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Clarification of transcellular transport mechanism of drugs utilizing tissue cultured cell systems

Research Project

Project/Area Number 04452305
Research Category

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

Allocation TypeSingle-year Grants
Research Field Physical pharmacy
Research InstitutionKanazawa University

Principal Investigator

TSUJI Akira  Kanazawa University, Pharmaceutics, Professor, 薬学部, 教授 (10019664)

Co-Investigator(Kenkyū-buntansha) TAMAI Ikumi  Kanazawa University, Pharmaceutics, Assistant Professor, 薬学部, 講師 (20155237)
TERASAKI Tetsuya  University of Tokyo, Pharmaceutics, Associate Professor, 薬学部, 助教授 (60155463)
Project Period (FY) 1992 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 1993: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1992: ¥4,400,000 (Direct Cost: ¥4,400,000)
KeywordsCaco-2 / Monocarboxylic acid / Proton cotransport / Gene expression / beta-Lactam antibiotics / Brain caillary endothelial cells / Blood-brain barrier / P-Glycoprotein / 培養細胞 / 内皮細胞 / P糖蛋白質 / ビンクリスチン
Research Abstract

Tissue cultured cells, which retain energy-dependent transport and metabolic functions in vivo, are useful as in vitro model to investigate drug transport at the cellular level. The purpose of the present research is to prove, by utilizing proper cultured cell systems, our new hypotheses, which are different from the passive diffusion mechanism for drug transports through the intestinal epithelial cells and brain capillary endothelial cells. The following results including several new findings were obtained :
1)Utilizing cultured human intestinal cell line Caco-2, we have successfully proved that characteristics of the apical to basolateral transepithelial transport of [^<14>C]benzoic acid and[^<14>] salicylic acid in Caco-2 are very similar to those obtained for intestinal brush-border membrane vesicle and that the pH dependent intestinal-absorption of weak-acidic drugs is attributed not to the previously believed "pH-partition theory" but to "protoncoupled and carrier-mediated transpo … More rt" for monocarboxylic acids.
2)A heterologous gene expression system, Xenopus laevis oocytes injected with mRNA from the intestinal mucosa, were used to prove the carrier-mediated transport of beta-lactam amtibiotics in small intestine. As the results, the intestinal transport of zwitterionic and dicarboxylic-acid beta-lactam antibiotics was confirmed to be mediated by a specialized transport system which is common to dipeptides. beta-lactam antibiotics were also to be transported by carrier-mediated mechanisms in rabbits and humans as well as rats.
3)The uptake of [^3H]vincristine (VCR) and [^3H]cyclosporin A(CsA) by cultured monolayrs of bovine brain capillary endothelial cells (BCECs), which express P-glycoprotein (P-gp) at the luminal membrane sruface, was significantly enhanced by treatment of MDR reversing agents, an anti-P-gp monoclonal antibody and metabolic inhibitors. These results indicate that low permeability of VCR and CsA into the brain is caused by the active efflux from BCEC by P-gp and suggest that P-gp functions as blood-brain barrier for lipophilic and cytotoxic comounds. Less

Report

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

    (27 results)

All Other

All Publications (27 results)

  • [Publications] T.Terasaki,et al.: "Absorptive-mediated endocytosis of an adrenocorticotropic hormone(ACTH) analogue,ebiratide,into the blood-brain barrier:Studies with monolayers of primary cultured bovine brain capillary endothelial cells." Pharm.Res.9. 529-534 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 辻 彰: "薬物の血液脳関門透過性" Info Medica. 3. 2-3 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 寺崎哲也,他: "血液脳関門特殊輸送系を利用した脳内ドラッグデリバリー戦略" ファルマシア. 28. 358-362 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 辻 彰: "小腸、脳における薬物の担体介在輸送" TDM研究. 9. 66-72 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Tsuji,et al.: "P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells" Life Sci.51. 1427-1437 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] T.Terasaki,et al.: "Expression of Na^+-dependent uridine transport system of rabbit small intestine:Studies with mRNA-injected Xenopus laevis Oocytes." Biol.Pharm.Bull.16. 493-496 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 寺崎哲也,他: "ペプチド性薬物およびオリゴヌクレオチドの脳へのデリバリー" BIOmedica. 8. 396-400 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 辻 彰: "P-糖蛋白質と血液脳関門(II)" Molecular Medicine. 30. 748-755 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 辻 彰: "薬物の血液脳関門透過性" Physicians' Therapy Manual. 6. 4-6 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Tsuji,et al.: "Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter,P-glycoprotein" Biochem.Pharmacol.46. 1096-1099 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Tsuji,et al.: "Transport mechanism of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors at the blood-brain barrier" J.Pharmacol.Exp.Ther.267. 1085-1090 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Tsuji,et al.: "Transcellular transport of benzoic acid across Caco-2 cells by a pH-dependent and carrier-mediated transport mechanism." Pharm.Res.11. 30-37 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] T.Terasaki, et al: "Absorptive-mediated endocytosis of an adrenocorticotropic hormone(ACTH) analogue, ebiratide, into the blood-brain barrier : Studies with monolayrs of primary cultured bovine brain capillary endothelial cells." Pharm.Res.9. 529-534 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Tsuji: "Blood-brain barrier transport of drugs." Info Medica. 3. 2-3 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] T.Terasaki, et al: "Drug delivery system by using blood-brain barrier specific transport mechanism." Farumashia. 28. 358-362 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Tsuji: "Carrier mediated transport of drugs on small intestine and brain." TDM Research. 9. 66-72 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Tsuji, et al: "P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells." Life Sci.51. 1427-1437 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] T.Terasaki, et al: "Expression of Na^+-dependent uridine transport system of rabbit small intestine : Studies with mRNA-injected Xenopus laevis Oocytes." Biol.Pharm.Bull.16. 493-496 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] T.Terasaki, et al: "Delivery of peptide drug and antisence oligonucleotide to the brain." BIOmedica. 8. 396-400 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Tsuji: "P-glycoprotein and blood-brain barrier (II)" Molecular Medicine. 30. 748-755 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Tsuji: "Blood-brain barrier transport of drugs." Physicians'Therapy Manual. 6. 4-6 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Tsuji, et al: "Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter, P-glycoprotein." Bioachem.Pharmacol.46. 1096-1099 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Tsuji, et al.: "Transport mechanism of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors at the blood-brain barrier." J.Pharm.Exp.Ther.267. 1085-1090 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Tsuji, et al: "Transcellular transport of benzoic acid across Caco-2 cells by a pH-dependent and carrier-mediated transport mechanism." Pharm.Res.11. 30-37 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] A.Saheki, et al: "In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors." Pharm.Res.11. 305-311 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] H.Takanaga, et al: "pH-Dependent and carrier-mediated transport of salicylic acid across Caco-2-cells." J.Pharm, Pharmacol.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Akira Tsuji,etal: "P-Glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells" Life Sciences. 51. 1427-1437 (1992)

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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