Pharmacokinetics of nifedipine in humans

Ahsan, Chowdhury Hafizul (1991) Pharmacokinetics of nifedipine in humans. University of Southampton, Doctoral Thesis.

Abstract

Nifedipine is a dihydropyridine calcium antagonist which is widely used in the treatment of hypertension and ischaemic heart disease. After oral administration, nifedipine undergoes extensive first-pass metabolism and shows wide interindividual variability in its pharmacokinetic parameters. Polymorphic oxidation of nifedipine has been found in one out of three published studies in Caucasian populations, which reported a very high area under the plasma concentration time curve in 17% of subjects. The different results in these studies may have originated from the different doses and formulations used. The influence of dose has been studied in a group of 30 subjects in Southampton given nifedipine doses ranging from 10 to 30mg as capsules. The Caucasians (n= 27) in this study showed essentially linear kinetics for the parent drug and for its nitropyridine first-pass metabolite. The distributions of all the kinetic parameters after each of the three doses were unimodal. One individual, who came from Bangladesh, showed a much higher AUC and terminal half-life (t¹/₂) of nifedipine. Standing and recumbent right postures were shown to favour gastric emptying and rapid delivery of nifedipine (20mg) given as capsules to the site of first-pass metabolism. This resulted in higher AUC values of the parent drug on standing and right recumbent postures compared to the left recumbent condition which was associated with delayed gastric emptying. No significant change in the AUC of the nitropyridine metabolism was noted. These findings were suggestive of saturation of the first-pass metabolism of nifedipine on standing and right recumbent postures. Therefore postures of a subject could contribute to interindividual variability in the AUC of nifedipine after oral administration. Food with a high fat content affected the plasma concentration-time profile of nifedipine given as 20mg slow release tablets and resulted in higher plasma concentrations from 5 to 12h after the dose compared to the fasting condition. Although a significantly higher AUC of nifedipine was observed when calculated from 0-24h, no significant difference in the overall AUC from 0-00 (which is the proper estimate of comparative bioavailability) was noticed. The high AUC and t¹/₂ values of nifedipine in the South Asian (in the study on different doses) was confirmed in a further 4 South Asian subjects given 20mg as capsules. Ingestion of a spicy curry diet for three days by Caucasians did not significantly increase either the AUC or t¹/₂ of nifedipine. Ethnic influences on the kinetics of nifedipine were studied further in 25 South Asians at Dhaka, Bangladesh and the kinetic results of a total of 30 South Asian subjects were compared with those observed in 27 Caucasians. South Asians showed two and half fold higher AUC and t¹/₂ of nifedipine; this suggests a decreased activity of cytochrome P-450IIIA, the enzyme responsible for oxidation of nifedipine. Interestingly the AUC and t¹/₂ of the nitropyridine metabolite were also higher in South Asians suggesting an additional deficiency in cytochrome P450_PB-B or P450_betaNF which is involved in the further biotransformation of the metabolite. The studies described in the present thesis investigated the importance of dose, formulation and factors such as food and posture on the kinetics of nifedipine. The studies demonstrated the lack of polymorphism and absence of non-linear kinetics of nifedipine in a Caucasian population but found significant inter-ethnic differences between Caucasians and South Asians. These findings have therapeutic implications in designing dosage regimens for treating patients of South Asian origin with nifedipine.

This record has no associated files available for download.

Contributors

Download statistics