Plasma nifedipine concentrations in cardiovascular disease : influencing factors and clinical applications

Challenor, Vivian Francis (1991) Plasma nifedipine concentrations in cardiovascular disease : influencing factors and clinical applications. University of Southampton, Doctoral Thesis.

Abstract

Studies were undertaken to evaluate the contribution of pharmaceutical, physiological and pharmacological influences to the wide inter-individual variability in the plasma concentration of nifedipine following oral administration. In addition, studies were also undertaken to determine the relationship between the plasma concentration of nifedipine and efficacy in chronic stable angina pectoris and Raynaud's phenomenon. A comparison of the pharmacokinetic properties of a novel biphasic formulation of nifedipine and the conventional slow-release tablet, in six healthy volunteers, demonstrated pharmacokinetic properties intermediate between the slow-release tablet and the conventional capsule formulation in the fasted state. Two studies, each containing eight healthy volunteers, demonstrated that food significantly altered the pharmacokinetic properties of both the biphasic and capsule formulations of nifedipine. After food, the pharmacokinetic properties of the biphasic formulation were intermediate between the slow-release and capsule formulations; whereas the pharmacokinetics of the capsule resembled that of the slow-release tablet. The effects of food in delaying gastric emptying appeared to be the major factor leading to these findings. A study of six patients undergoing cardiac catheterisation demonstrated that the liver is the major site of metabolism and clearance of nifedipine in man. Following an intravenous infusion of nifedipine, the trans-hepatic extraction of the drug was determined at 0.64, with hepatic clearance of 65%. Smoking did not have any effect on the pharmacokinetic of nifedipine when 10 healthy volunteers were compared with nine smokers. By contrast in 10 healthy volunteers the plasma concentrations of nifedipine were significantly increased by cimetidine (but not ranitidine). The increase in the plasma concentration of nifedipine as attributed to the inhibitory effect of cimetidine on cytochrome P₄₅₀ rather than any action of gastric secretion and subsequently drug absorption. A double-blind placebo controlled randomised cross-over study of 18 patients demonstrated that nifedipine in the slow-release form is an effective adjunct to β-adrenoceptor antagonist therapy in chronic stable angina. The additional reduction in effort-related angina was closely correlated with the plasma concentration of nifedipine. However, the value of measuring the plasma concentration of nifedipine in clinical practice was limited by the wide inter-individual variability in sensitivity to the drug. Two studies evaluated the efficacy and tolerability of the biphasic and slow-release formulation of nifedipine in Raynaud's phenomenon. Both formulations conferred some benefit in between two-thirds and three-quarters of patients, but the incidence of unwanted effects was higher with the biphasic formulation. Doubling the dose of the slow-release formulation was of additional benefit in some patients, but the response was unpredictable. No clear relationship could be found between plasma concentration of nifedipine and therapeutic response.

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