| Project/Area Number |
62570961
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Physical pharmacy
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| Research Institution | Tokyo University |
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Principal Investigator |
SUGIYAMA Yuichi Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Associated Professor, 薬学部・製剤学, 助教授 (80090471)
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| Co-Investigator(Kenkyū-buntansha) |
SAWADA Yasufumi Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Instructor, 薬学部・製剤学, 助手 (80114502)
IGA Tatsuji Department of Medicine, Associated Professor, 医学部・薬剤部, 助教授 (60012663)
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| Project Period (FY) |
1987 – 1988
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| Project Status |
Completed (Fiscal Year 1988)
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| Budget Amount *help |
¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1988: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 1987: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | epidermal growth factor / biologically active peptide / receptor / down-regulation / -endorphine / clearance / ベータエンドルフィン / クリアランス / エンドサイトーシス / ファーマコキネティクス |
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| Research Abstract |
Pharmacokinetics of biologically active popypeptide hormones, beta-endorphine(EP) and epidermal growth factor(EGF) have been analyzed using in vitro isolated cell system, perfused organ system and in vivo condition.
Kinetio analysis of the plasma disappearance curve and tissue uptake of iodine labeled EP in vivo has revealed the specific binding of the peptide in the lung and liver of the rats.
Kinetic analysis of the tissue distribution of human EGF in rats was also performed in vivo, and the following results were obatained. 1)The uptake of EGF by the liver, kidney and small intestine showed clear saturation, which may represent the receptor-dependent uptake mechanism. 2)The hepatic uptake of EGF at low dose was so rapid that the uptake rate is limited by the hepatic plasma flow rate. 3)Inthe whole animal, the bulk of the removal of EGF from the circulation was accounted for by the hepatic clearance. We then analyzed the hepatic handling of EGF by the multiple indicator dilution method ( a liver perfusion method), and obtained the parameters representing the interaction of EGF with the liver cell surface receptors. Comparison of the parameters thus obtained with those determined using isolated hepatocytes has shown that only the on-rate constant(K_<on>) was different depending on the experimental system. Unstirred water layer which may exsist in the interstitial space of the liver could be a cause for this discrepancy. Finally, based on a physiological pharmacokinetic model which incorporated thus obtained kinetic parameters, simulations of the time profiles of plasma concentrations of EGF and the surface receptors of the liver were carried out, and the importance of down-regulation of hepatic receptors to its overall kinetics has been brought out.
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