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Development of drug delivery systems for cytokines with an aim of efficient exertion of their pharmacological effect

Research Project

Project/Area Number 06557132
Research Category

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

Allocation TypeSingle-year Grants
Research Field 医薬分子機能学
Research InstitutionFaculty of Pharmaceutical Sciences, University of Tokyo

Principal Investigator

SUGIYAMA Yuichi  University of Tokyo, Faculty of Pharmaceutical Sciences Professor, 薬学部, 教授 (80090471)

Co-Investigator(Kenkyū-buntansha) NAMIKI Mitsuo  Pharmaceutical Company, Central Research Center, Senior Research Associate, 総合研究所, 副主任研究員
YAMANAKA Masami  Teikyo University, Faculty of Medicine, Professor, 医学部, 教授 (20082109)
NAKAMURA Toshikazu  Osaka University, Faculty of Medicine, Professor, 医学部, 教授 (00049397)
KATO Yukio  University of Tokyo, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 助手 (30251440)
TERASAKI Tetsuya  University of Tokyo, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助教授 (60155463)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥9,700,000 (Direct Cost: ¥9,700,000)
Fiscal Year 1995: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1994: ¥7,000,000 (Direct Cost: ¥7,000,000)
KeywordsCytokine / Polypeptide / Growth Factor / Pharmacokinetics / Drug delivery system / Clearance / Epidermal growth factor / Hepatocyte growth factor
Research Abstract

In this year, we atte mpted to clarify the elimination mechanism of hepatocyte growth factor (HGF), which is expected to be developed as a treatment for certain types of liver diseases, and to develop its drug delivery system considering its elimination mechanism. In addition, we also investigated the clearance mechanism for granulocyte-colony stimulating factor (G-CSF) analog, which is now developed as a treatment for bone suppression during cancer chemotherapy. To characterize the clearance mechanism of HGF,we examined its pharmacokinetics in rats after partial hepatectomy. Based on the findings in both in vivo and perfused liver system, we demonstrate that both receptor-mediated endocytosis and the other nonspecific uptake mechanism in the liver contribute to the over all disposition of HGF.Furthermore, in the liver-diseased conditions such as partial hepatectomy, HGF clearance via the former mechanism is dramatically downregulated while that via the latter mechanism is maintained a … More t the normal level (K.Liu et al.Am.j.Physiol., 269 : G1-G9,1995). The latter clearance mechanism, which is presumably the uptake of HGF by cell-surface heparin-like substance, is found out not only a the liver parenchymal cells (hepatocytes), but also at the non-parenchymal cells. The nonspecific uptake at the non-parenchymal cells contributs to the HGF disposition especially at the higher dose, which results in the pharmacological action of HGF (Ke-Xin Liu et al.Pharm.Res.12 : 1737-1740,1995). To suppress such a nonspecific elimination, HGF was incubated with heparin to form heparin-HGF complex, and subsequently administered into the ANIT-treated rats. Several marker enzyme levels for the livery injury (such as GOT,GPT,ALP,and LAP) were dramatically decreased after the administration of such heparin-HGF complex, compared with those values after the administration of HGF alone. Plasma clearance of HGF after the injection of complex was much lower than that after the injection of HGF alone, suggesting that this heparin-HGF complex can be a candidate for the drug delivery system for HGF (In preparation for submission to journal). However, stimulation of DNA synthesis in the liver, assessed by the labeling index technique, was comparable between for the heparin-HGF complex and HGF alone, implying that further studies are required for the adequate drug delivery system for HGF.Based on the pharmacokinetic analysis of the G-CSF analog, we found out that not the liver nor the kidney, but the bone marrow is the major clearance organ for G-CSF analog (T.Kuwabara et al.Am.J.Physiol., 269 : E1-E9,1995 ; T.Kuwabara et al.J.Pharmacol.Exp.Ther., 273 : 1114-1122,1995). Less

Report

(3 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (33 results)

All Other

All Publications (33 results)

  • [Publications] Y. Kato: "Heparin-hepatocyte growth factor(HGF) complex with low plasma clearance and retained hepatocyte proliferating activity." Hepatology. 20. 417-424 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T. Kuwabara: "Non-linear pharmacokinetics of the recombinant Granulocyte colony-stimulating factor Nartograstim: Species differences among rats, monkeys and humans." J. Pharmacol. Exp. Therap.271. 1535-1543 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 加藤将夫: "レセプターを標的としたDDS: キャリアの特徴と評価" Drug Delivery System. 38. 387-395 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K. Liu: "Change in hepatic handling of hepatocyte growth factor during liver tregeneration in rats." Am. J. Physiol.269. G1-G9 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K. Liu: "Contribution of parenchymal and non-parenchymal cells in the liver to the clearance of hepatocyte growth factor from the circulation in rats." Pharm. Res.12. 1737-1740 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Kuwabara: "Receptor-mediated clearance of G-CSF deribvative nartograstim in bone marrow of rats." Am. J. Physiol.269. E1-E9 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T. Kuwabara: "Saturble uptake of a recombinant human granulocyte colony-stimulating factor derivative, nartogarstim, by the bone marrow and spleen of rats in vivo." J. Pharmacol. Exp. Ther.273. 1114-1122 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T. Kuwabara: "Renal clearance of a recombinant granulocyte colony-stimulating factor, nartograstim, in rats." Pharm. Res.12. 1466-1469 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y. Kato: "Kinetic analysis of receptor-mediated endocytosis(RME) of proteins and peptides: Use of RME as a drug delivery system." J. Controlled Release. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 清田剛: "DDS研究の進歩III" バイオメディカル社(矢内原 昇編), 14 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Sugiyama: "Proceeding of 1993 FIP Taipei Post-Congress Symposium: Recent Development in Transdermal and Advanced Drug Delivery" Marcel Dekker, Inc., 24 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Sugiyama: "Peptide based drug design: Controlling transport and metabolism"" ACS Books, 26 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Kato, K.Liu, T.Nakamura and Y.Sugiyama: "Heparin-hepatocyte growth factor (HGF) complex with low plasma clearance and retained hepatocyte proliferating activity." Hepatology. 20. 417-424 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Kuwabara, Y.Kato, S.Kobayashi, H.Suzuki and Y.Sugiyama: "Non-linear pharmacokinetics of the recombinant Granulocyte colony-stimulating factor Nartograstim : Species differences among rats, monkeys and humans." J.Pharmacol.Exp.Therap.271. 1535-1543 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Kato and Y.Sugiyama : DDS targeted to receptors: "Characleristics and assessment of carriers." Drug Delivery System. 38. 387-395 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K.Liu, Y.Kato, T.Terasaki, T.Nakamura and Y.Sugiyama: "Change in hepatic handling of hepatocyte growth factor during liver tregeneration in rats." Am.J.Physiol. (Gastrointest.Liver Physiol.%, Pt.1) 269. G1-G9 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ke-Xin Liu, Y.Kato, T.Terasaki, K.Okumura, T.Nakamura and Y.Sugiyama: "Contribution of parenchymal and non-parenchymal cells in the liver to the clearance of hepatocyte growth factor from the circulation in rats." Pharm.Res.12 (11). 1737-1740 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Kuwabara, T.Uchimura, H.Kobayashi, S.Kobayashi and Y.Sugiyama: "Receptor-mediated clearance of G-CSF deribvative nartograstim in bone marrow of rats." Am.J.Physiol.269 (Endocrino.Metab.32). E1-E9 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Kuwabara, T.Uchimura, K.Takai, H.Kobayashi, S.Kobayashi and Y.Sugiyama: "Saturable uptake of a recombinant human granulocyte colony-stimulating factor derivative, nartograstim, by the bone marrow and spleen of rats in vivo." J.Pharmacol.Exp.Ther.273. 1114-1122 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Kuwabara, Y.Ishikawa, H.Kobayashi, S.Kobayashi and Y.Sugiyama: "Renal clearance of a recombinant granulocyte colony-stimulating factor, nartograstim, in rats." Pharm.Res.12. 1466-1469 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Kato, T.Seita, T.Kuwabara, and Y.Sugiyama: "Kinetic analysis of receptor-mediated endocytosis (RME) of proteins and peptides : Use of RME as a drug delivery system." J.Controlled Release, in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Seita, D.Nakai, T.Tetsuya, K.Koken, H.Tada, s.Iwasa and Y.Sugiyama: Hepatic Delivery of antisense DNA utitlizing asialoglycoprotein receptor : Experimental approach aiming at the development of optimum carriers. Progress in Drug Delivery System III,Shizuoka DDS symposium, N.Yanaihara ed. Biomedical Co., Tokyo, 29-42 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Sugiyama and Y.Kato: Pharmacokinetic aspects of peptide delivery and targeting : Importance of receptor-mdediated endocytosis. Drug Development and Industrial Pharmacy Vol 20, No 4. Marcel Dekker, Inc., 591-614 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Sugiyama and Y.Kato: In vitro models of hepatic clearance : Methods to determine the kinetic parameters for receptor-mediated hepatic clearance. in "Peptide based drug design : Controlling Transport and metabolism"ed.by M.D.Taylor and G.Amidon. ACS Books, Washington, DC., 525-551 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ke-Xin Liu: "Change in hepatic handling of hepatocyte growth factor during liver regeneration in rats." American Journal of Physiology. 269. G745-G753 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ke-Xin Liu: "Contribution of parenchymal and non-parenchymal liver cells to the clearance of hepatocyte growth factor from the circulation in rats." Pharmaceutical Research. 12. 1737-1740 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takashi Kuwabara: "Saturable uptake of a recombinant human granulocyte colony-stimulating factor derivative, nartograstim, by the bone marrow and spleen of rats in vivo." Journal of Pharmacology and Experimental Therapeutics. 273. 1114-1122 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takashi Kuwabara: "Receptor-mediated clearance of G-CSF deribvative nartograstim in bone marrow of rats." American Journal of Physiology. 269. E1-E9 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takashi Kuwabara: "Renal clearance of a recombinant granulocyte colony-stimulating factor, nartograstim, in rats." Pharmaceutical Research. (印刷中).

    • Related Report
      1995 Annual Research Report
  • [Publications] Yukio Kato: "Kinetic analysis of receptor-mediated endocytosis(RME) of proteins and peptides: Use of RME as a drug delivery system." Journal of Controlled Release. (印刷中).

    • Related Report
      1995 Annual Research Report
  • [Publications] Yukio Kato: "Heparin-hepatocyte growth factor complex with low plasma clearance and retained hepatocyte proliferating activity." Hepatology. 20. 417-424 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yuichi Sugiyama: "Pharmacokinetic aspects of peptide delivery and targeting:Importance of receptor-mediated endocytosis." Drug Development and Industrial Pharmacy. 20. 591-614 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yuichi Sugiyama: "Invitro models of hepatic clearance:Methods to determine the kinetic parameters for receptor-mediated hepatic uptake.In: “Peptide-Based Drug Design:Controlling Transport and Metabolism,"" American Chemical Society Books Department, 印刷中

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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