Oral absorption profile of nitrendipine in healthy subjects: a kinetic and dynamic study.

Abstract

1 In nine healthy male subjects the kinetics of nitrendipine were assessed after i.v. administration and its absorption profile was studied when given by a tablet formulation and by an osmotic pumping device (Osmet) with a zero-order in vitro release of 2.62 ± 0.19 mg h-' for 13 h.2 Plasma concentrations of nitrendipine and its pyridine metabolite, heart rate and blood pressure were determined at regular intervals after drug administration. 3 After i.v. nitrendipine, the plasma concentration declined triexponentially with a mean terminal elimination half-life of 11.7 ± 5.4 h. The mean systemic plasma clearance was 1.47 ± 0.22 1 min-1. 4 Administration of the Osmet resulted in a relatively smooth plasma concentrationtime profile in comparison with the tablet. The mean plateau concentration was 2.63 + 1.31 ng ml-1 and the duration of this plateau was 10.7 ± 3.2 h. The intake of food gave rise to a transient increase of the plasma concentration of both nitrendipine and its pyridine metabolite.5 The mean bioavailability of nitrendipine from the Osmet (8.2 ± 1.6%) was lower than from the tablet (11.1 ± 4.5%), which is probably due to release of nitrendipine in lower parts of the G.I. tract where absorption is not or less possible. 6 Intravenous administration caused a transient decrease in DBP of 26 ± 4%, accompanied by a maximal reflex tachycardia of 46 ± 17%. No clear haemodynamic effects were observed after oral administration. The Osmet produced less side-effects (headache) than the tablet.

Stereoselective pharmacokinetics of oral and intravenous nitrendipine in healthy male subjects.

“…The present data were obtained by reanalysing plasma samples obtained in a previous study published in this Journal where a full description of subjects, experimental drugs, ethics approval and experimental protocol is given (Soons et al, 1989).…”

“…A likelihood ratio test was applied to discriminate between functions (Landaw & DiStefano, 1984). All other pharmacokinetic parameters (area under plasma concentration-time curve (AUC), systemic plasma clearance (CL), absolute systemic bioavailability (F), volume of distribution at steady state (V,,), mean residence time (MRT) and mean absorption time (MAT) were calculated using standard non-compartmental techniques (Gibaldi & Perrier, 1982;Soons et al, 1989). As an index of stereoselectivity in pharmacokinetics, the S-to-R-ratio of pharmacokinetic parameters was calculated for each subject.…”

“…Data concerning haemodynamic and adverse effects, as well as pharmacokinetic data for the primary pyridine metabolite, have been reported previously (Soons et al, 1989), and will not be discussed in this paper.…”

“…Some preliminary results with nitrendipine, administered as unlabelled racemate, have been reported (Soons et al, 1990b). We have previously reported on the pharmacokinetics and oral absorption profile of racemic nitrendipine (Soons et al, 1989). At the time of that study (1986) stereoselective analytical methodology was not available.…”

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1 Stereoselectivity in the pharmacokinetics of nitrendipine was investigated by re-analysing plasma samples of a previously published study (Soons et al, 1989 4 The clearance of intravenously administered (S)-nitrendipine was slightly (7%) lower than that of (R)-nitrendipine, but elimination half-lives and volumes of distribution were similar. 5 The difference in disposition of nitrendipine enantiomers is most likely related to a difference in activity of the cytochrome P-450 system towards the enantiomers, giving rise to a two-fold difference in first-pass elimination.

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