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Pharmacokinetic and pharmacodynamic studies of anti-hypertensive agents and its interactions.

抗高血压药物的药代动力学和药效学及其相互作用的研究。

基本信息

批准号：
10672096
负责人：
SATO Shinji
金额：
$ 1.54万
依托单位：
Niigata College of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

It has been recognized that the blood pressure is always regulated by various blood pressure regulation systems. The treatment by the anti-hypertensive agents is required for the hypertensive patients who have the dysfunction of the blood pressure regulation systems. The establishment of the quantitative relationship between pharmacokinetics (PK) and pharmacodynamics (PD) of anti-hypertensive agents is very important to manage the optimal therapeutic response with the minimum adverse reactions. However, the enlargement of the plasma norepinephrine (NE) concentrations by the excitement of sympathetic nervous systems is induced by the hypotension after the administration of the anti-hypertensive agents. The purpose of the present study is to develop the PK-PD model for carvedilol (CVL) with the fluctuation of the plasma norepinephrine concentrations in the spontaneous hypertension rats, and to examine whether the constructed PK-PD model can be established the quantitative relationship be … More tween PK and PD of CVL.In order to construct PK-PD model with the excitement of sympathetic nervous systems, it is necessary to clarify the relationship between the pharmacokinetics and the hypertensive response of NE.The time course of plasma NE concentrations could be described by a two-compartment model included the linear and non-linear elimination kinetics, and the hypertensive response of NE could be described by the Emax model. The time courses of plasma CVL concentrations could be described by a two-compartment model with the linear elimination kinetics. The plasma NE concentrations during the infusion of CVL were increased with the enlargement of the infusion rates of CVL, and these time courses of the plasma NE concentrations could be described by the blood pressure regulation model in which the production rate for the endogenous plasma NE concentrations is increased by the decreasing of the blood pressure. The hypotensive effect of CVL could be described by the sigmoid Emax model which included the constructed blood pressure regulation model. Less

人们已经认识到，血压总是受到各种血压调节系统的调节。对于血压调节系统功能障碍的高血压患者，需要进行抗高血压药物治疗。建立抗高血压药物药代动力学（PK）和药效学（PD）之间的定量关系对于以最小的不良反应获得最佳的治疗反应非常重要。然而，服用抗高血压药后，低血压会引起交感神经系统兴奋，导致血浆去甲肾上腺素（NE）浓度升高。本研究的目的是建立卡维地洛（CVL）随自发性高血压大鼠血浆去甲肾上腺素浓度波动的PK-PD模型，并检验所构建的PK-PD模型能否建立CVL的PK与PD之间的定量关系。阐明了NE的药代动力学与高血压反应之间的关系。血浆NE浓度的时间过程可以用线性和非线性消除动力学的二室模型来描述，NE的高血压反应可以用Emax模型来描述。血浆 CVL 浓度的时间进程可以通过具有线性消除动力学的两室模型来描述。 CVL输注期间血浆NE浓度随着CVL输注速率的增大而增加，并且血浆NE浓度的这些时间过程可以通过血压调节模型来描述，其中内源性血浆NE浓度的产生速率随着血压的降低而增加。 CVL的降血压作用可以通过S形Emax模型来描述，该模型包括所构建的血压调节模型。较少的