Flecainide enantiomers: Disposition in human subjects and electrophysiologic actions in vitro

The antiarrhythmic agent flecainide is administered as a racemate. The disposition of the individual enantiomers and their electrophysiologic actions are unknown. We therefore determined trough plasma levels of S‐(+)‐flecainide and R‐(−)‐flecainide in 13 patients who were receiving long‐term oral flecainide therapy. In addition, the effects of the enantiomers on action potential characteristics in canine cardiac Purkinje fibers were assessed. Plasma concentrations of R‐(−)‐flecainide were significantly higher than those of the S‐(+)‐enantiomer (−/+ ratio, 1.10 ± 0.13, mean ± SD; range, 0.89 to 1.32, p < 0.01), suggesting that the drug undergoes enantioselective disposition. In the in vitro experiments, both enantiomers reduced phase 0 action potential V max (an index of the fast inward sodium current) and shortened action potential duration at 50% and 90% repolarization, but no differences between the enantiomers were detected. The time constants for development of V max depression were significantly longer for S‐(+)‐flecainide (13.4 ± 1.5 seconds) compared with R‐(−)‐flecainide (8.9 ± 0.6 seconds, p < 0.01). Thus, although S‐(+)‐flecainide and R‐(−)‐flecainide undergo modest enantioselective disposition, they exert similar electrophysiologic effects. These studies have provided no evidence to indicate that administration of a single enantiomer, rather than the racemic drug, would offer any advantage. Clinical Pharmacology and Therapeutics (1989) 46, 584–590; doi: 10.1038/clpt.1989.189