Flecainide acetate, an investigational class 1 antiarrhythmic agent, undergoes biotransformation in man with production of 2 major metabolites: meta-O-dealkylated flecainide (S-24623) and the meta-O-dealkylated lactam of flecainide (S-26191). This study compared the effects of flecainide, S-24623 and S-26191 on cardiac electrophysiologic characteristics in the anesthetized dog. Each dog received 2 dose levels of 1 of the 3 test compounds' after control measurements. Flecainide (2 and 4 mg/kg in 8 dogs), S-24623 (4 and 8 mg/kg in 8 dogs) and S-26191 (4 and 10 mg/kg in 7 dogs) were administered intravenously in dilute solution. Of the 3 compounds, only flecainide significantly prolonged sinus cycle length (p < 0.01). However, both flecainide and S-24623 significantly prolonged minimum atrial paced cycle length with 1:1 atrioventricular conduction, atrioventricular nodal effective and functional refractory periods, and right ventricular effective refractory period. Metabolite S-26191 exhibited qualitatively similar but much weaker electrophysiologic actions. The maximal electrophysiologic effects of flecainide and S-24623 were approximately equivalent, but the metabolite was about one-half as potent on a milligram-permilligram basis, and lacked marked effects on infranodal (HV interval) conduction. S-26191 was less than one-tenth as potent as flecainide. Therefore, since both flecainide metabolites occur primarily in the conjugated form in plasma (i.e., free metabolite concentrations are low), it is unlikely that these compounds either potentiate flecainide's antiarrhythmic action or increase susceptibility to drug toxicity in the clinical setting.
Bibliographical noteFunding Information:
From the Departments of Medicine, Surgery and Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, and Riker Laboratories, 3M Center, St. Paul, Minnesota. This study was funded in part by a grant-in-aid from Riker Laboratories, by a fellowship grant from the Veterans of Foreign Wars (JG), by a fellowship grant and a grant-in-aid from the American Heart Association-Minnesota Affiliate (CCG) and by grant lR23-HL-29460 (DGB) from the National institutes of Health, Bethesda, Maryland. This work was completed during Dr. Benditt’s tenure as an established Investigator of the American Heart Association, Dallas, Texas. Manuscript received July 19, 1984; revised manuscript received November 26, 1984, accepted November 29, 1984. Address for reprints: David G. Benditt, MD, Cardiovascular Division, Departmen? of Medicine, University of Minnesota Hospitals, Box 341 Mayo Memorial Building, Minneapolis, Minnesota 65455.