Quinidine reduces clearance of (+)-propranolol more than (-)-propranolol through marked reduction in 4-hydroxylation

Because both quinidine and propranolol bind to the cytochrome P-450 responsible for the oxidation of debrisoquin, six healthy male subjects were studied to determine whether an interaction occurred between the two drugs and the pharmacodynamic consequences of that interaction. The coadministration of quinidine resulted in a doubling of the area under the plasma concentration-time curve of (+/-)-propranolol (530 +/- 99 versus 1051 +/- 138 ng.hr/ml; p less than 0.05) and a reduction in the clearance of (+/-)-propranolol from 3087 +/- 648 to 1378 +/- 173 ml/min (p less than 0.05). The metabolism of propranolol by the 4-hydroxylation pathway was almost abolished by quinidine, resulting in a fall in the partial metabolic clearance by this pathway from 678 +/- 246 to 56 +/- 11 ml/min (p less than 0.05). Quinidine differentially affected the metabolism of (+)-propranolol and (-)-propranolol, resulting in an increase of 176.6% +/- 45.5% and 100.4% +/- 25.5% in the area under the plasma concentration-time curve of (+)-propranolol and (-)-propranolol, respectively (p less than 0.05). The pharmacokinetic changes were associated with pharmacodynamic effects. The combination of propranolol and quinidine resulted in increased beta-blockade measured by reduction in exercise heart rate and prolongation of the QTc and PR intervals. We conclude that quinidine stereoselectively inhibits the metabolism of propranolol through inhibition of the debrisoquin isozyme. The increased concentration of propranolol produced by quinidine results in increased beta-blockade.