Upton R N, Huang Y F, Mather L E, Doolette D J
Department of Anaesthesia and Intensive Care, Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia.
J Pharmacol Exp Ther. 1999 Aug;290(2):694-701.
The myocardial kinetics of meperidine and the relationship between these kinetics and the effect of meperidine on myocardial contractility (maximum positive rate of change of left ventricular pressure) were examined by analysis of previously published data collected in sheep after the i.v. injection of 100 mg of meperidine over 1 s. There was significant hysteresis between reductions in myocardial contractility and the arterial concentrations of meperidine, but not the coronary sinus blood (effluent from the heart) or calculated myocardial concentrations. The peak reduction in contractility occurred after the peak arterial concentration, at the time of the peak myocardial concentration, but before the peak coronary sinus concentration, suggesting that the site of drug action in the heart was not in equilibrium with either arterial blood or effluent blood from the heart. The most appropriate form of a dynamic model (a linear model with a threshold) was determined, without the need to assume a kinetic model, by directly fitting the observed reductions in myocardial contractility to the calculated myocardial concentrations. To determine the optimal kinetic and combined kinetic-dynamic models, a variety of one-, two-, and three-compartment models of the myocardium were fitted to the coronary sinus concentrations by using hybrid modeling. These included "tank in series" models that accounted well for drug dispersion and "peripheral compartment" models that accounted well for deep distribution. The most appropriate model was a "compilation" model, which incorporated features of both these extremes and was a better fit to the observed data than either a traditional single flow-limited compartment or a traditional membrane-limited model.
通过分析先前发表的在绵羊静脉注射100毫克哌替啶（1秒内注射完毕）后收集的数据，研究了哌替啶的心肌动力学以及这些动力学与哌替啶对心肌收缩力（左心室压力最大正向变化率）影响之间的关系。心肌收缩力降低与哌替啶动脉血浓度之间存在显著滞后现象，但与冠状窦血（心脏流出的血液）或计算出的心肌浓度之间不存在显著滞后现象。收缩力降低的峰值出现在动脉血浓度峰值之后、心肌浓度峰值之时，但在冠状窦浓度峰值之前，这表明药物在心脏中的作用部位与动脉血或心脏流出的血液均未达到平衡。通过直接将观察到的心肌收缩力降低值与计算出的心肌浓度进行拟合，确定了动态模型的最合适形式（具有阈值的线性模型），无需假设动力学模型。为了确定最佳的动力学模型以及联合动力学 - 动态模型，使用混合建模方法将多种心肌单室、双室和三室模型拟合到冠状窦浓度数据上。这些模型包括能很好解释药物扩散的“串联罐”模型以及能很好解释深部分布的“外周室”模型。最合适的模型是一个“综合”模型，它融合了这两种极端模型的特点，并且比传统的单流限制室模型或传统的膜限制模型更能拟合观察到的数据。
