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Toxicokinetics of a single intravenous dose of rac ‐propranolol versus optically pure propranolol in the rat
Author(s) -
Bode Wilhelmina,
Toet Arthur E.,
Stolker Alida A. M.,
Van Ginkel Leendert A.,
Groen Kees,
Wemer Johan,
De Wildt Dick J.
Publication year - 1995
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.530070813
Subject(s) - propranolol , chemistry , enantiomer , pharmacokinetics , volume of distribution , toxicokinetics , pharmacology , toxicity , endocrinology , stereochemistry , medicine , organic chemistry
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. © 1995 Wiley‐Liss, Inc.