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Intestinal Drug Absorption and Excretion-Detoxication Using Regulation of Membrane Permeation by Oligopeptide-produced Neutrophils

Research Project

Project/Area Number 11672280
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 応用薬理学・医療系薬学
Research InstitutionSchool of Pharmacy, Tokyo University of Pharmacy and Life Science (2000)
Tokyo University of Science (1999)

Principal Investigator

HAYASHI Masahiro  School of Pharmacy, Tokyo University of Pharmacy and Life Science, Professor, 薬学部, 教授 (20012669)

Co-Investigator(Kenkyū-buntansha) TOMITA Mikio  School of Pharmacy, Tokyo University of Pharmacy and Life Science, Assist.Prof., 薬学部, 講師 (60207610)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥2,400,000 (Direct Cost: ¥2,400,000)
Keywordsoligopeptide / neutrophil / active oxygen compounds / hydrogen peroxide / paracellular pathway / tight junction / absorption enhancer / P-glycoprotein / Caco-2細胞
Research Abstract

Formyl-methionyl-leucyl-phenylalanine which is produced by bacteria stimulates neutrophils and enlarges paracellular pathway, tight junction (TJ), suggesting that the oligopeptide can be an endogenous absorption enhancer. In the first year, we examined the enhancing action of the active oxygen compound which is produced by neutrophils, hydrogen peroxide, using changes in permeability (Pm) of the paracellular permeant compounds, FITC-dextran 4000 (FD-4) and the transepithelial electric resistance (Rm) in rat jejunum, ileum and colon.
Hydrogen peroxide reduces Rm and increases Pm in all absorption sites, indicating the enlargement of TJ.These actions are remarkable in jejunum and ileum, and greater in the mucosal side than in the serosal side. In addition to hydrogen peroxide, O_2^- and OH^- were found to participate the TJ opening mechanism.
In the second year, the effects of hydrogen peroxide were examined using human colon adrenocarcinoma (Caco-2). Also in Caco-2 cells, hydrogen peroxide decreases Rm and the action is more remarkable in the apical side than in the basal side, indicating that hydrogen peroxide has the same action in Caco-2 and the rat intestine. Further, the effects of hydrogen peroxide on the transcellular pathway were examined from the functional changes in P-glycoprotein (P-gp) which has the secretory action of the substrates from the cell to lumen. The transport of Rhodamine 123, which is a substrate of P-gp, from mucosal to serosal direction was increased but that of the reverse direction was decreased, indicating the reduction of P-gp function.
The analysis of production process of hydrogen peroxide by neutrophils, the participation of immunological cell, and the application of oligopeptide to the oral dosage formulation remained to be unresolved.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] M.Tomita,M.Hayashi,S.Awazu et al.: "Physiological Mechanism for Enhancement of Paracellular Drug Transport"J.Controlled Release. 62. 141-148 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tomita,S.Awazu et al.: "Polarized Transport Was Observed Not in Hydrophilic Compounds But in Caco-2 Cell Monolayers"Biol.Pharm.Bull.. 22(3). 330-331 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tomita,M.J.Menconi,R.L.Delude,M.P.Fink,: "Polarized Transport of Hydrophilic Compounds across Rat Colonic Mucosa from Serosa to Mucosa Is Temperature Dependent."Gastroenterology. 118. 535-543 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tofukuji,M.Tomita,M.P.Fink et al.: "Mesenteric Dysfunction after Cardiopulmonary Bypass : Role of Complement C5a."Annals of Thoracic Surgery. 69(3). 799-807 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] H.Kumagai,H.Tomioka,M.Hayashi: "Physiological Assessment of Epithelial Function in Damaged Colon."Colorectal Disease. 2. 77-83 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tomita,M.Nagira,M.Hayashi et al.: "Assessment Using Caco-2 Cell Monolayers for Barrier Dysfunction of Epithelial Cell during Ischemia/Reperfusion."Organ Biology. 7(4). 87-94 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 富田幹雄,林正弘: "今日のDDS・薬物送達システム"(株)医薬ジャーナル社. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 富田幹雄,林正弘: "バイオミメオティックスハンドブック"(株)エヌ・ティーエス. 1139 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Hayashi, M.Tomita, S.Awazu et al.: "Physiological Mechanism for Enhancement of Paracellular Drug Transport."J.Controlled Release. 62. 141-148 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tomita, S.Awazu et al.: "Polarized Transport Was Observed Not in Hydrophilic Compounds But in Dextran in Caco-2 Cell Monolayers."Biol.Pharm.Bull.. 22(3). 330-331 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tomita, M.J., Menconi, R.L.Delude, M.P.Fink: "Polarized Transport port of Hydrophilic Compounds across Rat Colonic Mucosa from Serosa to Mucosa Is Temperature Dependent."Gastroenterology. 118. 535-543 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tokufuji, M.Tomita, M.P.Fink et al.: "Mesentric Dysfunction after Cardiopulmonary Bypass : Role of Complement C5a."Annnals of Thoracic Surgery. 69(3). 779-807 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] H.Kumagai, H.Tomioka, M.Hayashi: "Physiological Assessment of Epithelial Function in Damaged Colon."Colorectal Disease. 2. 77-83 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tomita, M.Nagira, M.Hayashi: "Assessment Using Caco-2 Cell Monolayers for Barrier Dysfunction of Epithelial Cell during Ischemia/Reperfusion."Organ Biology. 7(4). 87-94 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tomita, M.Hayashi: "Drug Delivery System Ed.By T.Takahashi & M.Hashida, IYAKU JOURNAL-SHA Co.Ltd."Improvement of Membrane Permeability and New Adminstration Route : DDS by Oral Route.. (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tomita, M.Hayashi: "Handbook of Biomimetics Ed.Y.Osada, N・TS Co.Ltd."Gastrointestine : Intestinal Drug Absorption and Its Improvement. (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Tomita et al.,: "Mesenteric dysfunction after cardiopulmonary bypass : Role of complement C5a"Annals of Thoracic Surgery. 69(3). 799-807 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Tomita,M.Hayashi et al.,: "Assessment using Caco-2 cell monolayers for barrier dysfunction of epithelial cells during ischemia/reperfusion"Organ Biology. 7(4). 87-94 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 富田幹雄,林正弘: "バイオミメティックスハンドブック"(株)エヌティーエス. 1139 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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