Multiple pathways of propranolol's metabolism are inhibited by debrisoquin

We investigated the effect of debrisoquin on propranolol metabolism in six normal subjects who were extensive metabolizers of debrisoquin. Each subject was studied on two occasions. On the first occasion, each subject received oral propranolol (80 mg) alone; on the second occasion, 7 days later, each subject received a dose of propranolol (80 mg) 30 minutes after the administration of oral debrisoquin (40 mg). Oral propranolol clearance was reduced 33% ± 16% (p < 0.05) by the administration of debrisoquin. As predicted, the 4-hydroxypropranolol partial metabolic clearance was significantly (p < 0.05) inhibited by debrisoquin. However, the side-chain oxidation pathway, as measured by naphthoxylactic acid, was also significantly (p < 0.05) inhibited by debrisoquin. Debrisoquin administration did not change the renal clearance of any of the metabolites. These data support the usefulness of the in vivo inhibition model in the prediction of cosegregation of routes of metabolism. However, for propranolol, pathways of its metabolism that are not thought to cosegregate with debrisoquin were also inhibited.