Stereoselective disposition of propranolol in rabbits. Role of presystemic organs and dose.

The kinetics of propranolol enantiomers are stereoselective when high doses of the racemic drug are given po. To document whether the dose and/or the route of administration determines the stereoselective kinetics of propranolol enantiomers, conscious rabbits received 40, 80, or 120 mg/kg po or 0.5 or 10 mg/kg iv doses of racemic propranolol, and serial blood samples were obtained to assay propranolol enantiomers. At low po and iv doses, the kinetics of the propranolol enantiomers were identical. After the 120 mg/kg po dose, the kinetics of the enantiomers were stereoselective, i.e. the AUC0-->infinity for (S)-(-)-propranolol was greater than the AUC0-->infinity for (R)-(+)-propranolol (p < 0.05). The iv injection of 10 mg/kg generated zero-order kinetics, and (S)-(-)-propranolol was eliminated faster than the antipode. Propranolol enantiomer plasma protein binding was not stereoselective. In vitro, after the incubation of 5.8 or 58 microM (RS)-propranolol with cells of the intestinal mucosa or the liver, (R)-(+)-propranolol was more rapidly metabolized than (S)-(-)-propranolol at both concentrations in the intestine and at the higher concentration in the liver. Incubation of the individual enantiomers (2.9 and 29 microM) showed that in the intestine the intrinsic clearance of (R)-(+)-propranolol was greater than that of (S)-(-)-propranolol but in the liver there was preferential saturation of (S)-(-)-propranolol clearance. In conclusion, at low po or iv doses the kinetics of (RS)-propranolol are not stereoselective because the liver overshadows the effect of the intestine, and at high po doses the kinetics of propranolol enantiomers are stereoselective because of hepatic saturation of (S)-(-)-propranolol clearance.