Nifedipine: Influence of renal function on pharmacokinetic/hemodynamic relationship

Abstract

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 t1/2 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.

Serum binding of nifedipine and verapamil in patients with ischaemic heart disease on monotherapy.

“…However, we found no difference in the binding of the parent drugs measured after single dosing, during chronic treatment, and in vitro (Table 1). The extent of nifedipine binding measured in our study (Table 1) was within the limits reported previously in plasma in vitro: 0.8-4% unbound (Von Rosenkrantz et al, 1974;Otto & Lesko, 1986;Kleinbloesem et al, 1985).…”

“…Because of this, more reliable binding data may be obtained using the serum of patients under drug treatment. Comparing such ex vivo data with those found in vitro may detect the influence of metabolites (known and unidentified) and other possible factors which are absent under in vitro conditions There are data on the plasma binding of nifedipine (Von Rosenkrantz et al, 1974;Kleinbloesem et al, 1985;Otto & Lesko, 1986) and verapamil (Schomerus et al, 1976;Yong et al, 1980;Keefe et al, 1981;McGowan et al, 1983) in vitro and after intravenous administration (McGowan et al, 1983;Kleinbloesem et al, 1985). The concentration of metabolites is low after intravenous dosing (Waller et al, 1984) and might not influence the binding of unchanged nifedipine.…”

Pharmacokinetics and pharmacodynamics of nifedipine infusion in normal volunteers.

“…Gradual administration by slow-release tablet, by a rectal osmotic preparation and by slow i.v. infusion without bolus blunts the early tachycardia although the hypotensive effect still occurs (Kleinbloesem et al, 1984c(Kleinbloesem et al, , 1985. Our data suggest that cardiovascular adaptation is rapid.…”

Inhibitory effect of uraemia on the hepatic clearance and metabolism of nicardipine.

“…The protein binding of two dihydropyridine derivatives nifedipine and nitrendipine (Ankermann et al, 1989;Kleinbloesem et al, 1985) was found to be reduced in patients with renal impairment resulting in a significant increase in volume of distribution. The protein binding in the present study was about 98% for the three groups and the volume of distribution was not different between groups 1 and 2.…”

“…Several pharmacologically inactive metabolites are produced 60% of which are excreted via bile and 40% excreted via urine, with less than 1% of the parent drug being eliminated unchanged by the kidney. In general, the metabolism of highly extracted drugs is considered only to be significantly affected by disease of the liver, and not by renal impairment, and many investigators have reported that the pharmacokinetics of calcium antagonist drugs such as verapamil (Mooy et al, 1985) or nifedipine (Kleinbloesem et al, 1985) are not affected by renal impairment. However, since cardiovascular disease and renal impairment frequently coincide, it is important to consider and document the clinical pharmacology of calcium antagonist drugs in patients with renal impairment.…”