STEREOSELECTIVE INCREASE IN PROPRANOLOL BIOAVAILABILITY DURING CHRONIC DOSING IN THE DOG

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Abstract
The disposition of (+)- and (-)-propranolol [an autonomic antihypertensive] 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 6 dogs before and after chronic pretreatment with unlabeled propranolol. The bioavailability of (-)-propranolol (5.7 .+-. 1.6%; mean) was considerably lower (P < 0.01) 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 < 0.01), with only a 47% increase in (+)-propranolol to 23.7 .+-. 4.5% (N.S. [not significant]). Chronic pretreatment had no effect on the kinetics of i.v. doses of 3H-labeled racemic drug administered simultaneously or on blood binding. The stereoselective increase in the bioavailability of (-)-propranolol was associated with an unexpected 62% increase in the glucuronidation of this enantiomer (P < 0.01) with no effect on the glucuronidation of (+)-propranolol. There was 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 < 0.05), suggesting stereoselective inhibition of ring-oxidation of (-)-propranolol. This study demonstrates preferential presynaptic 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.