Contribution of quinidine metabolites to electrophysiologic responses in human subjects

The quinidine metabolites 3-hydroxyquinidine, 2'-oxoquinidione, and quinidine-N-oxide and the contaminant dihydroquinidine have been shown to have electrophysiologic activity. This study investigated the time-dependent contributions of quinidine, dihydroquinidine, and the quinidine metabolites to the electrophysiologic effects of a prolonged quinidine infusion in 14 patients referred for management of symptomatic ventricular tachyarrhythmias. Electrophysiologic testing and blood sampling were done at baseline and every 5 minutes throughout a 110-minute quinidine infusion. Changes in ventricular effective refractory periods correlated significantly with serum concentrations of quinidine-N-oxide (r = 0.54; p less than 0.001), 3-hydroxyquinidine (r = 0.50; p less than 0.001), and time (r = 0.52; p less than 0.001) but did not correlate with the quinidine concentrations (r = 0.19). Multiple linear regression revealed that only 3-hydroxyquinidine and time contributed independently to changes in the ventricular effective refractory period. Quinidine concentration was the only variable that contributed independently to changes in ventricular tachycardiac cycle lengths. Time was the only variable that correlated independently with changes in QRS and QTc durations. These data indicate that active metabolites accumulate during an intravenous infusion that attains therapeutic quinidine levels and that quinidine and its metabolites may have different electrophysiologic effects.