Key result
Alkaline pH drives a ~4-fold increase in myocardial propafenone concentration, altering drug pharmacodynamics.
Why the study?
Small changes in pH may significantly alter the myocardial distribution and pharmacodynamics of propafenone, but this effect was not well characterized.
Does pH alter the myocardial uptake and pharmacodynamics of propafenone in isolated rabbit hearts?
Does pH alter the myocardial uptake and pharmacodynamics of propafenone in isolated rabbit hearts?
Small changes in pH significantly alter the myocardial distribution and pharmacodynamics of propafenone, with alkalotic pH shifting the concentration-effect relationship to the right.
Alkaline pH may increase myocardial propafenone uptake; leaves open clinical relevance for dosing or toxicity in humans.
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 micrograms/g at pH 7.0 to 13.2 +/- 3.8 micrograms/g at pH 7.4 and 24.2 +/- 3.5 micrograms/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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Gillis et al. (1988) studied Myocardial disposition of propafenone. pH alteration (pH 7.0 to 7.8) vs. Different pH levels was evaluated on Myocardial propafenone accumulation and percent change in QRS duration. In isolated rabbit hearts, steady-state myocardial propafenone concentration increased significantly with pH, from 5.9 µg/g at pH 7.0 to 24.2 µg/g at pH 7.6, altering its pharmacodynamics.
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