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

Abstract 1. Stereoselectivity in the pharmacokinetics of nitrendipine was investigated by reanalysing plasma samples of a previously published study (Soons et al., 1989). 2. Racemic nitrendipine was administered intravenously (40 micrograms kg-1) and orally, both as plain tablet (20 mg) and in an osmotic pump device (40 mg Osmet) to nine healthy male subjects. Nitrendipine enantiomers were measured with a stereoselective assay. 3. Upon oral administration (tablet) the bioavailability of (S)-(-)-nitrendipine (13.4% +/- 5.6%) was 75% (50% - 98%) higher than that of (R)-nitrendipine (7.9% +/- 4.0%) (mean +/- s.d. (95% confidence interval)). Values of AUC and Cmax for (S)-nitrendipine were 90% (55% - 121%) and 77% (51% - 100%) higher respectively, than those for (R)-nitrendipine. Similar results were obtained with the osmotic system. 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. 6. Stereoselectivity in the first pass metabolism of nitrendipine exhibited little intersubject variability and therefore is not a major factor in the wide variability in systemic availability of the more-potent (S)-enantiomer.