Ritchie R H, Morgan D J, Horowitz J D
Department of Cardiology, Queen Elizabeth Hospital, University of Adelaide, Woodville, SA.
J Pharm Sci. 1998 Feb;87(2):177-82. doi: 10.1021/js9702776.
We have recently reported the time course of acute myocardial drug uptake and simultaneous pharmacodynamic effects for metoprolol (4 mg; n = 12) and sotalol (20 mg; n = 10) in patients with ischemic heart disease. The acute pharmacodynamic effects of the two drugs included reductions in both spontaneous heart rate and the contractile index peak positive rate of left ventricular pressure rise and prolongation of the electrocardiographic PR interval, all of which exhibited an equilibration delay compared with myocardial drug content. The objective of the current study was to analyze the relationship between myocardial drug content and effect for both metoprolol and sotalol using an effect compartment model, to examine the potential for the two drugs to share a common subsite of action in the myocardium. The time course of myocardial drug content was best described by a one-compartment model for metoprolol and a two-compartment model for sotalol. A linear pharmacodynamic model, relating the amount of drug at the effect-site (Ae) with each of the three effects, was used in the effect compartment modeling. The slope of each of these effects as a function of Ae was considerably flatter for sotalol than for metoprolol, reflecting the relative beta-adrenoceptor antagonistic potencies of the two drugs. The exit rate constant from the effect compartment (K(eo)) did not differ significantly from each other or from the exit rate constant from the "peripheral" compartment (K21) for sotalol. The results suggest that the effect compartment within the myocardium for both drugs may correspond to a "peripheral" compartment, even though a "peripheral" pharmacokinetic compartment for myocardial metoprolol content was not apparent. Thus, the effect compartment for many cardioactive drugs may correspond to a pharmacokinetically "peripheral" compartment, irrespective of localization of effect to a small (e.g. sinoatrial node) or large (e.g. ventricular myocardium) region of the heart.
我们最近报道了美托洛尔（4毫克；n = 12）和索他洛尔（20毫克；n = 10）在缺血性心脏病患者中的急性心肌药物摄取时间过程及同时发生的药效学效应。这两种药物的急性药效学效应包括自发性心率降低、左心室压力上升的收缩指数峰值阳性率降低以及心电图PR间期延长，所有这些效应与心肌药物含量相比均表现出平衡延迟。本研究的目的是使用效应室模型分析美托洛尔和索他洛尔的心肌药物含量与效应之间的关系，以研究这两种药物在心肌中共享共同作用亚位点的可能性。美托洛尔的心肌药物含量时间过程用一室模型能得到最佳描述，而索他洛尔的用二室模型能得到最佳描述。在效应室建模中使用了线性药效学模型，将效应部位的药物量（Ae）与三种效应中的每一种相关联。索他洛尔的这些效应中每一种作为Ae的函数的斜率比美托洛尔的要平缓得多，这反映了两种药物相对的β - 肾上腺素能受体拮抗效力。索他洛尔从效应室的消除速率常数（K(eo)）彼此之间以及与从“外周”室的消除速率常数（K21）相比均无显著差异。结果表明，尽管心肌美托洛尔含量的“外周”药代动力学室不明显，但这两种药物在心肌内的效应室可能对应于一个“外周”室。因此，许多心脏活性药物的效应室可能对应于一个药代动力学上的“外周”室，而不论效应定位于心脏的小区域（如窦房结）还是大区域（如心室肌）。
