Abstract
We characterized the pharmacokinetic interaction between nifedipine and ethanol as a function of route of administration with pharmacokinetic monitoring of both compounds. Nifedipine was infused (8.5 micrograms/min/kg) for 9 hr either i.a. or intraportally to assess the extent of hepatic first-pass metabolism of nifedipine in the rat. Nifedipine clearance and volume of distribution were similar for both routes of administration. Thus, hepatic first-pass metabolism of nifedipine was apparently negligible in our animal preparation. The pharmacokinetics of ethanol were also examined in the animal preparation in order to design a suitable ethanol dosing protocol for the interaction study. The apparent ethanol Vmax and volume of distribution were 1.85 +/- 0.25 mg/min and 723 +/- 91 ml/kg (mean +/- S.D.), respectively. The pharmacokinetic interaction between nifedipine and ethanol was assessed by the following protocol: nifedipine was infused (either i.a. or intraportally) for 9 hr. When nifedipine concentrations reached steady-state at 4 hr, a bolus dose of ethanol (2.0 g/kg) was administered, followed by ethanol infusion (1.85 mg/min). Constant concentrations of ethanol were obtained with this dosing protocol. Nifedipine clearance was decreased by 49% in the presence of blood ethanol concentrations of 2.5 to 2.7 mg/ml, after either route of administration. The volume of distribution of nifedipine was not changed. The ethanol concentrations observed with nifedipine coinfusion were similar to the ethanol concentrations predicted by the ethanol pharmacokinetic parameters. Thus, ethanol altered nifedipine pharmacokinetics in the rat, but not vice versa.