Titre du document / Document title

Determination of serum reboxetine enantiomers in patients on chronic medication with racemic reboxetine

Auteur(s) / Author(s)

ÖHMAN Daniel ⁽¹⁾ ; CHERMA Maria D. ⁽¹⁾ ; NORLANDER Björn ⁽¹⁾ ; BENGTSSON Finn ^{(1 2)} ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Department of Medicine and Care, Division of Clinical Pharmacology, University Hospital, Linköping University, SUEDE
⁽²⁾ Department of Pharmacology, Royal Danish School of Pharmacy, Copenhagen, DANEMARK

Résumé / Abstract

The chiral compound reboxetine is used as a selective noradrenaline re-uptake inhibitor (NARI) for the treatment of major depressive disorders. The pharmacokinetic variability of the enantiomers of the drug (S.S- and R,R-reboxetine) was studied using stereoselective high-performance liquid chromatography with mass spectrometric detection in a controlled clinical monotherapy situation (trial I) and a naturalistic clinical setting (trial II). Trial I included patients receiving racemic reboxetine as 6-month monotherapy for treatment of major depressive disorder. Trough level serum samples in steady state were analyzed for the concentration of the reboxetine enantiomers in study weeks 4, 12, and 24. In a therapeutic drug monitoring setting (trial II), 47 patients on doses ranging from 4 to 16 mg daily, including much polypharmacy, trough level steady-state serum samples were analyzed by the same bioanalytical method. Data from trials I and II were assessed to determine the inter- and intraindividual pharmacokinetic outcomes. The results showed that the median S,S/R,R ratio in steady state was 0.5 and ranged from 0.22 to 0.88. It was also shown that women have an approximately 30%higher S,S/R.R ratio than men.. The S,S/R,R ratios of reboxetine were not found to correlate with reboxetine concentrations. To investigate the NARI activity of a circulating serum reboxetine concentration, a recalculation of the determined enantiomeric concentrations to previously demonstrated experimental NARI potencies of the drug enantiomers was performed. This partly novel concept of estimating pharmacodynamic activity showed that the serum NARI activity in women tended to be higher than in men at a given reboxetine concentration. In conclusion, the variability in the NARI activity per nmol/L reboxetine and the variability in the concentration outcome of the reboxetine enantiomers may justify the use of enantioselective drug monitoring in the clinic. The gender aspects of the drug have to be further assessed.

Revue / Journal Title

Therapeutic drug monitoring   ISSN 0163-4356   CODEN TDMODV 

Source / Source

2003, vol. 25, n^o2, pp. 174-182 [9 page(s) (article)] (31 ref.)

Langue / Language

Anglais

Editeur / Publisher

Lippincott Williams & Wilkins, Hagerstown, MD, ETATS-UNIS  (1979) (Revue)

Mots-clés anglais / English Keywords

Mood disorder ; Comparative study ; Antidepressant agent ; Quantitative analysis ; HPLC chromatography ; Mass spectrometry ; Treatment ; Chemotherapy ; Human ; Stereoselectivity ; Enantiomer ; Racemic ; Methodology ; Therapeutic drug monitoring ; Metabolism ; Metabolite ; Pharmacokinetics ; Psychotropic ; Norepinephrine ; Reuptake inhibitor ; Depression ; Reboxetine ;

Mots-clés français / French Keywords

Trouble humeur ; Etude comparative ; Antidépresseur ; Analyse quantitative ; Chromatographie HPLC ; Spectrométrie masse ; Traitement ; Chimiothérapie ; Homme ; Stéréosélectivité ; Enantiomère ; Racémique ; Méthodologie ; Suivi thérapeutique pharmacologique ; Métabolisme ; Métabolite ; Pharmacocinétique ; Psychotrope ; Noradrénaline ; Inhibiteur recapture ; Etat dépressif ; Réboxétine ;

Mots-clés espagnols / Spanish Keywords

Trastorno humor ; Estudio comparativo ; Antidepresor ; Análisis cuantitativo ; Cromatografía HPLC ; Espectrometría masa ; Tratamiento ; Quimioterapia ; Hombre ; Estereoselectividad ; Enantiómero ; Racémico ; Metodología ; Monitorización farmacoterapéutica ; Metabolismo ; Metabolito ; Farmacocinética ; Psicotropo ; Noradrenalina ; Inhibidor recaptura ; Estado depresivo ; Reboxetina ;

Localisation / Location

INIST-CNRS, Cote INIST : 18087, 35400011793990.0060