Stereoselective increase in propranolol bioavailability during chronic dosing in the dog

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 chronic pretreatment with unlabeled propranolol. The bioavailability of (-)-propranolol (5.7 +/- 1.6%; mean +/- S.E.) was considerably lower (P less than .01) than that of (+)-propranolol (16.1 +/- 5.9%) after single doses. Chronic pretreatment led to a 167% increase in the bioavailability of (-)-propranolol to 15.2 +/- 3.7% (P less than .01), with only a 47% increase in (+)-propranolol to 23.7 +/- 4.5% (N.S.). Chronic pretreatment had no effect on the kinetics of i.v. doses of tritium-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 less than .01) with no effect on the glucuronidation of (+)-propranolol. There was, however, a change in the stereochemical composition of 4'-hydroxypropranolol from single doses, (-)/(+)-enantiomer ratio 1.37 +/- 0.14, to chronic doses, 1.23 +/- 0.13 (P less than 0.05), suggesting stereoselective 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.