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Research ArticleMetabolism, Transport, and Pharmacogenomics

Blood-Brain Barrier (BBB) Pharmacoproteomics: Reconstruction of In Vivo Brain Distribution of 11 P-Glycoprotein Substrates Based on the BBB Transporter Protein Concentration, In Vitro Intrinsic Transport Activity, and Unbound Fraction in Plasma and Brain in Mice

Yasuo Uchida, Sumio Ohtsuki, Junichi Kamiie and Tetsuya Terasaki
Journal of Pharmacology and Experimental Therapeutics November 2011, 339 (2) 579-588; DOI: https://doi.org/10.1124/jpet.111.184200
Yasuo Uchida
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Sumio Ohtsuki
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Junichi Kamiie
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Tetsuya Terasaki
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Abstract

The purpose of this study was to examine whether in vivo drug distribution to the brain can be reconstructed by integrating P-glycoprotein (P-gp)/mdr1a expression levels, P-gp in vitro activity, and drug unbound fractions in mouse plasma and brain. For 11 P-gp substrates, in vitro P-gp transport activities were determined by measuring transcellular transport across monolayers of mouse P-gp-transfected LLC-PK1 (L-mdr1a) and parental cells. P-gp expression amounts were determined by quantitative targeted absolute proteomics. Unbound drug fractions in plasma and brain were obtained from the literature and by measuring brain slice uptake, respectively. Brain-to-plasma concentration ratios (Kp brain) and its ratios between wild-type and mdr1a/1b(−/−) mice (Kp brain ratio) were obtained from the literature or determined by intravenous constant infusion. Unbound brain-to-plasma concentration ratios (Kp,uu,brain) were estimated from Kp brain and unbound fractions. Based on pharmacokinetic theory, Kp brain ratios were reconstructed from in vitro P-gp transport activities and P-gp expression amounts in L-mdr1a cells and mouse brain capillaries. All reconstructed Kp brain ratios were within a 1.6-fold range of observed values. Kp brain then was reconstructed from the reconstructed Kp brain ratios and unbound fractions. Kp,uu,brain was reconstructed as the reciprocal of the reconstructed Kp brain ratios. For quinidine, loperamide, risperidone, indinavir, dexamethasone, paclitaxel, verapamil, loratadine, and diazepam, the reconstructed Kp brain and Kp,uu,brain agreed with observed and estimated in vivo values within a 3-fold range, respectively. Thus, brain distributions of P-gp substrates can be reconstructed from P-gp expression levels, in vitro activity, and drug unbound fractions.

Footnotes

  • This study was supported in part by Grants-in-Aid for Scientific Research (S) [KAKENHI: 18109002]; the Japan Society for the Promotion of Science (JSPS) Fellows [KAKENHI: 207291] from the JSPS; a Grant-in-Aid for Scientific Research on Priority Area [KAKENHI: 17081002] from The Ministry of Education, Culture, Sports, Science and Technology; and a Grant for Development of Creative Technology Seeds Supporting Program for Creating University Ventures from Japan Science and Technology Agency. This study was also supported in part by the Industrial Technology Research Grant Program from New Energy and the Industrial Technology Development Organization of Japan.

  • T.T. is a full professor and S.O. is an associate professor of Tohoku University, respectively, and are also directors of Proteomedix Frontiers. This research was not supported by Proteomedix Frontiers and their position at Proteomedix Frontiers does not present any financial conflicts.

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

    doi:10.1124/jpet.111.184200.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    CNS
    central nervous system
    BBB
    blood-brain barrier
    bcrp
    breast cancer resistance protein
    ECF
    extracellular fluid
    fu,brain
    unbound fraction in brain
    fu,plasma
    unbound fraction in plasma
    HPLC
    high-performance liquid chromatography
    Kp brain
    brain-to-plasma concentration ratio
    Kp,uu,brain
    unbound brain-to-plasma concentration ratio
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    MDR1
    multidrug resistance protein 1
    mdr1a
    multidrug resistance protein 1a
    MRM
    multiple reaction monitoring
    P-gp
    P-glycoprotein
    PPx
    pharmacoproteomics
    QTAP
    quantitative targeted absolute proteomics
    Papp
    apparent permeability
    oatp2
    organic anion-transporting polypeptide 2
    KO
    knockout
    WT
    wild type
    MDCK
    Madin-Darby canine kidney
    GR205171
    (S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethylamino)-2(S)-phenylpiperidine.

  • Received May 23, 2011.
  • Accepted August 8, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 2
1 Nov 2011
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Reconstruction of In Vivo BBB P-gp Function

Yasuo Uchida, Sumio Ohtsuki, Junichi Kamiie and Tetsuya Terasaki
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 579-588; DOI: https://doi.org/10.1124/jpet.111.184200

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Reconstruction of In Vivo BBB P-gp Function

Yasuo Uchida, Sumio Ohtsuki, Junichi Kamiie and Tetsuya Terasaki
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 579-588; DOI: https://doi.org/10.1124/jpet.111.184200
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