition on Drug Transport across Blood-Brain Barrier in Rats

Hiroshi Sugimoto, Hideki Hirabayashi, Yoshiaki Kimura, Atsutoshi Furuta, Nobuyuki Amano and Toshiya Moriwaki
Drug Metabolism and Disposition January 1, 2011, 39 (1) 8-14; DOI: https://doi.org/10.1124/dmd.110.035774

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Research ArticleArticle

Quantitative Investigation of the Impact of P-Glycoprotein Inhibition on Drug Transport across Blood-Brain Barrier in Rats

Hiroshi Sugimoto, Hideki Hirabayashi, Yoshiaki Kimura, Atsutoshi Furuta, Nobuyuki Amano and Toshiya Moriwaki
Drug Metabolism and Disposition January 1, 2011, 39 (1) 8-14; DOI: https://doi.org/10.1124/dmd.110.035774
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