The influence of a single oral dose of 30 mg nicardipine on the pharmacokinetics of (R)- and (S)-propranolol, given orally as rac-propranolol 80 mg, was studied in 12 healthy volunteers. The plasma concentrations were higher for the (S)-enantiomer than for the (R)-enantiomer. The Cl(o) and the Cl'intr of (S)-propranolol were significantly lower than the Cl(o) and Cl'intr of (R)-propranolol. The unbound fraction of (R)-propranolol was significantly higher than that of (S)-propranolol. Coadministration of nicardipine significantly increased the AUC and Cmax 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 nicardipine. The enantioselective effect of nicardipine on the metabolic clearance of propranolol appears to be due to an interaction at the level of the metabolizing enzymes. The effect on blood pressure of rac-propranolol was little affected when nicardipine was coadministered with rac-propranolol, and its bradycardic effect was reduced.

1 The influence of a single oral dose of nicardipine 30 mg on the pharmacokinetics and pharmacodynamics of propranolol 80 mg was investigated in twelve healthy volunteers. 2 Co-administration of nicardipine significantly increased the AUC and the mean Cmax of propranolol. 3 Blood pressure and heart rate tended to decrease more when propranolol and nicardipine were administered together than when propranolol was given alone, but differences are of doubtful significance. 4 The results indicate that nicardipine alters the pharmacokinetics of propranolol by impaired hepatic 'first-pass' clearance, but pharmacodynamics were little affected.

The influence of the dihydropyridine calcium entry blockers nicardipine, amlodipine, nifedipine, isradipine and of the dihydropyridine calcium entry promotor BAY K 8644 on the disappearance rate of propranolol by isolated rat hepatocytes was compared to the effect of diltiazem and verapamil, two non-dihydropyridine calcium channel blockers and known inhibitors of hepatic cytochrome P450 mixed function oxidases. All compounds dose-dependently inhibited the disappearance rate of propranolol. Nicardipine and isradipine were more potent in inhibiting the disappearance rate of propranolol than the other dihydropyridines and than diltiazem and verapamil. The inhibitory effect of nicardipine on the disappearance rate of propranolol was not stereoselective and was not influenced by age.

To determine the effect of dihydropyridines on the metabolism of propranolol, we studied the effects of a single oral dose of nicardipine, nifedipine, and BAY-K-8644 on the pharmacokinetics of propranolol in male Wistar rats fitted with a catheter in the jugularis vein. Oral propranolol (15 mg/kg and 1.5 mg/kg) and intravenous propranolol (1.5 mg/kg) were administered either alone or together with oral nicardipine (2.5 mg/kg). Oral propranolol (15 mg/kg) was administered with oral nifedipine (1.5 mg/kg) and with oral BAY-K-8644 (1.5 mg/kg). Nicardipine increased significantly the AUC and Cmax of oral propranolol (1.5 mg/kg and 15 mg/kg). However, the plasma concentration time curve of intravenous propranolol (1.5 mg/kg) was unaffected. Nifedipine also significantly increased the AUC and Cmax of oral propranolol (15 mg/kg), whereas with BAY-K-8644 there was only a slight increase in the bioavailability of oral propranolol (15 mg/kg). The results indicate that the dihydropyridine calcium antagonists decrease the metabolism of propranolol as a result of a decrease in first-pass clearance. Although an interaction at the level of cytochrome P450 may also be involved, the results of the present study suggest that the inhibitory effect can be largely attributed to changes in liver blood flow.

After i.v. administration of racemic metoprolol in the rat, the plasma concentrations of (R)- and (S)-metoprolol were comparable, and no differences in pharmacokinetic parameters between the two enantiomers were found. From the 3rd to the 12th month, comparable changes were seen for both enantiomers: there was an increase in the area under the plasma concentration-time curve (AUC) and a decrease in blood and plasma clearance. Half-life showed a significant prolongation, volume of distribution decreased between 3 and 12 months and increased between 12 and 24 months. After oral administration of the racemate, AUC and Cmax (maximum plasma concentration) were slightly higher, while oral clearance was slightly lower for (R)-metoprolol than for (S)-metoprolol. With aging, Cmax and AUC increased for both enantiomers, while oral clearance decreased. The change in oral clearance as a function of age is different between (S)- and (R)-metoprolol, and thus enantioselective. In vitro disappearance rate in 3-month-old rats was significantly higher for (S)-metoprolol than for (R)-metoprolol, although the difference was small. With aging, the disappearance rates of both enantiomers increased significantly, but not enantioselectively.