EFFECTS OF DILTIAZEM ON THE DISPOSITION AND METABOLISM OF THE ENANTIOMERS OF PROPRANOLOL IN THE DOG DURING MULTIPLE ORAL DOSING

The intravenous and oral dose kinetics and metabolism of the enantiome rs of propranolol were investigated in five dogs during steady-state o ral racemic propranolol dosing (5 mg/kg, every 8 hr for 3 days). These results were compared with those obtained during concomitant administ ration of oral diltiazem (2.5 mg/kg, every 8 hr for 3 days) in the sam e animals. The oral and intravenous propranolol test doses consisted o f a pseudoracemic mixture of equal amounts of hexadeuterated-(R-(+))- and dideuterated-(S-(-))-propranolol. Propranolol metabolism in the ur ine was evaluated by coadministering 150 mu Ci of [4'-H-3]racemic prop ranolol HCl, along with the deuterum-labeled compounds. Plasma concent rations of the deuterated enantiomers were measured by HPLC-thermospra y MS, using undecadeuterated racemic propranolol as the internal stand ard. Diltiazem coadministration had no significant effects on either t he systemic clearance, renal clearance, the apparent volume of distrib ution, or the elimination half-lives of either enantiomer. On the othe r 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 apparen t steady-state oral availabilities of 129 and 106%. The SIR enantiomer ic ratio of the oral availability of propranolol was not significantly changed from control. The urinary propranolol metabolites were isolat ed and purified by solvent extraction and HPLC and quantitated by radi oactivity. Twelve metabolites, including propranolol, were isolated an d quantitated in the urine. A significant reduction in the percentage of ring oxidation products and a significant increase in the percentag e 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'-hy droxyprapranolol glucuronide, and its sulfate were not altered by dilt iazem. These results suggest that the decreased oral clearances of the enantiomers of propranolol by diltiazem is caused by a selective decr ease in the formation of ring oxidized products.