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 (R,S)-propranolol versus 20 mg t.i.d. optically pure (S)-propranolol. During exercise, both substances decreased heart rate (-14%, p less than 0.01), as well as the overall rate pressure product (-19%, p less than 0.01) to the same extent, indicating similar beta-blocking effects. After oral application of (R,S)-propranolol the maximal plasma concentration (Cmax) 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 Cmax, 1.36 [p less than 0.01] and AUC, 1.42 [p less than 0.01]) despite dose-equivalence of both enantiomers in the administered racemic (R,S)-propranolol preparation indicating different pharmacokinetic properties. Mean values of Cmax and the AUC of (S)-propranolol did not differ significantly after 1 week of oral administration of 40 mg (R,S)-propranolol and 20 mg (S)-propranolol t.i.d., respectively. The ratio of triiodothyronine to thyroxine was decreased by (R,S)-propranolol (-25%, p less than 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 (R,S)-propranolol. By contrast, the conversion of thyroxine to triiodothyronine is inhibited by (R)-propranolol only.(ABSTRACT TRUNCATED AT 250 WORDS)
Stoschitzky
K
K
Department of Medicine, Institute of Pharmaceutical Chemistry, Karl Franzens University, Graz, Austria.
Lindner
W
W
Egginger
G
G
Brunner
F
F
Obermayer-Pietsch
B
B
Passath
A
A
Klein
W
W
D000284:Administration, Oral; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D004311:Double-Blind Method; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D011433:Propranolol / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011897:Random Allocation; D013237:Stereoisomerism; D013963:Thyroid Hormones / Q000097:blood*
D013963:Thyroid Hormones; D011433:Propranolol