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An enantiomer-enantiomer interaction of (S)- and (R)-propafenone modifies the effect of racemic drug therapy.

Abstract：

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)-, (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 HRmax was 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.

journal_name

Circulation

journal_title

Circulation

authors

Kroemer HK,Fromm MF,Bühl K,Terefe H,Blaschke G,Eichelbaum M

doi

10.1161/01.cir.89.5.2396

subject

Has Abstract

pub_date

1994-05-01 00:00:00

pages

2396-400

issue

5

eissn

0009-7322

issn

1524-4539

journal_volume

89

pub_type

临床试验,杂志文章,随机对照试验

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