Key result
Nicardipine significantly increases systemic exposure and reduces clearance of unbound propranolol enantiomers.
Why the study?
The enantioselective inhibitory effect of nicardipine on the hepatic clearance of propranolol and its impact on pharmacokinetics were not fully characterized in humans.
Does a single oral dose of nicardipine alter the pharmacokinetics of (R)- and (S)-propranolol in healthy volunteers?
Does a single oral dose of nicardipine alter the pharmacokinetics of (R)- and (S)-propranolol in healthy volunteers?
Nicardipine enantioselectively inhibits the hepatic clearance of propranolol, increasing its plasma concentrations and reducing its bradycardic effect.
May increase propranolol exposure in healthy volunteers; leaves open clinical relevance and need for dose adjustment in patients.
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.
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Vercruysse et al. (1994) studied Healthy volunteers (n=12). Nicardipine vs. Propranolol alone was evaluated on Pharmacokinetics (AUC, Cmax, and clearance) of (R)- and (S)-propranolol. Coadministration of nicardipine significantly increased the AUC and Cmax and significantly decreased the clearance of unbound (R)- and (S)-propranolol.
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