The effects of encainide and its major metabolites, O-demethyl encainide and 3-methoxy-O-demethyl encainide, on experimental cardiac arrhythmias in dogs

Encainide (E) is a class I antiarrhythmic agent which is metabolised in humans, with the formation in the majority of patients of O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide (MODE). As it has been suggested that these metabolites may contribute to the antiarrhythmic effect of E in humans, we have investigated the effects of E, ODE, and MODE on ventricular arrhythmias produced by ouabain and by coronary artery ligation. In the ouabain model, E restored sinus rhythm (SR) in eight of 13 dogs after a mean dose of 0.81 +/- 0.19 mg/kg (mean +/- SEM). ODE returned SR in five of 10 dogs after 0.30 +/- 0.06 mg/kg, and MODE returned SR in two of nine dogs after doses of 0.40 and 0.68 mg/kg, respectively. For comparison, mexiletine returned SR in six of six dogs after 3.50 +/- 1.02 mg/kg. In conscious dogs with ventricular arrhythmias 24 h after two-stage coronary artery ligation E restored SR in four of four dogs after 2.38 +/- 0.50 mg/kg. ODE restored SR in four of four dogs after 0.63 +/- 0.14 mg/kg, and MODE restored SR in four of four dogs after 1.39 +/- 0.30 mg/kg. Thus, ODE and MODE have antiarrhythmic activity which may contribute to the effects of E in patients with cardiac arrhythmias.