PT  - JOURNAL ARTICLE
AU  - Richard N. Upton
AU  - Yi Fei Huang
AU  - Laurence E. Mather
AU  - David J. Doolette
TI  - The Relationship between the Myocardial Kinetics of Meperidine and Its Effect on Myocardial Contractility: Model-Independent Analysis and Optimal Regional Model
DP  - 1999 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 694--701
VI  - 290
IP  - 2
4099  - http://jpet.aspetjournals.org/content/290/2/694.short
4100  - http://jpet.aspetjournals.org/content/290/2/694.full
SO  - J Pharmacol Exp Ther1999 Aug 01; 290
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics