RACEMIC (R,S)-PROPRANOLOL VERSUS HALF-DOSED OPTICALLY PURE (S)-PROPRANOLOL IN HUMANS AT STEADY-STATE - HEMODYNAMIC-EFFECTS, PLASMA-CONCENTRATIONS, AND INFLUENCE ON THYROID-HORMONE LEVELS

In a randomized, double-blind, crossover study in 10 healthy volunteers the hemodynamic effects, drug plasma concentrations, and thyroid hormone profiles were compared after oral administration for 1 week of 40 mg t.i.d. racemic (RS)-propranolol versus 20 mg t.i.d. optically pure (S)-propranolol. During exercise, both substances decreased heart rate (-14%, p < 0.01), as well as the overall rate pressure product (-19%, p < 0.01) to the same extent, indicating similar beta-blocking effects. After oral application of (R,S)-propranolol the maximal plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) of (S)-propranolol were higher than those of (R)-propranolol (eudismic ratios (S)- over (R)-propranolol C(max), 1.36 [p < 0.01] and AUC, 1.42 [p < 0.01]) despite dose-equivalence of both enantiomers in the administered racemic (RS)-propranolol preparation indicating different pharmacokinetic properties. Mean values of C(max) and the AUC of (S)-propranolol did not differ significantly after 1 week of oral administration of 40 mg (RS)-propranolol and 20 mg (S)-propranolol t.i.d., respectively. The ratio of triiodothyronine to thyroxine was decreased by (RS)-propranolol (-25%, p < 0.01) but not by (S)-propranolol, suggesting that only the (R)-enantiomer inhibits the conversion of thyroxine to triiodothyronine. Thus, half-dosed optically pure (S)-propranolol is an equally effective beta-adrenergic receptor antagonist compared with currently used racemic (RS)-propranolol. By contrast, the conversion of thyroxine to triiodothyronine is inhibited by (R)-propranolol only. Because there is an efficient method available to separate the (R)- and (S)-enantiomers of propranolol they should be used as optically pure drugs according to their specific indications rather than racemic (RS)-propranolol.