Abstract

The intravenous and oral dose kinetics and metabolism of the enantiomers of propranolol were investigated in five dogs during steady-state oral racemic propranolol dosing (5 mg/kg, every 8 hr for 3 days). These results were compared with those obtained during concomitant administration of oral diltiazem (2.5 mg/kg, every 8 hr for 3 days) in the same animals. The oral and intravenous propranolol test doses consisted of a pseudoracemic mixture of equal amounts of hexadeuterated-(R-(+))- and dideuterated-(S-(-))-propranolol. Propranolol metabolism in the urine was evaluated by coadministering 150 muCi of [4'-3H]racemic propranolol HCl, along with the deuterium-labeled compounds. Plasma concentrations of the deuterated enantiomers were measured by HPLC-thermospray MS, using undecadeuterated racemic propranolol as the internal standard. Diltiazem coadministration had no significant effects on either the systemic clearance, renal clearance, the apparent volume of distribution, or the elimination half-lives of either enantiomer. On the other hand, concomitant diltiazem treatment significantly reduced the oral clearance of S-(-)- and R-(+)-propranolol by 58 and 61%, respectively. These reductions resulted in an increase in their respective apparent steady-state oral availabilities of 129 and 106%. The S/R enantiomeric ratio of the oral availability of propranolol was not significantly changed from control. The urinary propranolol metabolites were isolated and purified by solvent extraction and HPLC and quantitated by radioactivity. Twelve metabolites, including propranolol, were isolated and quantitated in the urine. A significant reduction in the percentage of ring oxidation products and a significant increase in the percentage of naphthoxylactic acid and propranolol glucuronide excreted in the urine occurred in the diltiazem-treated animals. The S/R enantiomeric ratios of urinary excreted propranolol, propranolol glucuronide, 4'-hydroxypropranolol glucuronide, and its sulfate were not altered by diltiazem. These results suggest that the decreased oral clearances of the enantiomers of propranolol by diltiazem is caused by a selective decrease in the formation of ring-oxidized products.