Propranolol's metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities

The relative contributions of the debrisoquin and mephenytoin isozymes of hepatic cytochrome P-450 to the stereoselective metabolism of propranolol have been studied in a panel of volunteers of known oxidative phenotypes. Six subjects were extensive metabolizers of both debrisoquin and mephenytoin (EM). Four subjects were poor metabolizers of debrisoquin but rapid for mephenytoin (PMD). Five subjects were poor metabolizers of mephenytoin but rapid for debrisoquin (PMM), and one individual had a deficiency for both test compounds (PMD/M). Partial metabolic clearances of each propranolol enantiomer to 4-hydroxypropranolol (4-OHP), the sulfate, and glucuronide conjugates of 4-OHP, naphthoxylactic acid (NLA) and propranolol glucuronide, were estimated after a single oral dose of racemic propranolol (80 mg). The partial metabolic clearance of both enantiomers to total 4-OHP in the PMD group was 75% less than in the EM and PMM groups, indicating the contribution of the debrisoquin isozyme to this route of metabolism. The R/S ratios for the clearance to 4-OHP were similar between EM and PMD (2.5 ± 0.5 vs 2.5 ± 0.4, respectively), implying that the different enzymes involved in ring hydroxylation (i.e., the debrisoquin isozyme and other hydroxylases) have similar stereoselective preferences. The partial metabolic clearance to NLA was 55% less in the PMM group than in the EM and PM, groups, indicating that S-mephenytoin 4-hydroxylase contributes to the metabolic conversion of propranolol to NLA. The R/S ratios for the clearance to NLA were close to unity in all groups. The partial metabolic clearance to propranolol glucuronide also did not exhibit stereoselectivity and was similar in all groups. The one subject with deficiencies in both debrisoquin and S-mephenytoin hydroxylase activities had reduced partial clearances of both 4-OHP and NLA and was the only individual to have a reduced total propranolol clearance. Thus two independent isozymes of cytochrome P-450, previously identified as being responsible for debrisoquin and S-mephenytoin hydroxylation, contribute to the two separate oxidative routes of metabolism of propranolol. Deficiencies of both routes result in impaired total clearance of propranolol.