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 through 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 less than 0.01), suggesting that the drug undergoes enantioselective disposition. In the in vitro experiments, both enantiomers reduced phase 0 action potential Vmax (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 Vmax depression were significantly longer for S-(+)-flecainide (13.4 +/- 1.5 seconds) compared with R-(-)-flecainide (8.9 +/- 0.6 seconds, p less than 0.001). 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 that the racemic drug, would offer any advantage.
Kroemer
H K
HK
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
Turgeon
J
J
Parker
R A
RA
Roden
D M
DM
D000200:Action Potentials / Q000187:drug effects; D000328:Adult; D000368:Aged; D000818:Animals; D046508:Culture Techniques; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D005424:Flecainide / Q000493:pharmacokinetics* / Q000494:pharmacology; D006329:Heart Conduction System; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism
D005424:Flecainide