Influence of protein binding on the myocardial uptake and pharmacodynamics of propafenone.

The relationship between plasma protein binding, myocardial uptake, and cardiac pharmacodynamics of propafenone was studied in an isolated perfused rabbit heart model. Hearts were perfused with buffer which contained varied concentrations of alpha 1-acid glycoprotein (alpha 1AGP). The rate and extent of myocardial uptake was assessed, as was the time course and magnitude of the change in QRS duration. The addition of alpha 1AGP has significant influence on both the rate and extent of myocardial accumulation as well as the resultant changes in QRS duration. The steady-state changes in QRS duration were linearly related to the free perfusate propafenone concentration. At times of disequilibrium, the relationship between free concentration and effect was not evident. However, at all times, a linear relationship between the myocardial concentration of propafenone and the resultant effect was observed. This relationship was not influenced by addition of alpha 1AGP protein to the perfusate; however, the amount of drug which was able to partition into the myocardium was greatly affected. These studies demonstrate that protein binding does influence the partitioning of drug into the myocardium and subsequently modulates the cardiac effect.