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Development of novel systems for evaluation and prediction of drug inteactions based on the reconstruction of drug excretion systems in vitro.

Research Project

Project/Area Number 09557211
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 応用薬理学・医療系薬学
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

INUI Ken-ichi  Graduate School of Medicine, KYOTO UNIVERSITY, Professor, 医学研究科, 教授 (70034030)

Co-Investigator(Kenkyū-buntansha) KATSURA Toshiga  Graduate School of Medicine, KYOTO UNIVERSITY, Research Associate, 医学研究科, 助手 (10283615)
SAITO Hideyuki  Graduate School of Medicine, KYOTO UNIVERSITY, Lecturer, 医学研究科, 講師 (40225727)
HASHIMOTO Yukiga  Graduate School of Medicine, KYOTO UNIVERSITY, Associate Professor, 医学研究科, 助教授 (90228429)
YANO Ikuko  Graduate School of Medicine, KYOTO UNIVERSITY, Research Associate, 医学研究科, 助手 (50273446)
増田 智先  京都大学, 医学研究科, 助手 (90303825)
奥田 真弘  京都大学, 医学研究科, 助手 (70252426)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 1999: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1998: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1997: ¥6,700,000 (Direct Cost: ¥6,700,000)
Keywordsdrug transport / tubular secretion / organic ahion transporter / organic cation transporter / P-glycoprotein / transfection / Xenopus oocyte / cDNA cloning / 有機カチオントランスポータ / P・糖タンパク質 / アフリカメガユル卵母細胞 / 動物細胞安定発現系 / メトトレキセート / テトラエチルアンモニウム
Research Abstract

We have studied the development of novel systems for evaluation and prediction of drug interactions based on the reconstruction of drug excretion systems in vitro.
First, we cloned and characterized two renal organic anion transporters, OAT1 and OAT-K2. Using X enopus oocyte expression system, OAT1 mediated various organic anion uptake, and the OAT1-mediated p-aminohippuric acid uptake was markedly inhibited in the presence of various anionic diuretics. In addition, OAT-K2 mediated transport of hydrophobic organic anions (Masuda et al., Mol. Pharmacol., 55,743-752,1999).
Second, We have constructed the various transfectants, stably expressing OAT-K1, OAT-K2, renal organic cation transporter OCT1 and OCT2, respectively. The OAT-K1-mediated methotrexate transport was competitively inhibited by nonsteroidal antiinflammatory drugs such as indomethacin and ketoprofen (Masuda et al., J. Pharmacol. Exp. Ther., 283, 1039-1043, 1997), The OCT1-and OCT2-mediated tetraethylammonium uptake was markedly inhibited by various cationic drugs, such as tetraalkylammoniums, antiarrthythmis, endogenous metabolite NィイD11ィエD1-methylnicotinamide and guanidine (Urakami et al., J. Pharmacol. Exp. Ther., 287, 800-805, 1998). In addition, we demonstrated the inhibitory effect of clarithromycin on renal excretion of digoxin via P-glycoprotein (Wakasugi et al., Clin. Ther., 64, 123-128,1998).
These results suggest that the drug transporter expressing systems appeared to be useful for evaluating and predicting the transporter-mediated drug interactions.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Masuda,S.: "Interactions of nonsteroidal anti-inflammatory drugs with rat renal organic anion transporter, OAT-K1"J. Pharmacol. Exp. Ther.. 283. 1039-1042 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Terada,T.: "Interactions of β-lactam antibiotics with histidine residue of rat H+/peptide cotransporters, PEPT1 and PEPT2"J. Biol. Chem.. 273. 5582-5585 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Urakami,Y.: "Functional characteristics and membrane localization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs"J. Pharmacol. Exp. Ther.. 287. 800-805 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Uwai,Y.: "Functional characterization of the rat multispecific organic anion transporter OAT1 mediating basolateral uptake of anionic drugs in the kidney"FEBS Lett.. 438. 321-324 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Wakasugi,H.: "Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein"Clin. Pharmacol. Ther.. 64. 123-128 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Masuda,S.: "Cloning and functional characterization of a new multispecific organic anion transporter, OAT-K2, in rat kidney"Mol. Pharmacol.. 55. 743-752 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Satohiro Masuda et al: "Interactions of nonsteroidal anti-inflammatory drugs with rat renal organic anion transporter, OAT-K1."J. Pharmacol. Exp. Ther.. 283. 1039-1042 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tomohiro Terada et al: "Interaction of β-lactam antibiotics with histidine residue of rat HィイD1+ィエD1/peptide cotransporters, PEPT1 and PEPT2."J. Biol. Chem.. 273. 5582-5585 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yumiko Urakami et al.: "Functional characteristics and membrane localization of rat multispecific organic cation transporters, OCT1 and OCT2, mediating tubular secretion of cationic drugs."J. Pharmacol. Exp. Ther.. 287. 800-805 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yuichi Uwai et al: "Functional characterization of the rat multispecific organic anion transporter OAT1 mediating basolateral uptake of anionic drugs in the kidney."FEBS lett.. 438. 321-324 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hiroko Wakasugi et al.: "Effect of clarithromycin on renal excretion of digoxin : interaction with P-glycoprotein."Clin. Pharmacol. Ther.. 64. 123-128 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Satohiro Masuda et al.: "Cloning and functional characterization of a new multispecific organic anion transporter, OAT-K2, in rat kidney."Mol. Pharmacol.. 55. 743-752 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T.Terada: "The N-terminal Halves of rat H/peptide transporters are responsible for their substrate recognition"Pharm. Res.. 17・1. 15-20 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Y.Urakami: "Gender differences in expression of organic cation transporter OCT2 in rat kidney"FEBS Lett.. 461・3. 339-342 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] J.Nagai: "Inhibitory effect of KW-3902, an adenosine Al receptor antagonist, on paminohippurate transport in OK cells"Biochim. Biophys. Acta. 1419・1. 164-172 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] S.Masuda: "Functional analysis of rat renal organic anion transporter OAT-K1: bidirectional methotrexate transport in apical membrane"FEBS Lett.. 459・1. 128-132 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K.Sawada: "Effects of glibenclamide on glycylsarcosine transport by the rat peptide transporters PEPT1 and PEPT2"Br. J. Pharmacol.. 128・6. 1159-1164 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] T.Terada: "Functional characteristics of basolateral peptide transporter in the human intestinal cell line Caco-2"Am. J. Physiol. 276・6. G1435-G1441 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] S.Masuda: "Cloning and functional characterization of a new multispecific organic anion transporter,OAT-K2 in rat kidney." Mol.Pharmacol.in press (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] M.Okuda: "Molecular mechanisms of organic cation transport in OCT2-expressing Xenopus oocytes." Biochim.Biophys.Acta. 1417・2. 224-231 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] K.Inui: "Cellular and molecular mechanisms of renal tubular secretion of organic anions and cations." Clin.Exp.Nephrol.2・2. 100-108 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Terada: "Interaction of β-lactam antibiotics with histidine residue of rat H_+/peptide cotransporters,PEPT1 and PEPT2." J.Biol.Chem.273-10. 5582-5585 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Y.Urakami: "Functional characteristics and membrane localization of rat multispecific organic cation transporters,OCT1 and OCT2,mediating tubular secretion of cationic drugs." J.Pharmacol Exp.Ther.287・2. 800-805 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Y.Uwai: "Functional characterization of the rat multispecific organic anion transporter OAT1 mediating basolateral uptake of anionic drugs in the kidney." FEBS Lett.438・3. 321-324 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Ito: "Transport of quinolone antibacterial drugs by human P-glycoprotein expressed in a kidney epithelial cell line,LLC-PK_1" J.Pharmacol.Exp.Ther.282(2). 955-960 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] S.Masuda: "Interactions of nonsteroidal anti-inflammatory drugs with rat renal organic anion transporter,OAT-K1" J.Pharmacol.Exp.Ther.283(3). 1039-1042 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] S.Masuda: "mRNA distribution and membrane localization of the OAT-K1 organic anion transporter in rat renal tubules." FEBS Lett.407(2). 127-131 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] J.Nagai: "Inhibition of PAH transport by parathyroid hormone in OK cells : involvement of protein kinase C pathway." Am.J.Physiol.273(5). F674-F679 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] M.Okuda: "Characterization of organic ion transporters involved in renal excretion of xenobiotics." Jpn.J.Physiol.47(S1). S58-S59 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Tomita: "Kinetic analysis of tetraethylammonium transport in the kidney epithelial cell line,LLC-PK_1" Pharm.Res.14(9). 1236-1240 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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