STEREOCHEMICAL COMPOSITION OF PROPRANOLOL METABOLITES IN THE DOG USING STABLE ISOTOPE-LABELED PSEUDORACEMATES

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 11  (6) , 544-549
Abstract
A larger oral bioavailability of (+)- as compared to (-)-propranolol is seen in the dog. This difference is reflected in the metabolism in the drug. The stereochemical composition of propranolol [an autonomic antihypertensive] and its metabolites was determined in the urine of 4 dogs after single 160-mg oral doses of stable isotope-labeled pseudoracemates of propranolol. All major metabolites, accounting for 84% of the dosage excreted in urine, were isolated by solvent extraction or HPLC [high performance liquid chromatography], glucuronic acid conjugates after enzymatic hydrolysis and analyzed by GC/MS [gas chromatography/mass spectrometry] after chemical derivatization. Of the 3 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. All of the side-chain oxidation metabolites, about 30% of the dose, were mainly derived from (+)-propranolol, (-)/(+)-enantiomer ratio ranging from 0.35-0.74. Ring oxidation, involved in the metabolism of the remainder of the dose studied, about 38%, was also 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, may be due to stereoselective presystemic hepatic removal of (-)-propranolol by glucuronidation and ring oxidation.