微透析作为抗高血压β受体阻滞剂药代动力学-药效学（PK-PD）建模技术的适用性。
Applicability of microdialysis as a technique for pharmacokinetic-pharmacodynamic (PK-PD) modeling of antihypertensive beta-blockers.
作者信息
Höcht Christian, DiVerniero Carla, Opezzo Javier A W, Taira Carlos A
机构信息
Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Batalla de Junín 956, C1113AAD Buenos Aires, Argentina.
出版信息
J Pharmacol Toxicol Methods. 2005 Sep-Oct;52(2):244-50. doi: 10.1016/j.vascn.2005.01.002.
INTRODUCTION
The aim of the present work was to examine microdialysis as a technique for the study of pharmacokinetic-pharmacodynamic modeling of antihypertensive drugs. For this purpose, we studied the antihypertensive and the chronotropic effect of metoprolol and its plasma concentrations in sham operated (SO) and aortic coarctated (ACo) rats at an early hypertensive stage.
METHODS
Plasma metoprolol concentrations were obtained by means of a "shunt" vascular microdialysis probe. Changes in mean arterial pressure and heart rate were also measured in the same experiment.
RESULTS
A rapid decay of metoprolol levels was observed in both experimental groups. For the chronotropic effect, a good association between plasma levels and the chronotropic effect was observed in SO and ACo rats. ACo rats had a greater sensitivity to the chronotropic effect (Emax:-38+/-2%, n=5, p<0.05) than SO animals (Emax:-27+/-1%, n=5). A delay in the blood pressure reduction induced by metoprolol was observed in both experimental groups. A good association was observed between concentrations of metoprolol in the effect compartment and the corresponding hypotensive effect in both experimental groups. The calculated PK-PD parameters were not different between SO and ACo groups.
DISCUSSION
A good correlation was found between metoprolol concentration and its chronotropic and antihypertensive effects in normotensive and ACo hypertensive rats, allowing the employment of PK-PD models. The microdialysis technique allows simultaneous determination of plasma levels of antihypertensive drugs and their cardiovascular effects, and is therefore a powerful tool for PK-PD modeling.
引言
本研究的目的是检验微透析作为一种研究抗高血压药物药代动力学-药效学模型的技术。为此，我们在假手术（SO）和早期高血压阶段的主动脉缩窄（ACo）大鼠中研究了美托洛尔的降压和变时作用及其血浆浓度。
方法
通过“分流”血管微透析探针获得血浆美托洛尔浓度。在同一实验中还测量了平均动脉压和心率的变化。
结果
在两个实验组中均观察到美托洛尔水平迅速下降。对于变时作用，在SO和ACo大鼠中观察到血浆水平与变时作用之间有良好的相关性。ACo大鼠对变时作用的敏感性（Emax：-38±2%，n = 5，p < 0.05）高于SO动物（Emax：-27±1%，n = 5）。在两个实验组中均观察到美托洛尔诱导的血压降低出现延迟。在两个实验组中，效应室中美托洛尔的浓度与其相应的降压作用之间观察到良好的相关性。计算得到的药代动力学-药效学参数在SO组和ACo组之间没有差异。
讨论
在正常血压和ACo高血压大鼠中，美托洛尔浓度与其变时和降压作用之间发现了良好的相关性，这使得可以应用药代动力学-药效学模型。微透析技术能够同时测定抗高血压药物的血浆水平及其心血管效应，因此是药代动力学-药效学建模的有力工具。
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