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

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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.

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