Background: Reboxetine [(R,S)-2[(R,S)-alpha-(2-ethoxyphenoxy)benzyl]morpholine methanesulfonate] is a racemic compound that consists of equal proportions of R,R- and S,S-enantiomers. This study investigated the hemodynamic effects of reboxetine and the R,R-enantiomer compared with placebo in volunteers. The pharmacokinetics of reboxetine and its enantiomers were also investigated in the study.
Methods: Nine healthy, male volunteers received single doses of 4 mg reboxetine, 2 mg R,R-enantiomer, and placebo at weekly intervals. Reboxetine and the R,R-enantiomer were well tolerated in all volunteers.
Results: The heart rates of patients in the supine and standing positions were increased after reboxetine administration compared with the R,R-enantiomer (P < .05, except supine heart rate at 6 hours) and placebo (P < .05). Supine systolic and diastolic blood pressure was also increased by 3 +/- 4 and 1 +/- 4 mm Hg, respectively, after reboxetine compared with R,R-enantiomer (-2 +/- 4 and -4 +/- 3 mm Hg) and placebo (-4 +/- 4 and -4 +/- 4 mm Hg) administration. The systolic and diastolic blood pressure measurements for subjects while standing did not differ significantly among treatments. There was no significant difference between the maximum plasma concentration, mean time to maximum plasma concentration, plasma half-life, or area under the plasma concentration-time curve (AUC) of the R,R-enantiomer after reboxetine or R,R-enantiomer administration. The ratio of the mean AUC values for the R,R- and S,S-enantiomers was 2.1.
Conclusion: These findings suggest that the S,S-enantiomer is responsible for the hemodynamic effects of reboxetine in humans. Increases in supine blood pressure after reboxetine administration may be interpreted as regression to the mean value and not caused by any treatment effect.