Toxicokinetics of a single intravenous dose of rac‐propranolol versus optically pure propranolol in the rat

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.

Pharmacokinetic interaction of ibuprofen enantiomers in rabbits

“…Enantiomeric interactions (Zhou et al 2002) have been reported for D-cefalexin (Tamai et al 1988) during the absorption phase, propranolol (Bode et al 1995) and disopyramide (Takahashi et al 1991) during the distribution phase, cisapride (Desta et al 2001), propafenone (Li et al 1998) and nitrendipine (Tokuma & Noguchi 1995) during the metabolic phase and sotalol (Carr et al 1994) during the excretion phase. As far as the 2-arylpropionic acids (2-APAs) of NSAIDs are concerned, an enantiomer± enantiomer interaction after intravenous administration of flurbiprofen has been demonstrated following displacement from plasma protein binding sites (Berry & Jamali 1989), but there was no evidence of a pharmacokinetic interaction between the enantiomers of etodolac (Brooks & Jamali 1990).…”

Quantification of enantiomers by mass spectrometry based on chemical derivatization and spectral shape deformation quantitative theory

“…Their metabolisms have stereoselective differences . Animal experiments show that the S‐type enantiomer beta‐blockade is about 100 times stronger than the R‐type and has a longer half‐life in the blood . Meanwhile, R‐propranolol can inhibit sexual desire and is a male contraceptive .…”

Supramolecular Systems-Based HPLC for Chiral Separation of Beta-Adrenergics and Beta-Adrenolytics in Drug Discovery Schemes

“…Sometimes, racemic betablockers are toxic showing some serious side effects. For example racemic propranolol is more toxic than its individual enantiomers in rat [39].…”

“…It is also clear from that S-propranolol is capable of providing strong bonding to receptor in comparison to R-enantiomer, and that is why Senantiomer is more pharmacologically active. Besides, other forces such as van der Waals, dipole induced dipole and steric may contribute for the binding of beta-blockers on beta-receptor site [39,40]. …”