ENANTIOSELECTIVE INHIBITORY EFFECT OF NICARDIPINE ON THE HEPATIC-CLEARANCE OF PROPRANOLOL IN MAN

The influence of a single oral dose of 30 mg nicardipine on the pharma cokinetics of (R)- and (S)-propranolol, given orally as rac-propranolo l 80 mg, was studied in 12 healthy volunteers. The plasma concentratio ns were higher for the (S)-enantiomer than for the (R)-enantiomer. The Cl-o, and the Cl'(intr) of (S)-propranolol were significantly lower t han the Cl-o and Cl'(intr) of(R)-propranolol The unbound fraction of ( R)-propranolol was significantly higher than that of(S)-propranolol, C oadministration of nicardipine significantly increased the AUC and C-m ax and significantly decreased the Cl-o and Cl'(intr) for unbound drug of (R)- and (S)-propranolol. These changes were more important for (R )- than for (S)-propranolol. The protein binding was not altered by ni cardipine. The enantioselective effect of nicardipine on the metabolic clearance of propranolol appears to be due to an interaction at the l evel of the metabolizing enzymes. The effect on blood pressure of rac- propranolol was little affected when nicardipine was coadministered wi th rac-propranolol, and its bradycardic effect was reduced. (C) 1994 W iley-Liss, Inc.