Enantioselective inhibitory effect of nicardipine on the hepatic clearance of propranolol in man

Abstract

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.

Protein binding of propranolol and verapamil enantiomers in maternal and foetal serum.

“…In maternal serum there was a small but significant difference in binding between the propranolol enantiomers, as reported previously in non-pregnant subjects [4,6] …”

“…It is not known to what extent binding in foetal serum is enantioselective. Therefore we have measured the binding of the isomers of propranolol and verapamil in pairs of maternal and foetal serum samples obtained at delivery; both drugs are bound to AAG and show enantioselective serum binding in adults [4][5][6]. We also determined whether, based on the foetal/maternal AAG concentration ratio, foetal binding of the enantiomers can be predicted from maternal binding data [1].…”

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

“…This may be due to an enantioselective influence of the interacting drug on not only hepatic, but perhaps also gastrointestinal availability of the enantiomers. The effects of inhibitory interactions at the level of metabolism are generally more apparent on the oral clearance of the ðþÞ enantiomer of propranolol than the ðÀÞ enantiomer, leading to significant increases in the ðþÞ : ðÀÞ ratio in plasma and/or serum [81][82][83][84]. Induction also can lead to stereoselectivity in plasma concentrations, as is demonstrated for verapamil after coadministration of rifampin.…”

Inhibitory Effects of Nicardipine to Cytochrome P450 (CYP) in Human Liver Microsomes

“…Not only CYP3A4 and CYP2D6, but essentially all CYP forms investigated in the present study were also inhibited by nicardipine in vitro as reported by Katoh et al 19) This may account for a reported in vivo pharmacokinetic interaction between nicardipine and other drugs such as propranolol. 20,21) Considering the mechanism of inhibition, a competitive inhibition of these CYPs was suggested in the present study (data not shown). In conclusion, nicardipine can be metabolized mainly by human CYP2C8, CYP2D6 and CYP3A4, whereas it could be a relatively potent competitive inhibitor of these CYPs.…”