The proposed studies will provide useful information for assessing the clinical significance of the simultaneous accumulation of parent drug and active metabolites in patients when treated chronically with antiarrhythmic agents for cardiac rhythm disturbances. It represents modification of a previously submitted proposal utilizing the excellent suggestions provided in the critique by the study section. The clinical protocols have been extensively redesigned to account for non-steady state conditions and the relationship of animal and human experiments have been clarified.
The specific aims of this proposed research are to evaluate the individual electro-physiologic and hemodynamic properties of several selected antiarrhythmic drugs, and their active metabolites. The disposition kinetics of the metabolites and the net effect produced by the simultaneous accumulation of parent drug and active metabolites will be determined. Several studies will be conducted in both a canine moded and in patients with cardiac rhythm disturbances. An anesthetized dog model will be employed to determine the electro-physiologic and hemodynamic characteristics of selected drugs and their metabolites. These studies will involve evaluations of parent drugs and metabolites individually and when present concurrently. Whether the net effects of the parent drug and metabolites are additive, synergistic or antagonistic will be determined. Studies in patients will involve direct administration of metabolities to evaluate their effect on the ECG and frequency of premature ventricular contractions. In addition, their disposition characteristics will be determined. Chronic oral administration of parent drugs will facilitate evaluation of the accumulation of active metabolites during chronic therapy as well as assessment of their contribution to arrhythmia control. These studies will form a basis for evaluating the accumulation of cardioactive metabolites of antiarrhythmic drugs and will establish a rational approach for optimizing the clinical efficacy of these agents.
