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Single dose pharmacokinetics of (S)‐atenolol administered orally as a single enantiomer formulation and as a racemic mixture (tenormin™)
Author(s) -
Clementi William A.,
Garvey Thomas Q.,
Clifton G. Dennis,
McCoy Randall A.,
Brandt Steven,
Schwartz Sheldon
Publication year - 1994
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530060303
Subject(s) - atenolol , chemistry , pharmacokinetics , heart rate , crossover study , blood pressure , oral administration , dosing , urine , enantiomer , pharmacology , medicine , stereochemistry , biochemistry , alternative medicine , organic chemistry , pathology , placebo
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)‐atenolol (Tenormin™) in man. Eight male subjects were given single oral doses of 50 mg of SATN as a single enantiomer formulation (SEF) and 100 mg of Tenormin™ (TMN) using a randomized, double‐blind, 2‐period, complete crossover study design. Subjects performed exercise tolerance 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. Urine was collected for the first 48 h after dosing. Plasma and urine samples were analyzed for SATN and RATN by an enantioselective HPLC method. SEF and Tenormin™ attenuated exercise‐induced increases in heart rate and systolic blood pressure. Mean changes in exercise heart rates 4 h after dosing were −38 ± 3 bpm and −37 ± 3 bpm for SEF and TMN, respectively, P = 0.792. Mean changes in exercise systolic blood pressure were −42 ± 12 mm Hg and −55 ± 14 mm Hg for SEF and TMN, respectively, 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 for SATN after TMN. Mean SATN AUCs 0–24 were 1867 ± 261 and 2543 ± 223 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 SATN 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 urine was significantly lower after SEF than after TMN (18.7 ± 2.7 and 24.2 ± 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 AUCs, C max s, and Aus for RATN compared to SATN were 2806 ± 239 vs 2543 ± 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 bioavailability compared to TMN and RATN plasma levels are higher than SATN after TMN administration. © 1994 Wiley‐Liss, Inc.