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Membrane Permeability and Its Improvement in Intestinal Absorption of Macromolecular Drugs

Research Project

Project/Area Number 03671103
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field 応用薬理学・医療系薬学
Research InstitutionFaculty of Pharmaceutical Sciences, Science University of Tokyo (1992-1993)
Tokyo University of Pharmacy and Life Science (1991)

Principal Investigator

HAYASHI Masahiro  Faculty of Pharmaceutical Sciences, Sci.Univ.of Tokyo Professor, 薬学部, 教授 (20012669)

Co-Investigator(Kenkyū-buntansha) MIZUMA Takashi  Faculty of Pharmaceutical Sciences, Tokyo Coll.of Pharmacy (Associate Professor), 薬学部, 講師 (80229715)
HORIE Toshiharu  Faculty of Pharmaceutical Sciences, Chiba Univ. Professor, 薬学部, 教授 (90120154)
TOMITA Mikio  Faculty of Pharmaceutical Sciences, Tokyo Coll.of Pharmacy (Research Associate), 薬学部, 助手 (60207610)
KAIHO Fusao  Faculty of Pharmaceutical Sciences, Sci.Univ.of Tokyo (Research Associate), 薬学部, 助手 (10120180)
Project Period (FY) 1991 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1993: ¥200,000 (Direct Cost: ¥200,000)
Fiscal Year 1992: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1991: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsAbsorption Enhancer / Paracellular Pathway / Polypeptide / Actomyosin / Caco-2 Cells / Caprate / Peyer's Patches / Adsorptive Endocytosis / カルモジュリン / 高分子ペプチド / 細胞間隙 / 空腸 / M細胞 / Caco‐2細胞 / 結腸 / 細胞内経路 / 高分子量物質 / インピ-ダンス解析
Research Abstract

To improve the absorbability of macromolecular compounds such as polypeptides, enhancement of the paracellular transport by absorption enhancer was examined. In rat jejunum and colon, caprate (C10) induced reduction of junctional resistance and increase in menmbrane capacitance, and increased FD4K permeability, indicating C10 to be an effective paracellular enhancer. The C10 effect was inhibited by calmodulin inhibitor W7, suggesting that the effect relates to calmodulin-dependent contraction of perijunctional actomyosin. The above effects were also observed in human colon carcinoma cell lines (Caco-2). In Caco-2 cells, C10 also increased the intracellular Ca^<2+> level and W7 suppressed the increasing effect, suggesting that increase in Ca^<2+> level relates to contraction of actomyosin. Absorption of peptides across Peyer's patches (PP) was examined. More bovine serum albumin (BSA) and concanavalin A (ConA) were transported across PP than jejunal epithelium. Especially, ConA was suggested to bind to mannose binding sites on membrane surface of M cell in PP and then tranported by adsorptive endocytosis. When BSA is conjugated with ConA, the transport was observed to be increased. Preparation of PP-target microspheres including BSA or ConA is now under investigation.
In summary, in this study, useful information on the improvement of intestinal absorption of macromolecule compounds was obtained from effective application of C10 as theparacellular enhancer and PP as the absorption site.

Report

(4 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • 1992 Annual Research Report
  • 1991 Annual Research Report
  • Research Products

    (22 results)

All Other

All Publications (22 results)

  • [Publications] Toyohiro Sawada et al.: "Role of Paracellular Pathway in Nonelectrolyte Permeation across Rat Colon Epithelium Enhanced by Sodium Caprate and Sodium Caprylate" Pharmaceutical Research. 8. 1365-1371 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 林 正弘: "イオン形薬物の腸管膜透過機構" 表面. 30. 22-31 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Mikio Tomita et al.: "Differences in the Enhancing Effects of Sodium Caprate on Colonic and Jejunal Drug Absorption" Pharmaceutical Research. 9. 648-653 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 林 正弘: "薬物の腸管吸収を制御する生理解剖学的要因およびその修飾による吸収改善" 薬物動態. 11. 621-631 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Shingo Haseto et al.: "Transport of Low and High Molecular Peptides across Rabbit Peyer's Patches" Pharmaceutical Research. 11. 361-364 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Mikio Tomita et al.: "Comparison of Absorption-enhancing Effects between Sodium Caprate and Ethylenediaminetetraacetate in Caco-2 Cells" Biological & Pharmaceutical Bulletin. 17(in press). (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 林 正弘: "続医薬品の開発 第4巻 薬物の生体膜輸送と組織標的化I(寺田弘,辻彰 編集)" 廣川書店, 327 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masahiro Hayashi: "Current Status on Targeted Drug Delivery to The Gastrointestinal Tract" Capusugel Library, 201 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Toyohiro Sawada et al.: "Role of Paracellular Pathway in Nonelectrolyte Permeation across Rat Colon Epithelium Enhanced by Sodium Caprate and Sodium Caprylate" Pharm.Res. 8(11). 1365-1371 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Msahiro Hayashi: "Mechanism of Intestinal Membrane Permeation of Ionic Drugs" Hyomen. 30(1). 22-31 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Mikio Tomita et al.: "Differences in the Enhancing Effects of Sodium Caprate on Colonic and Jejunal Drug Absorption" Pharm.Res. 9(5). 648-653 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masahiro Hayashi: "Physiological and Anatomical Factors Affecting Intestinal Drug Absorption and Absorption Enhancement by Modifying Their Factors" Xenobio.Metabol.and Dispos. 11(5). 621-631 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Shingo Haseto et al.: "Transport of Low and High Molecular Peptides across Rabbit Peyer's Patches" Pharm.Res. 11(3). 361-364 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Mikio Tomita et al.: "Comparison of Absorption-enhancing Effects between Sodium Caprate and Disodium Ethylenediaminetetraacetate in Caco-2 Cells" Biol.Pharm.Bull.17(in press). (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masahiro Hayashi: Paracellular Transport. The Second Series of Pharmaceutical Research and Development-23 Volumes, Volume 4, Biomembrane Transport and Targeting of Drugs Ed. by Hirosi Terada and Akira Tsuji. Hirokawa Publishing Company, 197-209 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masahiro Hayashi: Strategies to Improve Intestinal Membrane Transport of Poorly Absorbed Drugs and Peptides. Current Status on Targeted Drug Delivery to The Gastrointestinal Tract. Capsugel Library, 151-160 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Shingo Haseto et al.: "Transport of Low and High Molecular Peptides across Rabbit Peyer´s Patches" Pharmaceutical Research. 11. 361-364 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Mikio Tomita et al.: "Comparison of Absorption-enhancing Effects between Sodium Caprate and Disodium Ethylenediaminetetraacetate in Caco-2 Cells" Biological & Pharmaceutical Bulletin. 17 in press. (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Masahiro Hayashi: "Current Status on Targeted Drug Delivery to The Gastro-intestinal Tract" Capsugel Library, 201 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] M. Tomita, T. Sawada, T. Ogawa, H. Ouchi, M. Hayashi, and S. Awazu: "Differences in the Enhancing Effects of Sodium Caprate on Colonic and Jejunal Drug Absorption" Pharmaceutical Research. 9. 648-653 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 林 正弘: "薬物の腸管吸収を制御する生理解剖学的要因およびその修飾による吸収改善" 薬物動態. 7. 621-631 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] T.Sawada,T.Ogawa,M.Tomita,M.Hayashi,and S.Awazu: "Role of Paracellular Pathway in Nonelectrolyte Permeation across Rat Colon Epithelium Enhanced by Sodium Caprate and Sodium Caprylate" Pharmaceutical Research. 8. 1365-1371 (1991)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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