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New strategy for the drug development of CNS acting drugs by regulating drug transport across the blood-brain barrier

Research Project

Project/Area Number 15390035
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Drug development chemistry
Research InstitutionThe University of Tokyo

Principal Investigator

SUGIYAMA Yuichi  The University of Tokyo, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学系研究科, 教授 (80090471)

Co-Investigator(Kenkyū-buntansha) SUZUKI Hiroshi  The University of Tokyo, Hospital, Professor, 医学部附属病院, 教授 (80206523)
KUSUHARA Hiroyuki  The University of Tokyo, Graduate School of Pharmaceutical Sciences, Lecturer, 大学院・薬学系研究科, 講師 (00302612)
MAEDA Kazuya  The University of Tokyo, Graduate School of Pharmaceutical Sciences, Assistant Professor, 大学院・薬学系研究科, 助手 (00345258)
HIRONO Shuichi  Kitasato University, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (30146328)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 2004: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2003: ¥7,400,000 (Direct Cost: ¥7,400,000)
Keywordsblood-brain barrier / transporter / efflux transport / organic anion / pharmacophore / substrate specificity / pharmacophore
Research Abstract

The purpose of the present project was aimed at establishing a rational drug-design to overcome the efflux transport across the blood-brain barrier. In order to realize the goal, the substrate specificity of the efflux transporter was characterized by an in silico approach. Homology modeling predicted the 3-D structure model of rat organic anion transporter 3 using a glycerol transporter from E.Coli as template. In the 3-D structure model, the amino acid residues, which have been suggested to be important for substrate recognition and/or translocation, were found to be located in one region. Furthermore, the pharmacophore model of Oat3 substrates fitted to this arrangement of the amino acid residues, suggesting rationality of the 3-D structure model.
The role of Oat3 in the blood-cerebrospinal fluid barrier was investigated. In addition to benzylpenicillin and p-aminohippurate, it was suggested that Oat3 is involved in the uptake of 2,4-dichlorophenoxyacetate (an organic herbicide) by the choroid plexus. Furthermore, although H_2 receptor antagonists, such as cimetidine, ranitidine and famotidine, are weak or cationic compounds at physiological pH, it was suggested that Oat3 accounts for their uptake by the choroid plexus. Calculation of molecular electrostatic potential of the H_2 receptor antagonists revealed that there is a region showing negative MEP in their chemical structures. This region may be important for the interaction of the H2 receptor antagonists with rOat3. Comparison of the intrinsic parameter revealed the species difference in the transport by rat and human OAT3. Therefore, it is difficult to predict pharmacokinetics in human from animal experiments for some compounds.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (21 results)

All 2005 2004 2003 Other

All Journal Article (17 results) Publications (4 results)

  • [Journal Article] Active Efflux across the Blood-Brain Barrier : Role of the Solute Carrier Family.2005

    • Author(s)
      Kusuhara H, Sugiyama Y
    • Journal Title

      NeuroRx 2

      Pages: 73-85

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Efflux transport systems at the blood-brain barrier and blood-CSF barrier.2005

    • Author(s)
      Kusuhara H, Sugiyama Y
    • Journal Title

      the proceedings : Esteva Foundation Symposium X1 (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Efflux transport systems at the blood-brain barrier and blood-CSF barrier.2005

    • Author(s)
      Kusuhara H, Sugiyama Y
    • Journal Title

      Int Congr Ser 1277

      Pages: 111-122

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Efflux transport systems at the blood-brain barrier and blood-CSF barrier.2005

    • Author(s)
      Kusuhara H, Sugiyama Y
    • Journal Title

      Esteva Foundation Symposium X1 (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Characterization of uremic toxin transport by organic anion transporters in the kidney.2004

    • Author(s)
      Deguchi T., et al.
    • Journal Title

      Kidney Int. 65

      Pages: 162-174

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Quantitative evaluation of the drug-drug interactions between methotrexate and nonsteroidal anti-inflammatory drugs in the renal uptake process based on the contribution of organic anion transporters and reduced folate carrier.2004

    • Author(s)
      Nozaki Y., et al.
    • Journal Title

      J.Pharmacol.Exp.Ther. 309

      Pages: 226-234

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The renal-specific transporter mediates facilitative transport of organic anions at the brush border membrane of mouse renal tubules.2004

    • Author(s)
      Imaoka T., et al.
    • Journal Title

      J Am Soc Nephrol. 15

      Pages: 2012-2022

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Involvement of rat organic anion transporter 3 in the uptake of an organic herbicide, 2,4-dichlorophenoxyacetate, by the isolated rat choroid plexus.2004

    • Author(s)
      Nagata Y., et al.
    • Journal Title

      J Pharm Sci 93

      Pages: 2724-2732

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Carrier-mediated uptake of H2-receptor antagonists by the rat choroid plexus : involvement of rat organic anion transporter 3.2004

    • Author(s)
      Nagata Y., et al.
    • Journal Title

      Drug Metab Dispos. 32

      Pages: 1040-1047

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Characterization of uremic toxin transport by organic anion transporters in the kidney.2004

    • Author(s)
      Deguchi, T., et al.
    • Journal Title

      Kidney Int 65

      Pages: 162-174

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Quantitative evaluation of the drug-drug interactions between methotrexate and nonsteroidal anti-inflammatory drugs in the renal uptake process based on the contribution of organic anion transporters and reduced folate carrier.2004

    • Author(s)
      Nozaki, Y., et al.
    • Journal Title

      J Pharmacol Exp Ther 309

      Pages: 226-234

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The renal-specific transporter mediates facilitative transport of organic anions at the brush border membrane of mouse renal tubules.2004

    • Author(s)
      Imaoka T., et al.
    • Journal Title

      J Am Soc Nephrol 15

      Pages: 2012-2022

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Carrier-mediated uptake of H2-receptor antagonists by the rat choroid plexus involvement of rat organic anion transporter 3.2004

    • Author(s)
      Nagata Y., et al.
    • Journal Title

      Drug Metab Dispos 32

      Pages: 1040-1047

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Impact of drug transporter studies on drug discovery and development2003

    • Author(s)
      Mizuno N., et al.
    • Journal Title

      Pharmacol.Rev. 55

      Pages: 425-461

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ABCG2 transports sulfated conjugates of steroids and xenobiotics2003

    • Author(s)
      Suzuki M., et al.
    • Journal Title

      J Biol Chem. 278

      Pages: 22644-22649

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Impact of drug transporter studies on drug discovery and development.2003

    • Author(s)
      Mizuno, N., et al.
    • Journal Title

      Pharmacol Rev 55

      Pages: 425-461

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ABCG2 transports sulfated conjugates of steroids and xenobiotics2003

    • Author(s)
      Suzuki, M., et al.
    • Journal Title

      J.Biol.Chem 278

      Pages: 22644-22649

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Nozaki Y et al.: "Quantitative Evaluation of the Drug-Drug Interactions between Methotrexate and Nonsteroidal Anti-inflammatory Drugs in the Renal Uptake Process based on the Contribution of Organic Anion Transporters and Reduced Folate Carrier"J Pharmacol Exp Ther. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Deguchi T et al.: "Characterization of uremic toxin transport by organic anion transporters in the kidney"Kidney Int.. 65. 162-174 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Suzuki M et al.: "ABCG2 transports sulfated conjugates of steroids and xenobiotics"J Biol Chem. 278. 22644-22649 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizuno N et al.: "Impact of drug transporter studies on drug discovery and development"Pharmacol Rev. 55. 425-461 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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