PREDICTION OF DRUG-INDUCED CATALEPSY BASED ON DOPAMINE D1, D2, AND MUSCARINIC ACETYLCHOLINE RECEPTOR OCCUPANCIES

基于多巴胺 D1、D2 和毒蕈碱乙酰胆碱受体占用的药物引起的昏厥的预测

• 批准号: 11470510
• 负责人: IGA Tatsuji
• 金额: $ 5.31万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470510/
• 关键词: PREDICTION OF DRUG-EFFECT; DYNAMIC MODEL; RECEPTOR OCCUPANCIES; PARKINSONISM; DOPAMINE RECEPTOR; MUSCARINIC RECEPTOR; PHARMACODYNAMIC; CATALEPSY; 薬剤性パーキンソニズム; P-糖タンパク質; シクロスポリン; ドンペリドン; L-dopa; パーキンソン病モデルラット; PK; PDモデル

In this study, the relationship between in vivo dopamine Dl and D2 receptor occupancies and catalepsy was investigated to predict the intensity of catalepsy induced by drugs which bound to Dl and D2 receptors nonselectively. Intensities of catalepsy predicted by using this pharmacodynamic model considering the interaction between Dl and D2 receptors overestimated the observed values, suggesting that these drugs had catalepsy-reducing properties as well. Since muscarinic acetylcholine (mACh) receptor antagonists inhibited the induction of catalepsy, the anticholinergic activities of the drugs were investigated. Relationship between mACh receptor occupancy and change in catalepsy was used as the measure of catalepsy-reducing effects of the drugs.After coadministration of domperidone and cyclosporin A, intensity of catalepsy was stronger than that predicted after administration of each drug. It is suggested that changes in permeability of the blood-brain barrier (BBB) to domperidone following exposure to cyclosporin A.In conclusion, the pharmacodynamic model considering Dl , D2, and mACh receptor occupancies and synergism between Dl and D2 receptors may be useful for quantitative prediction of drug-induced catalepsy.

本研究旨在探讨多巴胺D_1和D_2受体在体与僵住症之间的关系，以预测非选择性结合D_1和D_2受体的药物所引起的僵住症的强度。通过使用考虑Dl和D2受体之间的相互作用的该药效学模型预测的僵住症的强度高估了观察到的值，表明这些药物也具有减少僵住症的性质。由于毒蕈碱乙酰胆碱（mACh）受体拮抗剂抑制木僵的诱导，药物的抗胆碱能活性进行了研究。mACh受体结合率与僵住症变化之间的关系被用作药物减轻僵住症作用的量度。多潘立酮和环孢素A联合给药后，僵住症的强度比每种药物给药后预测的更强。结果表明，多潘立酮对环孢素A的血脑屏障通透性发生了变化。结论：考虑D1、D2和mACh受体的占位作用以及D1和D2受体之间的协同作用的药效学模型可能有助于定量预测药物诱导的僵住症。

项目成果

Yamada Y, Matsuyama K, Iga T, et al.: "Kietic analysis of therapeutic dose of β-blockers for angina pectoris based on receptor occupancy theory"Yakugaku Zasshi. 119(7). 495-501 (1999)

Yamada Y、Matsuyama K、Iga T 等：“基于受体占据理论的 β-阻滞剂治疗心绞痛剂量的动力学分析”Yakugaku Zasshi 119(7) (1999)。

Yamada Y, Takayanagi R, Iga T, et al.: "Assessment of systemic adverse reactions induced by ophthalmic β-adrenergic receptor antagonists"J. Ocul. Pharmacol. Ther.. 17(3). 235-248 (2001)

Yamada Y、Takayanagi R、Iga T 等：“眼用 β-肾上腺素受体拮抗剂引起的不良全身反应的评估”J. Ocul. 17(3) (2001)。

Yamada Y,Matsuyama K,Iga T et al.: "Kinetic analysis of β-blockers for angina pectoris based on receptor occupancy theory"Yakugaku.Zasshi. 119・7. 495-501 (1999)

山田Y、松山K、伊贺T等：“基于受体占据理论的β-阻滞剂对心绞痛的动力学分析”Yakugaku 119・7（1999）。

Yamada Y,Takayanagi R,Iga T, et al: "Assessment of Systemic adverse reactions induced by ophthalmic β-adrenergic receptor antagonists"J,Ocul.Pharmacol.Ther,. (in press). (2001)

Yamada Y、Takayanagi R、Iga T 等人：“眼用 β-肾上腺素受体拮抗剂引起的全身不良反应的评估”J，Ocul.Pharmacol.Ther，（2001 年出版）。

YamadaY, Matsuyama K, IgaT, et al.: "Kietic analysis of β-blockers for angina pectoris based onreceptor occupancy theory"Yakugaku Zasshi. 119(7). 495-501 (1999)

YamadaY、Matsuyama K、IgaT 等人：“基于受体占据理论的 β 受体阻滞剂治疗心绞痛的动力学分析”Yakugaku Zasshi 119(7) (1999)。