Clinical pharmacokinetics of encainide.

The disposition kinetics of the new antiarrhythmic agent encainide are a function of the genetic polymorphism which also controls debrisoquin 4-hydroxylation. In the majority of subjects (extensive metabolisers) encainide undergoes extensive first-pass hepatic biotransformation to the active metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE). The plasma concentrations of these metabolites are higher than those of encainide, and pharmacological effects correlate better with plasma metabolite concentrations than they do with those of encainide itself. In poor metabolisers, who make up to 7% of the population, a first-pass effect is absent, encainide clearance is lower, and plasma encainide concentrations are higher than those in extensive metabolisers. In poor metabolisers, plasma concentrations of active metabolites are low or undetectable, and the effects of encainide therapy can be closely correlated with plasma concentrations of the parent drug. Despite the marked differences in encainide disposition between extensive and poor metabolisers, the dosages which produce pharmacological effects (QRS prolongation and arrhythmia suppression) are similar in both groups. Encainide biotransformation is impaired in hepatic disease, but no major dosage changes are required. On the other hand, excretion of encainide and its metabolites is impaired in individuals with renal disease, and starting dosages should be decreased. The time required to achieve steady-state concentrations of metabolites (in extensive metabolisers) and of encainide itself (in poor metabolisers) is similar (3 to 5 days); therefore, the dosage should be increased no more often than every 3 to 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)