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Quantitative relationship between in vivo receptor occupancy of psychotropic and the change of glucose utilization in brain

Research Project

Project/Area Number 63571017
Research Category

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

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

Principal Investigator

SAWADA Yasufumi  Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Instructor, 薬学部, 助手 (80114502)

Co-Investigator(Kenkyū-buntansha) SUGIYAMA Yuichi  Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Associated Prof, 薬学部, 助教授 (80090471)
Project Period (FY) 1988 – 1989
Project Status Completed (Fiscal Year 1989)
Budget Amount *help
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1989: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1988: ¥1,300,000 (Direct Cost: ¥1,300,000)
KeywordsBenzodiazepine / clonazepam / deoxyglucose / glucose / zolpidem / metabolism / brain / デオキシグルコース / グルコース
Research Abstract

To evaluate the relationship between the pharmacological effect of benzodiazepine (BZP) and BZP receptor binding in the conscious mouse brain, a response of the glucose utilization (GU) to clonazepam (CNZ) or zolpidem was measured as an index for the pharmacological effect. GU was measured by the simultaneous use of [14C]2-deoxyglucose (2DG), the glucose analogue which can be phosphorylated in the brain, and [3H]3-0-methylglucose (3MG), the nonmetabolizable glucose analogue. The distribution volume of unphosphorylated 2DG in the brain was not significantly different from that of 3MG (VM), indicating that the phosphorylation rate of 2DG can be estimated by subtracting VM from apparent volume of distribution of 2DG. By this double tracer technique, it is possible to determine GU within 10 min after administration of both tracers. Pharmacological and pathophysiological changes of the isotope correction factor (lumped constant) can also be estimated by this technique.
In the cerebral cortex … More , GU decreased to 70-80 % at 60 min after i.v. administration of CNZ (0.005-1.0 mg/kg), and this effect was completely diminished by the administration of a benzodiazepine antagonist, Ro-15-1788 (5 mg/kg). The maximum effect of CNZ on GU (about 30 % decrease) was found at 0.1 mg/kg of CNZ, but increasing the dose to 1 mg/kg bad very little additional effect. In vivo BZP receptor occupancy, measured using [3H]Ro-15-1788, increased from less than 10 % at a dose of 0.005 mg/kg up to essentially 100 % at doses of 1 mg/kg or greater. ID50 in dose response curve of the receptor occupancy for CNZ and ED50 in that of decrease in GU were 0.3 mg/kg and 0.007 mg/kg, respectively. A nonlinear and hyperbolic relationship was observed between the receptor occupancy and the response for the glucose metabolic rate, indicating that BZP exerts the maximum glucose metabolic change at a low fractional receptor occupancy (30-40%). In zolpidem similar results were also obtained. By using positron emission tomography, these techniques can be applied to living human brain, which makes it possible to determine the optimal doses of BZP in the effective therapeutic drug monitoring. Less

Report

(3 results)
  • 1989 Annual Research Report   Final Research Report Summary
  • 1988 Annual Research Report
  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] 伊東清美: "マウスにおける脳内グルコ-ス利用率算出のためのダブルラベル法" 薬物動態. 3. 564-565 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 石塚一志: "Clonazepamの中枢作用の指標としての脳内グルコ-ス利用率の変化" 薬物動態. 3. 566-567 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 沢田康文: "向精神薬・レセプタ-相互作用の局所脳グルコ-ス代謝に及ぼす効果" 神経精神薬理. 11. 391-411 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Hitoshi Ishizuka: "Nonlinear relationship between benzodiazepine receptor occupancy and glucose metabolic response in the conscions mouse brain in vivo" The Journal of Pharmacology and Experimental Therapeutics. 251. 362-367 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Kiyomi Ito: "Measurment of cerebral glucose utilization from brain uptake of 〔^<14>C〕^2-deoxyglucose and 〔^3H〕-3-0-methylglucose in the mouse" Journal of Pharmacological Methods.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 沢田康文: "薬による脳の探究" 南山堂, 296 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] K.Ito: "Double label method for estimation of glucose utilization in the mouse brain" Xenobiotic Metabolism and Disposition 3 : 564-565 (1988).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] H.Ishizuka: "Glucose utilization as an pharmacological of clonazepam in the central nervous system" Xenobiotic Metabolism and Disposition 3 : 566-567 (1988).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] H.Ishizuka: "Nonlinear relationship between receptor occupancy and glucose metabolic response in the conscious mouse brain in vivo" J.Pharmacol.Exp.Ther.251 : 362-367 (1989).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] K.Ito: "Measurement of cerebral glucose utilization from brain uptake of [^<14>C]2-deoxyglucose and [^3H]3-O-methylglucose in the mouse" J.Pharmacol.Methods (1990).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Y.Sawada: "Effect of psychotropic drug-receptor interaction on the regional cerebral glucose utilization" Jap.J.Neuropsychopharmacol.11 : 391-411 (1989).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Y.Sawada: "Pharmacologic research of in vivo brain function" Nanzando Company Limited, Tokyo P.1-P.296 (1989).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Hitoshi Ishizuka: "Nonlinear relationship between benzodiazepine receptor occupancy and glucose metabolic response in the conscions mouse brain in vivo" The Journal of Pharmacology and Experimental Therapeutics. 251. 362-367 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Kiyomi Ito: "Measurement of cerebral glucose utilization from brain uptake of〔^<14>C〕^<2-> deoxyglucose and〔^3H〕-3-0-methylglucose in the mouse" Journal of Pharmacological Methods.

    • Related Report
      1989 Annual Research Report
  • [Publications] 沢田康文: "薬による脳の探究" 南山堂, 296 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] 伊藤清美: 薬物動態. 3. 564-565 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] 石塚一志: 薬物動態. 3. 566-567 (1988)

    • Related Report
      1988 Annual Research Report

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Published: 1988-04-01   Modified: 2016-04-21  

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