MYOCARDIAL UPTAKE KINETICS AND PHARMACODYNAMICS OF PROPAFENONE IN THE ISOLATED PERFUSED RABBIT HEART

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Abstract
The myocardial disposition of propafenone was studied in an isolated perfused rabbit heart. Six hearts were perfused with a modified Krebs-Henseleit buffer containing propafenone 110 .+-. 5 ng/ml. Pharmacokinetic parameters were determined by fitting the coronary sinus effluent propafenone concentration-time data to a one-compartment pharmacokinetic model. The mean half-life of myocardial uptake (T1/2d) was 22.3 .+-. 5.9 min and the average time to approach steady-state tissue levels was 112 .+-. 29 min. Propafenone accumulated extensively in myocardium and at equilibrium the average (.+-. S.D.) myocardial concentration was 114 .+-. 21 times that of the perfusate. The electrophysiological effect was measured as percentage of change of the baseline QRS duration. The half-life of onset of effect (T1/2e) and the effect at steady state were determined by fitting the effect-time data to a monoexponential function. The T1/2e averaged 26.0 .+-. 9.4 min and did not differ significantly from T1/2d. The relationship between myocardial propafenone concentration and effect was linear but there was interexperimental variability in the slopes of the lines of this concentration-effect relationship. The interexperimental differences in steady-state effect could not be accounted for by differences in myocardial concentration.