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

精神药物体内受体占有率与脑葡萄糖利用变化的定量关系

• 批准号: 63571017
• 负责人: SAWADA Yasufumi
• 金额: $ 1.28万
• 依托单位: Tokyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1988
• 资助国家: 日本
• 起止时间: 1988 至 1989
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-63571017/
• 关键词: Benzodiazepine; clonazepam; deoxyglucose; glucose; zolpidem; metabolism; brain; デオキシグルコース; グルコース

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

为了评价苯二氮卓类（BZP）的药理作用和清醒小鼠大脑中BZP受体结合之间的关系，测量葡萄糖利用（GU）对氯硝西泮（CNZ）或唑吡坦的反应作为药理作用的指标。通过同时使用[14C]2-脱氧葡萄糖（2DG）进行测量，[14C]2-脱氧葡萄糖（2DG）是一种可以在大脑中磷酸化的葡萄糖类似物，并且[3H]3-0-甲基葡萄糖（3MG），不可代谢的葡萄糖类似物，未磷酸化的2DG在脑中的分布体积与3MG（VM）没有显着差异，表明2DG的磷酸化率可以通过减去来估计。根据 2DG 的表观分布体积，通过这种双示踪剂技术，可以在施用药理学和示踪剂后 10 分钟内确定 GU。同位素校正因子（集总常数）的病理生理变化也可以通过这种技术来估计。 在静脉注射 CNZ（0.005-1.0 mg/kg）后 60 分钟，大脑皮层中的 GU 下降至 70-80%，服用苯二氮卓类拮抗剂 Ro-15-1788 (5 mg/kg) 后，这种作用被完全减弱。CNZ 对的作用最大。在 0.1 mg/kg 的 CNZ 浓度下发现 GU（约减少 30%），但将剂量增加至 1 mg/kg 时，使用 [3H]Ro-15-1788 测量的体内 BZP 受体占用率却增加了。在ID50的剂量反应曲线中，从0.005mg/kg剂量时的小于10%到1mg/kg或更大剂量时的基本上100%。 GU减少时CNZ和ED50的受体占有率分别为0.3 mg/kg和0.007 mg/kg，在受体占有率和葡萄糖代谢率的反应之间观察到非线性和双曲线关系，表明BZP发挥作用。在唑吡坦中，通过使用正电子发射也获得了在低受体占有率（30-40%）下的最大葡萄糖代谢变化。断层扫描，这些技术可以应用于活体人脑，这使得在有效的治疗药物监测中确定BZP的最佳剂量成为可能。

项目成果

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)

Hitoshi Ishizuka：“体内小鼠大脑中苯二氮卓受体占据与葡萄糖代谢反应之间的非线性关系”《药理学与实验治疗学杂志》。

Measurement of cerebral glucose utilization from brain uptake of [14C]2-deoxyglucose and [3H]3-O-methylglucose in the mouse.

测量小鼠大脑摄取[14C]2-脱氧葡萄糖和[3H]3-O-甲基葡萄糖的脑葡萄糖利用率。

• DOI: 10.1016/0160-5402(90)90040-r
• 发表时间: 1990-04-01
• 期刊: Journal of pharmacological methods
• 作者: Ito Kiyomi;Sawada Yasufumi;I. Hitoshi;Sugiyama Yūichi;Suzuki Hiroshi;I. Tatsuji;Hanano Manabu
• 通讯作者: Hanano Manabu

沢田康文: "薬による脳の探究" 南山堂, 296 (1989)

泽田康文：“通过药物探索大脑” Nanzando，296 (1989)

石塚一志: 薬物動態. 3. 566-567 (1988)

石冢一史：药代动力学。3. 566-567 (1988)

Kiyomi Ito: "Measurment of cerebral glucose utilization from brain uptake of 〔^C〕^2-deoxyglucose and 〔^3H〕-3-0-methylglucose in the mouse" Journal of Pharmacological Methods.

Kiyomi Ito：“通过小鼠大脑摄取〔^<14>C〕^2-脱氧葡萄糖和〔^3H〕-3-0-甲基葡萄糖来测量脑葡萄糖利用率”药理学方法杂志。