Quantitative account of propranolol metabolism in urine of normal man.

A recent study, identifying several sulfate conjugates, appears to have led to a full qualitative account of propranolol metabolism in man. The objective of the present investigation was to determine the quantitative fate of propranolol, including the relationship between the primary metabolic pathways, i.e. glucuronidation, side-chain oxidation and ring oxidation. Single 80-mg oral doses of propranolol together with [3H]propranolol were administered to seven normal subjects. Urinary metabolites were determined by HPLC with radiometric detection after hydrolysis of glucuronic acid conjugates and fractionation by solvent extraction. About 90% of the dose was recovered in urine. Twelve metabolites accounted for 91% of the recovered dose. When examining the metabolites based on the primary metabolic pathways, 17% of the dose (range, 10-25%) was going through glucuronidation, 41% (range, 32-50%) through side-chain oxidation, and 42% (range, 27-59%) through ring oxidation. These data show that the net elimination of propranolol is largely due to oxidative metabolism. The relative contribution of the primary pathways is well reflected by the four major propranolol metabolites, i.e. propranolol glucuronide, naphthoxylactic acid, and the glucuronic acid and sulfate conjugates of 4'-hydroxypropranolol. These observations should greatly facilitate future studies of the biochemical mechanisms of propranolol disposition.