SINGLE-DOSE PHARMACOKINETICS OF (S)-ATENOLOL ADMINISTERED ORALLY AS ASINGLE ENANTIOMER FORMULATION AND AS A RACEMIC-MIXTURE (TENORMIN(TM)

The purpose of this study was to describe the pharmacokinetics of and heart rate and blood pressure responses to (S)-atenolol (SATN) and (R) -atenolol (RATN) after oral administration of (S)-atenolol and (R,S)-a tenolol (Tenormin(TM)) in man. Eight male subjects were given single o ral doses of 50 mg of SATN as a single enantiomer formulation (SEF) an d 100 mg of Tenormin(TM) (TMN) using a randomized, double-blind, 2-per iod, complete crossover study design. Subjects performed exercise tole rance tests (Bruce Protocol) before and 2, 4, 6, 8, 12, and 24 h after drug administration. Plasma samples were obtained 2 min before and 30 min, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 h after dosing. Uri ne was collected for the first 48 h after dosing. Plasma and urine sam ples were analyzed for SATN and RATN by an enantioselective HPLC metho d. SEF and Tenormin(TM) attenuated exercise-induced increases in heart rate and systolic blood pressure. Mean changes in exercise heart rate s 4 h after dosing were -38 +/- 3 bpm and -37 +/- 3 bpm for SEF and TM N, respectively, P = 0.792. Mean changes in exercise systolic blood pr essure were -42 +/- 12 mm Hg and -55 +/- 14 mm Hg for SEF and TMN, res pectively, P = 0.484. Mean area under the plasma level time curve (AUC 0-24) and mean C(max) for SATN for SEF were significantly lower than f or SATN after TMN. Mean SATN AUCs0-24 were 1867 +/- 261 and 2543 +/- 2 23 ng . h/ml (P = 0.005) and mean C(max)s were 225 +/- 29 and 333 +/- 30 ng/ml, for SEF and TMN, respectively (P = 0.011). Mean T(max) for S ATN occurred significantly earlier after SEF than after TMN (2.9 +/- 0 .3 and 3.3 +/- 0.3 h, P = 0. 028). The amount of SATN excreted in urin e was significantly lower after SEF than after TMN (18.7 +/- 2.7 and 2 4.2 +/- 2. 0 mg, P = 0.017). AUC, C(max), and amount excreted in urine (Au) were significantly higher for RATN than SATN after TMN. Mean AUC s, C(max)s, and Aus for RATN compared to SATN were 2806 +/- 239 vs 254 3 +/- 223 ng . h/ml (P < 0.0001), 360 +/- 31 vs 333 +/- 30 ng/ml (P < 0.0001), and 25 +/- 2.1 vs 24 +/- 2 mg (P = 0.004), respectively. SEF and TMN are equieffective in attenuating exercise-induced increases in heart rate and systolic blood pressure. The SEF has lower bioavailabi lity compared to TMN and RATN plasma levels are higher than SATN after TMN administration. (C) 1994 Wiley-Liss, Inc.