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Effect of pH on the Myocardial Uptake and Pharmacodynamics of Propafenone in the Isolated Rabbit Heart.

Gillis, Anne M.; Kates, Robert E.
Journal of Cardiovascular Pharmacology: November 1988
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Summary: The influence of pH on the myocardial disposition of propafenone was studied in isolated perfused rabbit hearts. Five pH groups were evaluated: pH 7.0, 7.2, 7.4, 7.6, and 7.8. Hearts were perfused with a modified Krebs-Henseleit buffer containing approximately 100 ng/ml propafenone. Myocardial propafenone accumulation was determined from differences in the aortic perfusate and coronary sinus effluent propafenone concentrations. The myocardial accumulation of propafenone was significantly pH dependent. The steady-state propafenone concentration increased from 5.9 +/- 1.3[mu]g/g at pH 7.0 to 13.2 +/- 3.8 [mu]g/g at pH 7.4 and 24.2 +/- 3.5 [mu]g/g at pH 7.6. The time to reach steady-state myocardial propafenone levels increased proportionately with the increased propafenone levels. Steady-state was not reached by 150 min at pH of 7.6 or 7.8. Percent change in QRS duration was measured to monitor the electrophysiologic effect of propafenone. The relationship between the myocardial drug concentration and the measured changes in QRS also was evaluated. The myocardial concentration-effect relationships were linear over the observed myocardial concentration range. The slopes of these concentration-effect relationships were similar for three groups (pH 7.0, 7.2, and 7.4). Over the pH range 7.0-7.4, the steady-state effect increased as a function of pH and correlated with the differences in propafenone steady-state myocardial concentrations. However, at alkalotic pH. the concentration-effect relationship was shifted to the right; less effect was observed than might be predicted for the myocardial propafenone concentration. Thus, small changes in pH may significantly alter the myocardial distribution and pharmacodynamics of propafenone.

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