Myocardial uptake kinetics and pharmacodynamics of propafenone in the isolated perfused rabbit heart

AM Gillis and RE Kates

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 T 1/2e averaged 26.0 +/- 9.4 min and did not differ significantly from T 1/2d. 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.

Volume 237, Issue 3, pp. 708-712, 06/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics

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