Most antiarrhythmic drugs are extensively metabolized, and the accumulation of the metabolites of several of these drugs has been documented. In some cases, the steady-state plasma concentrations of metabolites are considerably greater than is the concentration of the parent drug. Several of these metabolites have been evaluated in animal models for antiarrhythmic activity and their potencies have been defined relative to the activity of their parent compound. Evaluations of activity are generally conducted in animal arrhythmia models, and very few metabolites of antiarrhythmic drugs have been evaluated directly in patients. However, from knowledge of antiarrhythmic activity in animals and the degree to which a metabolite accumulates in the plasma of patients, one can make qualitative judgments about its therapeutic role. Such judgments, however, need to be recognized as tenuous. Quantitative judgments require further information regarding the relationship between the parent drug and metabolite when present simultaneously in the myocardium. One must consider whether the effects of the parent drug and metabolite are additive, synergistic, or even antagonistic. The latter case is most possible with drug-metabolite pairs where the metabolite accumulates substantially, but does not have significant antiarrhythmic potency. Other considerations include noncardiac effects of the metabolites. As in the case of the mono-desethyl metabolite of lidocaine, the significance of its accumulation relates more to central nervous system side effects than to direct cardiac actions. The role of active metabolites also much be considered in regard to differences in the disposition kinetics between the parent drug and metabolite. The most obvious situation where this is important is in designing clinical drug evaluation protocols. As illustrated by the metabolites of encainide and lorcainide, the time course of accumulation and disappearance of the metabolites may be much longer than that of the parent drug. Clinical evaluations at steady state must take into account the time required to achieve steady-state concentrations of the metabolites as well. Similarly, after discontinuation of drug administration, the time required before washout is complete may be totally dependent on the kinetics of the metabolite, and not the parent drug. Variability in metabolic activity also needs to be considered. It has been shown with procainamide and encainide that genetic factors can influence the rate of production of active metabolites and consequently influence the clinical efficacy of these drugs. Another consideration that deserves attention is the question of drug interactions.(ABSTRACT TRUNCATED AT 400 WORDS)