Pharmacokinetics and pharmacodynamics of nitrendipine in healthy subjects and patients with kidney and liver disease

Abstract

Nitrendipine [3-ethyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate] is a calcium antagonist with a dihydropyridine structure that has a great structural resemblance to nifedipine. Instead of a methyl group in position 3, it has an ethyl group and the NO2 group is in the meta instead of in the ortho position. These minor structural differences have a pronounced impact with respect to both the pharmacokinetics and pharmacodynamics of nitrendipine as compared to nifedipine. Based on equimolar plasma concentrations, nitrendipine is on average three times more potent than nifedipine with regard to the reduction of peripheral vascular resistance, arterial blood pressure, and increased leg blood flow. The terminal half-life is on average 8 h, and thus substantially longer than the terminal half-life of 2-3 h for nifedipine. Despite its almost complete absorption, bioavailability is on average 15-25% and shows great interindividual variability ranging from 7 to 40%. The systemic plasma clearance of the drug is on average 18 ml/min/kg and thus approaches the liver blood flow. In patients with liver cirrhosis, the half-life is prolonged to 19.6 h, the total plasma clearance is decreased by 50%, and the bioavailability is more than doubled to 54%. No data are available if liver disease alters the pharmacodynamic response of the drug. Kidney disease has some effect on the disposition of the drug. Systemic clearance is not changed but the terminal elimination half-life is slightly prolonged to 10.5 h. This increase in half-life is due to an increased volume of distribution. Bioavailability, which is 21.2%, is not grossly altered in renal failure.