Background Therapy with racemic compounds produces effects that can be attributed to both (S)-and (R)-enantiomers. Here we have tested the hypothesis that an enantiomer-enantiomer interaction would modulate the effects of treatment with a racemate, the antiarrhythmic propafenone. Previous studies have shown that while the enantiomers of propafenone exert similar sodium channel-blocking (QRS widening) effects, it is the (S)-enantiomer that produces beta -blockade; moreover, we have demonstrated recently that (R)-propafenone inhibits the metabolism of (S)-propafenone in vitro.Methods and Results This single-blind, randomized study compared the effects of (R/S)-, (S)-, and (R)-propafenone (150 mg q 6 hours for 4 days) and placebo on QRS duration (Delta QRS) and on maximum exercise heart rate (Delta HRmax), an index of beta -blockade. The clearance of (S)-propafenone was significantly lower (-55+-24%, P<.001) during treatment with (R/S)-propafenone than with the (S)-enantiomer alone, and Delta HRmaxwas significantly altered during (R/S)-propafenone (-8.8+-6.6 beats per minute; P<.01) and during (S)-propafenone (-4.3+-4.8 beats per minute; P<.01) but not during (R)-propafenone (-1.8+-6.4 beats per minute) or placebo (0.3+-7.1 beats per minute). In contrast, (R/S)-, (S)-, and (R)-propafenone all prolonged QRS compared with placebo.Conclusions These data indicate that (R)-propafenone impairs the disposition of (S)-propafenone in humans. As a result, the beta -blocking effects of 150 mg of racemic propafenone (75 mg of the (S)-enantiomer) were more pronounced than those of 150 mg of (S)-propafenone alone. Thus, the effects of racemic drug therapy are not necessarily those predicted by summation of the effects of the individual enantiomers. (Circulation. 1994;89:2396-2400.)