美托洛尔对自发性高血压大鼠心血管效应的药代动力学-药效学（PK-PD）建模：一项微透析研究。
Pharmacokinetic-pharmacodynamic (PK-PD) modeling of cardiovascular effects of metoprolol in spontaneously hypertensive rats: a microdialysis study.
作者信息
Höcht Christian, Di Verniero Carla, Opezzo Javier A W, Bramuglia Guillermo F, Taira Carlos A
机构信息
Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, C1113AAD, Buenos Aires, Argentina.
出版信息
Naunyn Schmiedebergs Arch Pharmacol. 2006 Jul;373(4):310-8. doi: 10.1007/s00210-006-0078-x. Epub 2006 May 30.
The present work addressed possible alterations in the pharmacokinetics and the in vivo pharmacodynamic of metoprolol (MET) in spontaneously hypertensive (SH) rats and Wistar Kyoto (WKY) animals by means of the microdialysis technique. The correlation between MET unbound plasma concentrations and its pharmacological effects, such as heart rate and blood pressure change, was also examined in SH and WKY rats by the application of a PK-PD model. MET dialysate concentrations and its chronotropic and blood pressure effect were determined during 3 h after the administration of 3 and 10 mg.kg(-1) of the drug. A PK-PD model with a separate effect compartment was used to analyse the data. A good correlation between plasma MET concentrations and its hypotensive and chronotropic effect was found in all experimental groups. Although a greater maximal effect (E(max)) for the antihypertensive effect of MET was observed in SH rats (WKY: E(max): -17+/-1 mmHg; SH: E(max): -28+/-4 mmHg; P<0.05 versus WKY rats), no differences were found in the concentration yielding half-maximal response (IC(50)) comparing SH (IC(50): 583+/-146 ng x ml(-1)) and WKY animals (IC(50): 639+/-187 ng x ml(-1)). The bradycardic effect of MET was greater in SH rats (E(max): -29+/-1%, P<0.05 versus WKY rats) than in WK animals (E(max): -22+/-2%), but no differences were observed in the IC(50) comparing both experimental groups (WKY: IC(50): 187+/-53 ng x ml(-1); SH: IC(50): 216+/-62 ng x ml(-1)). Pharmacokinetic analysis shows that the volume of distribution of MET was greater in SH rats (Vd: 3.4+/-0.5 l, P<0.05 versus WKY rats) with regard to Wistar Kyoto (WKY) animals (Vd: 1.9+/-0.2 l). The results suggest that the pharmacokinetic behaviour of metoprolol are modified in SH rats, resulting in an increased volume of distribution. A greater maximal efficacy to the hypotensive effect of metoprolol was observed in SH rats, suggesting participation of beta-adrenoceptors in the maintenance of the hypertension. Also, a greater chronotropic response to metoprolol was found in the hypertensive group compared with WKY animals, suggesting that, at least in part, the greater cardiac effect of metoprolol explained the enhanced hypotensive response of the beta blocker in the SH animals.
本研究通过微透析技术探讨了美托洛尔（MET）在自发性高血压（SH）大鼠和Wistar Kyoto（WKY）大鼠体内的药代动力学及体内药效学的可能变化。还通过应用药代动力学-药效学（PK-PD）模型，研究了SH大鼠和WKY大鼠中美托洛尔的游离血浆浓度与其药理作用（如心率和血压变化）之间的相关性。在给予3和10 mg·kg⁻¹药物后的3小时内，测定了美托洛尔的透析液浓度及其变时性和血压效应。使用具有独立效应室的PK-PD模型分析数据。在所有实验组中，均发现血浆美托洛尔浓度与其降压和变时性效应之间存在良好的相关性。虽然在SH大鼠中观察到美托洛尔的降压作用具有更大的最大效应（E(max)）（WKY：E(max)：-17±1 mmHg；SH：E(max)：-28±4 mmHg；与WKY大鼠相比，P<0.05），但在产生半数最大反应的浓度（IC(50)）方面，SH大鼠（IC(50)：583±146 ng·ml⁻¹）与WKY大鼠（IC(50)：639±187 ng·ml⁻¹）之间未发现差异。美托洛尔的减慢心率作用在SH大鼠中（E(max)：-29±1%，与WKY大鼠相比，P<0.05）比在WKY大鼠中（E(max)：-22±2%）更大，但在比较两个实验组的IC(50)时未观察到差异（WKY：IC(50)：187±53 ng·ml⁻¹；SH：IC(50)：216±62 ng·ml⁻¹）。药代动力学分析表明美托洛尔在SH大鼠中的分布容积（Vd：3.4±0.5 l，与Wistar Kyoto（WKY）大鼠相比，P<0.05）大于WKY大鼠（Vd：1.9±0.2 l）。结果表明，美托洛尔在SH大鼠中的药代动力学行为发生了改变，导致分布容积增加。在SH大鼠中观察到美托洛尔对降压作用具有更大的最大疗效，提示β-肾上腺素能受体参与了高血压的维持。此外，与WKY大鼠相比，高血压组中美托洛尔的变时性反应更大，这表明美托洛尔更大的心脏效应至少部分解释了β受体阻滞剂在SH动物中增强的降压反应。
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