Nifedipine: Kinetics and dynamics in healthy subjects

Abstract

Nifedipine, a Ca entry-blocker, is used in agina pectoris and more recently also in arterial hypertension. Kinetics and pharmacologic effects of 3 formulations of nifedipine were examined in 6 healthy young men in a crossover design. Each subject received i.v. nifedipine, 0.015 mg/kg body wt, 20 mg in a capsule and 20 mg in a slow-release tablet. Changes in heart rate (HR), blood pressure, heart dimensions and plasma norepinephrine levels (PNE) were examined serially. Plasma concentrations of nifedipine (Cp) and urinary metabolite concentrations were measured by liquid chromatography. After i.v. injection the elimination t1/2 [half-life] was 1.7 .+-. 0.4 h, systemic clearance was 26.7 .+-. 5.4 l/h and volume of distribution was 0.8 .+-. 0.2 l/kg. After the capsule, Cp rose rapidly, to a maximum concentration (Cmax) of 117 .+-. 15 ng/ml at a maximum time (tmax) of 1.4 .+-. 0.5 h. After the sustained release tablet tmax was 4.2 .+-. 0.7 h and Cmax was 26 .+-. 10 ng/ml. Nifedipine bioavailability was 56% .+-. 25% for the capsule and 52% .+-. 13% for the tablet, but there were large interindividual differences. Urinary excretion was 58% .+-. 13% 24 h after i.v. injection, and after 32 h was 55% .+-. 13% after capsules and 32% .+-. 8% after tablets. HR increased briefly after i.v. injection and after capsules (15-20 bpm [beats/min]), but not significantly after tablets. Diastolic blood pressure (DBP) fell briefly after capsules (8-10 mm Hg), but there was a sustained effect after tablets. Cardiac dimensions were unchanged. PNE levels paralled plasma drug levels in the 3 experiments. There was a hyperbolic correlation between nifedipine Cp and changes in DBP (r2 = 0.86), with a minimal effective concentration of about 15 ng/ml. Nifedipine kinetics evidently correlate directly with the effect on blood pressure and HR. Side effects from a high Cmax can be avoided with the tablet. It is likely that twice-daily dosing will induce a continued effect.