Stereoselective ring oxidation of propranolol in man.

Abstract

1 The objective of this study was to elucidate stereoselective mechanisms of propranolol metabolism in man. Five normal subjects were given single 80 mg oral doses of deuterium-labeled pseudoracemates of propranolol, and the stereochemical composition of propranolol and its major metabolites in urine was determined by GC/MS. 2 The (-)/(+)-enantiomer ratios for unchanged propranolol, 1.50 + 0.10 (mean ± s.e. mean), and propranolol glucuronide, 1.76 + 0.10, were similar to previous findings in plasma. 3 All products of side-chain oxidation also consisted mainly of the (-)-enantiomer, with an overall (-)/(+) ratio of 1.61 + 0.11. 4 A (-)/(+) ratio of 1.04 + 0.17 for 4-hydroxypropranolol did not indicate stereoselectivity in ring oxidation. However, the ratio for its glucuronic acid conjugate of 1.78 ± 0.19 and for its sulphate conjugate of 0.27 ± 0.03 suggested stereoselectivity in either the glucuronidation or sulphation of 4-hydroxypropranolol, or both. 5 When the stereoselectivity in these secondary pathways was taken into consideration, the overall ring oxidation strongly favoured (+)-propranolol with a (-)/(+)-enantiomer ratio of 0.59 ± 0.09.6 The composite observations of the stereochemistry of propranolol metabolism in man are consistent with stereoselective ring oxidation of (+)-propranolol, leading to a greater bioavailability of the pharmacologically more active (-)-propranolol and subsequent preferential side-chain oxidation and glucuronidation of this enantiomer.

Monitoring the Effects of Chiral Pharmaceuticals on Aquatic Microorganisms by Metabolic Fingerprinting

“…Propranolol is routinely administered to humans as the racemate. The (S) enantiomer accounts for the majority of the ␤-blocking effect, while the (R) enantiomer has a predominantly membrane-stabilizing effect (3,17,36,51). We hypothesized that the results for the racemate [(Ϯ)-propranolol] were different from the results for either of the enantiomers because of the difference in the physical properties between the racemate and the enantiomers (8,42).…”

Chiral recognition of Propranolol enantiomers by β-Cyclodextrin: Quantum chemical calculation and molecular dynamics simulation studies

“…Study on properties of Propranolol pharmacological activity is historically long standing [2]. The pharmacological properties of the enantiomers of Propranolol are quite different, and the b-adrenergic blocking activity resides in the (S)-(À) enantiomer, while the (R)-(+)-enantiomer has only a membrane stabilizing effect [3][4][5][6]. Thus, separation of the enantiomers is necessary to meet the increasing demand for evaluation of the pharmacokinetic attributes of each enantiomer and to control the enantiomeric purity of pharmaceutical preparations [7].…”

Chiral Separation of β-Adrenergic Blockers in Human Plasma by SPE-HPLC

“…[1] but, unfortunately, these occur in racemic forms [2]. It is well known that S-(-)-enantiomers of these drugs are about 50-500 times pharmaceutically more active than their antipodes, which act as ballast or other medication; leading to various side effects and, sometimes, toxicities [3][4][5][6][7]. It has been reported that a prolonged use of these drugs (racemic mixtures) might cause diabetes in hypertensive patients [8][9][10].…”