Stereoselective disposition and pharmacologic activity of propafenone enantiomers

Abstract

Propafenone is an antiarrhythmic drug that produces a variable degree of β-blockade in humans and is administered as a racemate. To examine the relative contribution of the individual enantiomers to pharmacologic effects seen during treatment with propafenone, we assessed the steady-state plasma concentrations of (+)-S-propafenone and (-)-R-propafenone in seven patients who were on long-term oral therapy, and we evaluated the electrophysiologic and β-blocking properties of both enantiomers in vitro. The metabolism of propafenone is known to be polymorphic and to cosegregate wit that of debrisoquine-4-hydroxylation. Among five patients with the extensive metabolizer phenotype (EM), the ratio of the area under the plasma concentration-time curve of (+)-S-propafenone to (-)-R-propafenone was 1.73 ± 0.15 (mean ± SD). In the other two patients, who had the poor metabolizer phenotype (PM), the concentrations of both enantiomers were elevated but the S/R ratios were similar to those seen in patients wit EM. In canine cardiac Purkinje fibers, both enantiomers produced similar frequency-dependent depression of maximum upstroke of phase 0. In contrast, the affinity of the human lymphocyte β2-adrenoceptor was approximately 100-fold greater for (+)-S-propafenone (K(i), 7.2 ± 2.9 nM) than for the (-)-R-enantiomer (K(i), 571 ± 141 nM). We conclude that during long-term oral therapy, propafenone undergoes stereoselective disposition in patients with either EM or PM. β-Blockade during propafenone therapy is likely related to accumulation of (+)-S-propafenone. The lower β-blocking activity of the (-)-R-enantiomer without significant difference in sodium channel blockade suggests that administration of this enantiomer rather than the racemic mixture may be of advantage in patients intolerant of β-blockade.