Kroemer H K, Fromm M F, Bühl K, Terefe H, Blaschke G, Eichelbaum M
Dr Margarete Fischer-Bosch-Institut für Klinische, Pharmakologie, Stuttgart, Germany.
Circulation. 1994 May;89(5):2396-400. doi: 10.1161/01.cir.89.5.2396.
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.
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.
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.
外消旋化合物治疗所产生的效应可归因于（S）-和（R）-对映体两者。在此，我们检验了一种假设，即对映体-对映体相互作用会调节用外消旋体（抗心律失常药普罗帕酮）治疗的效应。既往研究表明，虽然普罗帕酮的对映体发挥相似的钠通道阻滞（QRS波增宽）效应，但产生β受体阻滞作用的是（S）-对映体；此外，我们最近证明（R）-普罗帕酮在体外抑制（S）-普罗帕酮的代谢。
这项单盲、随机研究比较了（R/S）-、（S）-、（R）-普罗帕酮（150mg，每6小时1次，共4天）和安慰剂对QRS波时限（ΔQRS）以及对最大运动心率（ΔHRmax，β受体阻滞的一项指标）的影响。与单独使用（S）-对映体相比，在使用（R/S）-普罗帕酮治疗期间，（S）-普罗帕酮的清除率显著降低（-55±24%，P<.001），并且在使用（R/S）-普罗帕酮期间（-8.8±6.6次/分钟；P<.01）和（S）-普罗帕酮期间（-4.3±4.8次/分钟；P<.01）ΔHRmax有显著改变，但在使用（R）-普罗帕酮期间（-1.8±6.4次/分钟）和安慰剂期间（0.3±7.1次/分钟）则无改变。相比之下，与安慰剂相比，（R/S）-、（S）-和（R）-普罗帕酮均使QRS波延长。
这些数据表明，（R）-普罗帕酮损害人体内（S）-普罗帕酮的处置。结果，150mg外消旋普罗帕酮（75mg的[S]-对映体）的β受体阻滞作用比单独使用150mg（S）-普罗帕酮更明显。因此，外消旋药物治疗的效应不一定是各对映体效应相加所预测的那样。
