J. Van Harten

Liquid chromatographic determination of nifedipine in plasma and of its main metabolite in urine.

A high-performance liquid chromatographic method was developed for the assay of nifedipine in plasma and its main metabolite (M-I) in urine. After liquid-liquid extraction nifedipine was chromatographed in a reversed-phase system with ultraviolet detection at 238 nm. The method was sensitive to 2 ng nifedipine per ml plasma and the standard curve was linear to at least 400 ng/ml. Standard deviations did not exceed 8.5%. There was no interference with photodecomposition products or metabolites. M-I was determined in urine after liquid-liquid extraction by ion-pair chromatography with ultraviolet detection at 290 nm. The method was sensitive to 0.02 micrograms M-I per ml urine and the standard curve was linear to at least 5 micrograms/ml. Standard deviations did not exceed 5.0%. The methods were used to study nifedipine disposition in healthy volunteers.

Nifedipine: kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration

The pharmacokinetics and hemodynamic effects of nifedipine were studied in patients with liver cirrhosis and in age‐matched healthy control subjects. In a randomized order each subject received nifedipine by intravenous infusion (4.5 mg in 45 minutes) and as a tablet (20 mg). After intravenous nifedipine patients had a longer elimination t½ (420 ± 254 vs. 111 ± 22 minutes; P < 0.01), a greater volume of distribution (1.29 ± 0.60 vs. 0.97 ± 0.42 L/kg), and a lower systemic clearance (233 ± 109 vs. 588 ± 140 ml/min; P < 0.001). Plasma protein binding of nifedipine was lower in the patients (P < 0.001). After oral nifedipine systemic availability was much higher in patients (90.5% ± 26.2% vs. 51.1% ± 17.1%; P < 0.01) and maximal in patients with a portacaval shunt. Blood pressure decreased and heart rate increased after intravenous nifedipine and these effects could be fitted to plasma concentrations by a sigmoidal model. Maximal effects on heart rate and diastolic blood pressure were not different in liver cirrhosis. When free drug levels were considered, the concentrations corresponding to half the maximal effect were also not different. Blood pressure changes with oral nifedipine were comparable with those after intravenous infusion. We conclude that in patients with liver cirrhosis the pharmacokinetics of nifedipine are considerably altered; dose reduction is recommended when such patients need oral nifedipine.

Nifedipine: influence of renal function on pharmacokinetic/hemodynamic relationship.

The hemodynamic effects and kinetics of nifedipine were examined in four groups of five subjects with different degrees of impaired renal function. In a randomized order, each subject received nifedipine by an intravenous infusion (4.5 mg in 45 minutes) and by mouth as a sustained‐release tablet (20 mg). Plasma concentrations of nifedipine and urinary metabolite excretion were measured by liquid chromatography. Heart rate, blood pressure, forearm blood flow, and plasma norepinephrine levels were examined serially. After intravenous nifedipine infusion, the elimination t½ was 106 ± 24 minutes in controls and increased gradually across the groups to 230 ± 94 minutes in the group with severe renal impairment. In these same groups, the volume of distribution at steady state was 0.78 ± 0.23 and 1.47 ± 0.24 L/kg, but total systemic clearance did not differ. Plasma protein binding decreased from 96.0% ± 0.5% in controls to 93.5% ± 0.4% in severe renal insufficiency. Except for systemic clearance, kinetics were closely related to creatinine clearance, as was the urinary excretion of the main nifedipine metabolite. Except for systemic availability, which tended to decrease, the kinetics of nifedipine tablets were not influenced by the degree of renal failure. Hemodynamic effects after intravenous nifedipine could be fit to plasma concentrations under a sigmoidal model. When compared with control values, the maximal effect on diastolic blood pressure was more than doubled in severe renal failure. The inverse correlation between maximal effect on diastolic blood pressure and creatinine clearance (r = − 0.68) was independent of pretreatment values. Neither free drug levels corresponding to 50% of the maximal effect on diastolic blood pressure nor the slope of the concentration‐effect curve was influenced by the degree of renal impairment. The maximal effect on forearm blood flow tended to increase in renal failure, whereas the effect on heart rate was unchanged. Blood pressure changes after oral nifedipine were of the order of those after intravenous infusion. We conclude that, although nifedipine kinetics differ in patients with renal failure, these changes do not explain the greater blood pressure lowering effect.

Nifedipine kinetics and dynamics during rectal infusion to steady state with an osmotic system

Nifedipine steady‐state kinetics and dynamics were investigated in a placebo‐controlled study of six healthy subjects. Nifedipine was given rectally through an osmotic system at a zero‐order rate for 24 hr. Steady‐state plasma concentrations of approximately 20 ng/ml were achieved within 6 to 8 hr. Nifedipine lowered diastolic blood pressure (DBP) and increased forearm blood flow (FBF) and plasma norepinephrine concentration. On the other hand, heart rate (HR) and systolic blood pressure were not affected. Changes in DBP and FBF were closely related to nifedipine plasma concentrations during and immediately after the infusion period. Our data indicate that nifedipine lowers blood pressure in subjects with normotension and that it is possible by infusing the drug at a relatively low rate to dissociate its effect on blood pressure from that on HR.

Nisoldipine: Kinetics and effects on blood pressure and heart rate in patients with liver cirrhosis after intravenous and oral administration

SummaryThe pharmacokinetics and effects on blood pressure and heart rate of nisoldipine were studied in 8 patients with cirrhosis and in 8 age-matched healthy controls. On separate occasions each subject received nisoldipine by i.v. infusion (0.37 mg in 40 min) and as a tablet (5 mg for patients and 20 mg for control subjects).After i.v. nisoldipine, the elimination half-life was 9.7 h in control subjects and 16.6 h in the cirrhotics. The volume of distribution was 4.1 l/kg and 6.4 l/kg and the total systemic clearance was 847 ml/min and 494 ml/min, respectively. On oral nisoldipine, systemic availability was fourfold higher in patients with cirrhosis: 14.7% versus 3.7%.After i.v. administration of nisoldipine there was a brief decrease in systolic and diastolic blood pressure in both groups, whereas the heart rate increased. After 4 h a second effect peak appeared in the control subjects. After oral nisoldipine similar effect-time profiles were found, but effects lasted longer than after i.v. administration.Comparison of the maximal total plasma concentration of nisoldipine and the maximal effect in the two groups revealed that sensitivity to nisoldipine was not different in patients with cirrhosis.A reduction in the dose of nisoldipine is recommended when cirrhotics require oral nisoldipine in therapeutic practice.

Pharmacokinetics and Haemodynamic Effects of Nisoldipine in Patients with Liver Cirrhosis

In eight patients with liver cirrhosis and in eight control subjects the pharmacokinetics and haemodynamic effects of nisoldipine were studied. In a randomised crossover study design the participants received nisoldipine by intravenous infusion (0.37 mg in 40 min) and as a tablet (5 mg for the patients; 20 mg for control subjects). Heart rate and blood pressure were measured serially. Blood samples were taken regularly for determination of nisoldipine concentration. After intravenous nisoldipine, plasma half-life was 9.7 ± 5.4 h in the control subjects and 16.6 ± 4.6 h in the liver patients (P <0.02). Volume of distribution was 4.1 ± 2.1 liter/kg and 6.4 ± 2.3 liter/kg (NS) respectively, and systemic clearance was 0.85 ± 0.31 liter/min and 0.49 ± 0.12 liter/ min, respectively (P <0.01). On oral nisoldipine systemic availability was much higher in the patient group (14.7 ± 10.1% vs 3.7 ± 2.1% (P <0.01)).