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 a nd/or the route of administration determines the stereoselective kinet ics 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 s erial 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 enantiome rs were stereoselective, i.e. the AUC(0-->infinity) for (S)-(-)-propra nolol was greater than the AUC(0-->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. Prop ranolol enantiomer plasma protein binding was not stereoselective. In vitro, after the incubation of 5.8 or 58 mu M (RS)-propranolol with ce lls of the intestinal mucosa or the liver, (R)-(+)-propranolol was mor e rapidly metabolized than (S)-(-)-propranolol at both concentrations in the intestine and at the higher concentration in the liver, Incubat ion of the individual enantiomers (2.9 and 29 mu M) showed that in the intestine the intrinsic clearance of (R)-(+)-propranolol was greater than that of (S)-(-)-propranolol but in the liver there was preferenti al saturation of (S)-(-)-propranolol clearance, In conclusion, at low po or iv doses the kinetics of (RS)-propranolol are not stereoselectiv e because the liver overshadows the effect of the intestine, and at hi gh po doses the kinetics of propranolol enantiomers are stereoselectiv e because of hepatic saturation of (S)-(-)-propranolol clearance.