1. Toxicokinetics of a single intravenous dose ofrac-propranolol versus optically pure propranolol in the rat
- Author
-
Bode W, L. A. Van Ginkel, D.J. de Wildt, K. Groen, A.A.M. Stolker, A. E. Toet, and J. Wemer
- Subjects
Male ,Adrenergic beta-Antagonists ,Stereoisomerism ,Propranolol ,Pharmacology ,Catalysis ,Analytical Chemistry ,Pharmacokinetics ,Drug Discovery ,medicine ,Animals ,Toxicokinetics ,Rats, Wistar ,Chromatography, High Pressure Liquid ,Spectroscopy ,Volume of distribution ,Dose-Response Relationship, Drug ,Chemistry ,Organic Chemistry ,Half-life ,Rats, Inbred Strains ,Blood Proteins ,Rats ,Dose–response relationship ,Injections, Intravenous ,Enantiomer ,Half-Life ,Protein Binding ,medicine.drug - Abstract
Conscious male Wistar SPF Riv:TOX rats were dosed intravenously with 2.5, 5, or 10 mg/kg rac-propranolol.HCl, or with 5 mg/kg of either (-)-(S)- or (+)-(R)-propranolol.HCl. Disposition of (-)-(S)- and (+)-(R)-propranolol after dosing of rac-propranolol was linear in the dose range examined. Total plasma clearance was not changed in animals dosed with the individual enantiomers compared to the animals that were dosed with rac-propranolol. However, for (-)-(S)-propranolol both volume of distribution and elimination half-life decreased, whereas for (+)-(R)-propranolol increases were observed for these characteristics, in animals dosed with the individual enantiomers. Our observations suggest that the (+)-(R)-enantiomer competes with (-)-(S)-propranolol for plasma protein binding sites, resulting in lower plasma protein binding of the (-)-(S)-enantiomer when the racemate is administered. From recent toxicological experiments, it was concluded that rac-propranolol is more toxic than the individual enantiomers in the rat, when dosed iv at the same total mass. It is concluded that the observed potentiation of toxic effects of propranolol enantiomers when administered as a racemate can at least partly be explained by a pharmacokinetic interaction.
- Published
- 1995
- Full Text
- View/download PDF