Partial metabolic clearances as determinants of the oral bioavailability of propranolol

The objective of this study was to determine the relationships between the total oral clearance of propranolol and the partial clearances through its primary metabolic pathways, i.e. glucuronidation, side-chain oxidation and ring oxidation. Seven young, white males were given single 80 mg oral doses of the drug together with tritium-labelled propranolol. Plasma propranolol was measured by GC/MS and fourteen metabolites were measured in urine by h.p.l.c. with radiometric detection. The total oral clearance of propranolol in these subjects varied about three-fold, from 27.5 to 71.4 ml min-1 kg-1. The clearance through glucuronidation was very similar in all subjects, ranging from 6.8 to 9.9 ml min-1 kg-1. The clearance through side-chain oxidation varied 2.4-fold, from 10.9 to 25.8 ml min-1 kg-1. Increased clearance through this pathway correlated with increased total oral clearance (r = 0.84; P less than 0.02). The clearance through ring oxidation varied as much as 5.6-fold, from 7.5 to 41.8 ml min-1 kg-1. Increased clearance through this pathway correlated highly with increased total oral clearance (r = 0.94; P less than 0.002). These observations indicate that the intersubject variability in the oral clearance of propranolol in young, white males is due mainly to differences in the activity of the ring oxidation pathway, to some extent in the side-chain oxidation pathway, but not to differences in the glucuronidation pathway. The partial metabolic clearance approach adopted in this study may be useful in the investigation of factors influencing the oral bioavailability of propranolol.