The stereoselective metabolism of fluoxetine in poor and extensive metabolizers of sparteine.

Détails

ID Serval
serval:BIB_8A7E2096B5D1
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
The stereoselective metabolism of fluoxetine in poor and extensive metabolizers of sparteine.
Périodique
Pharmacogenetics
Auteur(s)
Fjordside L., Jeppesen U., Eap C.B., Powell K., Baumann P., Brøsen K.
ISSN
0960-314X (Print)
ISSN-L
0960-314X
Statut éditorial
Publié
Date de publication
1999
Peer-reviewed
Oui
Volume
9
Numéro
1
Pages
55-60
Langue
anglais
Notes
Publication types: Clinical Trial ; Journal ArticlePublication Status: ppublish
Résumé
The selective serotonin reuptake inhibitor fluoxetine is administered as a racemic mixture, and R- and S-fluoxetine are metabolized in the liver by N-demethylation to R- and S-norfluoxetine, respectively. R- and S-fluoxetine and S-norfluoxetine are equally potent selective serotonin reuptake inhibitors, but R-norfluoxetine is 20-fold less potent in this regard. Racemic fluoxetine and norfluoxetine are potent inhibitors of cytochrome P450 (CYP) 2D6 in vivo and in vitro and recent studies in vivo have shown that racemic fluoxetine is metabolized by CYP2D6. The primary aim of the present study was to investigate the stereoselective metabolism of fluoxetine and norfluoxetine by CYP2D6 in vivo. A single oral dose of fluoxetine (60 mg) was administered to six poor and six extensive metabolizers of sparteine. Blood samples were collected during 6 weeks for poor metabolizers and 3 weeks for extensive metabolizers. Once a week a sparteine test was performed. The R- and S-enantiomers of fluoxetine and norfluoxetine were determined by a stereoselective gas chromatography-mass spectroscopy method. In the poor metabolizers, the oral clearance of R- and S-fluoxetine was 3.0 l/h and 17 l/h, respectively, the corresponding values in the extensive metabolizers were 36 l/h and 40 l/h, respectively. For both enantiomers, the phenotype difference was statistically significant. In poor metabolizers, the elimination half-lives were 6.9 days and 17.4 days for R- and S-norfluoxetine, respectively, and in the extensive metabolizers it was 5.5 days for both enantiomers, a significant phenotypical difference only for S-norfluoxetine. For fluoxetine the elimination half-lives were 9.5 and 6.1 days in poor metabolizers for the R- and S-enantiomer, respectively. The corresponding values in the extensive metabolizers were 2.6 and 1.1 days, respectively. Also for this parameter, the differences were statistically significant. This study shows that CYP2D6 catalyses the metabolism of R- and S-fluoxetine and most likely the further metabolism of S-norfluoxetine but not of R-norfluoxetine.
Mots-clé
Area Under Curve, Fluoxetine/metabolism, Fluoxetine/pharmacokinetics, Half-Life, Humans, Reference Values, Serotonin Uptake Inhibitors/metabolism, Serotonin Uptake Inhibitors/pharmacokinetics, Sparteine/metabolism, Stereoisomerism
Pubmed
Web of science
Création de la notice
01/03/2013 12:09
Dernière modification de la notice
20/08/2019 15:49
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