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2013 Fiscal Year Final Research Report

Elucidation of disease-related changes of drug brain distributions based on intrinsic efflux activity and absolute expression level of P-glycoprotein at the brain barrier

Research Project

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Project/Area Number 23790170
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Medical pharmacy
Research InstitutionTohoku University

Principal Investigator

UCHIDA YASUO  東北大学, 薬学研究科(研究院), 助教 (70583590)

Project Period (FY) 2011 – 2013
Keywords血液脳関門 / 病態 / P糖タンパク / 絶対発現量 / 単分子輸送活性 / In vivo機能の再構築 / Caveolin1 / Pharmacoproteomics
Research Abstract

This study aimed to establish a methodology to clarify drug efflux function of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in disease conditions. We experimentally demonstrated that, in the disease which the absolute protein expression level of P-gp changes (epilepsy), the in vivo function of P-gp at the BBB can be reconstructed from in vitro by integrating the efflux activity per one P-gp molecule measured in its overexpressing cell lines and the absolute expression level in isolated brain capillaries. We found that, in the disease condition which the efflux activity per one P-gp molecule changes (inflammatory oxidative stress), the phosphorylation level of caveolin1 Tyr14 is one of the biomarkers to estimate the change of the activity. We also demonstrated the reconstruction of P-gp function in monkeys as well as rodents, and opened the new way to clarify the efflux function of P-gp at the human BBB in diseases from in vitro system.

  • Research Products

    (22 results)

All 2014 2013 2012 2011 Other

All Journal Article (10 results) (of which Peer Reviewed: 6 results) Presentation (10 results) (of which Invited: 3 results) Book (1 results) Remarks (1 results)

  • [Journal Article] Blood–Brain Barrier (BBB) Pharmacoproteomics : A New Research Field Opened Up by Quantitative Targeted Absolute Proteomics (QTAP). Margareta Hammarlund-Udenaes, Elizabeth de Lange and Robert Thorne (Ed.)2014

    • Author(s)
      Y Uchida, M Tachikawa, S Ohtsuki, T Terasaki
    • Journal Title

      Drug Delivery to the Brain. Physiological Concepts, Methodologies and Approaches, Springer, New York

      Pages: 63-100

    • URL

      http://link.springer.com/chapter/10.1007/978-1-4614-9105-7_3

  • [Journal Article] Quantitative atlas of blood-brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset2013

    • Author(s)
      Hoshi Y, Uchida Y, Tachikawa M, Inoue T, Ohtsuki S, Terasaki T
    • Journal Title

      J Pharm Sci

      Volume: 102(9) Pages: 3343-3355

    • DOI

      10.1002/jps.23575

    • Peer Reviewed
  • [Journal Article] A study protocol for quantitative targeted absolute proteomics (QTAP) by LC-MS/MS : application for inter-strain differences in protein expression levels of transporters, receptors, claudin-5, and marker proteins at the blood-brain barrier in ddY, FVB, and C57BL/6J mice2013

    • Author(s)
      Uchida Y, Tachikawa M, Obuchi W, Hoshi Y, Tomioka Y, Ohtsuki S, Terasaki T
    • Journal Title

      Fluids Barriers CNS

      Volume: 10(1) Pages: 21

    • DOI

      10.1186/2045-8118-10-21.

    • Peer Reviewed
  • [Journal Article] 定量的標的プロテオミクス(QTAP)に基づく血液脳関門機能のin vitro再構築2013

    • Author(s)
      内田康雄、立川正憲、寺崎哲也
    • Journal Title

      細胞工学

      Volume: 32(9) Pages: 955-961

    • URL

      http://gakken-mesh.jp/journal/detail/9784780901467.html

  • [Journal Article] 血液脳関門における定量的標的絶対プロテオミクス解析2013

    • Author(s)
      内田康雄、佐藤和貴、黒田広樹、星裕太朗、立川正憲、寺崎哲也
    • Journal Title

      血管医学

      Volume: 14(4) Pages: 56-69

    • URL

      http://www.m-review.co.jp/magazine/detail/J04_14_04

  • [Journal Article] Quantitative proteomics of transporter expression in brain capillary endothelial cells isolated from P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), and P-gp/Bcrp knockout mice2012

    • Author(s)
      Agarwal S, Uchida Y, Mittapalli RK, Sane R, Terasaki T, Elmquist WF
    • Journal Title

      Drug Metab Dispos

      Volume: 40(6) Pages: 1164-1169

    • DOI

      10.1124/dmd.112.044719.

  • [Journal Article] Quantitative membrane protein expression at the blood-brain barrier of adult and younger cynomolgus monkeys2011

    • Author(s)
      Ito K, Uchida Y, Ohtsuki S, Aizawa S, Kawakami H, Katsukura Y, Kamiie J, Terasaki T
    • Journal Title

      J Pharm Sci

      Volume: 100(9) Pages: 3939-3950

    • DOI

      10.1002/jps.22487.

    • Peer Reviewed
  • [Journal Article] Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors2011

    • Author(s)
      Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, Terasaki T
    • Journal Title

      J Neurochem

      Volume: 117(2) Pages: 333-345

    • DOI

      10.1111/j.1471-4159.2011.07208.x.

    • Peer Reviewed
  • [Journal Article] Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels2011

    • Author(s)
      Shawahna R, Uchida Y, Declèves X, Ohtsuki S, Yousif S, Dauchy S, Jacob A, Chassoux F, Daumas-Duport C, Couraud PO, Terasaki T, Scherrmann JM
    • Journal Title

      Mol Pharm

      Volume: 8(4) Pages: 1332-1341

    • DOI

      10.1021/mp200129p.

    • Peer Reviewed
  • [Journal Article] 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 mice2011

    • Author(s)
      Uchida Y, Ohtsuki S, Kamiie J, Terasaki T
    • Journal Title

      J Pharmacol Exp Ther

      Volume: 339(2) Pages: 579-598

    • DOI

      10.1124/jpet.111.184200.

    • Peer Reviewed
  • [Presentation] トランスポーターのタンパク質発現量を考慮したin vitroからの薬物脳移行性の予測2013

    • Author(s)
      内田康雄
    • Organizer
      第36回薬物動態談話会年会
    • Place of Presentation
      オークラアクトシティホテル浜松(浜松)
    • Year and Date
      20131107-08
    • Invited
  • [Presentation] Quantitative proteomics-based investigation of regulatory mechanism for P-glycoprotein efflux activity at the blood-brain barrier in central nervous system disease : epilepsy and inflammation2013

    • Author(s)
      Uchida Y., Hoshi Y., Tachikawa M., Ohtsuki S., Terasaki T
    • Organizer
      日本薬物動態学会第28年会
    • Place of Presentation
      タワーホール船堀(東京都江戸川区).
    • Year and Date
      20131009-11
  • [Presentation] Pharmacoproteomics(PPx)に基づく血液脳関門P-gp・Bcrpの輸送機能の再構築2013

    • Author(s)
      内田康雄、大槻純男、寺崎哲也
    • Organizer
      日本薬剤学会第28年会
    • Place of Presentation
      ウインクあいち(名古屋)
    • Year and Date
      20130523-25
  • [Presentation] 定量的プロテオミクス技術を用いた血液脳関門におけるABCトランスポーターのin vivo輸送機能の再構築2013

    • Author(s)
      内田康雄
    • Organizer
      熊本大学拠点形成研究B主催特別講演会
    • Place of Presentation
      熊本大学(熊本)
    • Year and Date
      2013-12-02
    • Invited
  • [Presentation] In vitro-to-in vivo reconstruction (IVIVR) of brain distribution for dual P-gp and BCRP substrates based on pharmacoproteomic (PPx) approach2012

    • Author(s)
      Uchida Y., Ohtsuki S., Terasaki T
    • Organizer
      日本薬物動態学会第27年会
    • Place of Presentation
      タワーホール船堀(東京都江戸川区)
    • Year and Date
      20121120-22
  • [Presentation] Quantitative targeted absolute proteomics of human, monkey and mouse blood-brain barrier transporters. Human Proteome Organization (HUPO)2012

    • Author(s)
      Uchida Y., Ito K., Ohtsuki S., Katsukura Y., Ikeda C., Suzuki T., Kamiie J., Terasaki T
    • Organizer
      11th Annual World Congress
    • Place of Presentation
      Boston, USA
    • Year and Date
      20120909-13
  • [Presentation] Reconstruction of drug distribution in monkey brain based on absolute quantification of MDR1 expression at blood-brain barrier. Gordon Research Conference2012

    • Author(s)
      Uchida Y., Wakayama K., Ohtsuki S., Ohe T., Chiba M., Ishii Y., Terasaki T
    • Organizer
      Barriers of the CNS
    • Place of Presentation
      New London, USA.
    • Year and Date
      20120617-22
  • [Presentation] Quantitative targeted absolute proteomics (QTAP) based reconstruction of drug resistance mechanism at blood-brain barrier in epileptic model2012

    • Author(s)
      Y Uchida, S Ohtsuki, T Terasaki
    • Organizer
      Network Medicine Winter Camp of GCOE 2012
    • Place of Presentation
      秋保(仙台)
    • Year and Date
      20120204-05
  • [Presentation] IN VITRO-TO-IN VIVO RE-CONSTRUCTION OF BBB DRUG TRANSPORT FUNCTION BASED ON QUANTITATIVE TARGETED ABSOLUTE PROTEOMICS IN A NATURAL MODEL OF EPILEPSY (EL MOUSE)2011

    • Author(s)
      Y Uchida, S Ohtsuki and T Terasaki
    • Organizer
      14th Symposium on Signal Transduction in the Blood Brain Barriers
    • Place of Presentation
      Istanbul, Turkey
    • Year and Date
      20110907-09
  • [Presentation] Reconstruction of Drug Distribution in the Monkey Brain based on the BBB MDR1 Protein Quantification2011

    • Author(s)
      Uchida Y., Wakayama K., Ohtsuki S., Ohe T., Chiba M., Ishii Y., Terasaki T
    • Organizer
      9th Cerebral Vascular Biology, International Meeting
    • Place of Presentation
      Leiden, Netherland
    • Year and Date
      20110621-24
    • Invited
  • [Book] 薬剤学実験法必携マニュアルII2014

    • Author(s)
      内田康雄、立川正憲、南江堂
    • Total Pages
      312-324
    • Publisher
      生物薬剤学
  • [Remarks] 薬物送達学分野研究室ホームページ

    • URL

      http://www.pharm.tohoku.ac.jp/~soutatsu/dds/index.htm

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Published: 2015-06-25  

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