Metabolite cumulation during long-term oral encainide administration.

Cumulation of encainide and its major metabolites, O-demethylencainide (ODE), 3-methoxy-ODE (MODE), and N-demethylencainide (NDE) was examined in patients with frequent complex ventricular ectopy. After 6 mo on encainide patients were admitted to Stanford University Hospital and the drug was discontinued for 24 hr. During this time blood samples were drawn to characterize the cumulation and disposition of the drug and metabolites. The mean steady-state concentrations of encainide, ODE, and MODE were 56.3, 214.6, and 184.6 ng/ml after doses ranging from 100 to 250 mg/day. The concentration ratios of ODE/encainide and MODE/encainide were 5.02 +/- 2.61 and 5.15 +/- 4.13. NDE was detected in the plasma of only one patient. Elimination half lifes of encainide and ODE were 1.16 +/- 0.5 and 11.41 +/- 9.58 hr. MODE disappeared slowly and at 24 hr the plasma concentration was still 59.8 +/- 39.9% of its mean steady-state concentration. Our data indicate that the metabolites of encainide cumulate in the plasma of patients on long-term oral therapy and must be considered when evaluating its clinical efficacy.