Stereoselective Increase in Propranolol Bioavailability during Chronic Dosing in the Dog1

The disposition of (+)- and (-)-propranolol was determined after chronic as compared to single oral doses of racemic drug. Single oral doses (80 mg) of a stable isotope-labeled pseudoracemate were given to six dogs before and after thronic pretreatment with unlabeled propranolol. The bioavailability of (-)-propranolol (5.7 ± 1.6%; mean ± S.E.) was considerably lower (P <.01) than that of (+)-propranolol (1 6.1 ± 5.9%) after single doses. Chronic pretreatment led to a 1 67 % increase in the bioavailability of (-)-propranolol to 1 5.2 ± 3.7 % (P <.01), with only a 47% increase in (+)-propranolol to 23.7 ± 4.5 % (N.S.). Chronic pre-treatment had no effect on the kinetics of i.v. doses of tntium-labeled racemic drug administered simultaneously or on blood binding. This stereoselective increase in the bioavailability of (-)-propranolol was associated with an unexpected 62 % increase in the glucuronidation of this enantiomer (P <.01) with no effect on the glucuronidation of (+)-propranolol. There was, however, a change in the stereochemical composition of 4’-hydroxypro-pranolol from single doses, (-)/(+)-enantiomer ratio 1.37 ± 0.14, to chronic doses, 1.23 ± 0.1 3 (P < 0.05), suggesting stereose-lective inhibition of ring-oxidation of (-)-propranolol. This study demonstrates preferential presystemic hepatic removal of (-)-propranolol in the dog by a process, probably ring-oxidation, that becomes partially inhibited after chronic doses, leading to a stereoselective increase in the bioavailability of this enantiomer. Propranolol (Inderal) is used as a racemate, the (-)-enanti-omer of which is responsible for most of its pharmacological effects (Nies and Gerber, 1980). A number of studies have demonstrated stereochemical differences in the disposition of this drug in both animals (Kawashima et al., 1976; Walle an