Stereochemical composition of propranolol metabolites in the dog using stable isotope-labeled pseudoracemates

Previous studies have demonstrated a larger oral bioavailability of (+)- as compared to (-)-propranolol in the dog. The objective of the present study was to examine how this difference is reflected in the metabolism in the drug. The stereochemical composition of propranolol and its metabolites was, therefore, determined in the urine of four dogs after single 160-mg oral doses of stable isotope-labeled pseudoracemates of propranolol. All major metabolites, accounting for 84% of the dose excreted in urine, were isolated by solvent extraction or HPLC, glucuronic acid conjugates after enzymatic hydrolysis, and analyzed by GC/MS after chemical derivatization. Of the three primary metabolic pathways, glucuronidation of the parent drug, about 16% of the dose recovered in urine, was highly selective for (-)-propranolol, (-)/(+)-enantiomer ratio 3.5. In contrast, all of the side-chain oxidation metabolites, about 30% of the dose, were mainly derived from (+)-propranolol, (-)/(+)-enantiomer ratio ranging from 0.35 to 0.74. Ring oxidation, involved in the metabolism of the remainder of the dose studied, about 38%, was, however, also found to be selective for (-)-propranolol, with the greatest selectivity observed in 4'-hydroxypropranolol, (-/(+)-enantiomer ratio 1.49. There was an excellent mass balance for the enantiomers of the metabolites studied, i.e. the total (-)/(+)-enantiomer ratio was close to unity. The higher oral bioavailability of (+)-propranolol in the dog, well reflected in the stereochemical composition of unchanged propranolol in urine, is suggested to be due to stereoselective presystemic hepatic removal of (-)-propranolol by glucuronidation and ring oxidation.