Influence of CYP2C9, 2C19 and 2D6 genetic polymorphisms on the steady-state plasma concentrations of the enantiomers of fluoxetine and norfluoxetine

Maria Gabriella Scordo, Edoardo Spina, Marja Liisa Dahl, Giuliana Gatti, Emilio Perucca

Research output: Contribution to journalArticle

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Abstract

The antidepressant fluoxetine is administered as racemic mixture of two enantiomers (S- and R-fluoxetine). While S- and R-fluoxetine are equipotent in blocking serotonin reuptake, the enantiomers of the demethylated metabolite, norfluoxetine, show marked differences in pharmacological activity, S-norfluoxetine being about 20 times as potent as R-norfluoxetine as a serotonin reuptake inhibitor. In vitro and in vivo data suggest that the metabolism of fluoxetine to norfluoxetine is stereoselective and mediated, at least in part, by the polymorphic cytochrome P450 (CYP) isoenzymes CYP2D6, CYP2C9 and CYP2C19. In the present study, the influence of CYP2D6, CYP2C9 and CYP2C19 polymorphisms on the steady-state plasma concentrations of fluoxetine and norfluoxetine enantiomers was evaluated in 78 patients receiving chronic fluoxetine treatment (10-60 mg/day). The plasma concentrations of fluoxetine and norfluoxetine enantiomers were measured and CYP2D6, CYP2C9 and CYP2C19 genotypes were analyzed. No statistically significant relationship was identified between CYP2D6 or CYP2C19 genotypes and the dose normalised plasma concentrations of any of the enantiomers or the active moiety (i.e. the sum of S-fluoxetine, R-fluoxetine and S-norfluoxetine). However, the plasma concentration of S-norfluoxetine was very low in the only CYP2D6 poor metaboliser. Furthermore, the median S-norfluoxetine/S-fluoxetine ratios were higher in homozygous than in heterozygous extensive metabolisers (P

Original languageEnglish
Pages (from-to)296-301
Number of pages6
JournalBasic and Clinical Pharmacology and Toxicology
Volume97
Issue number5
DOIs
Publication statusPublished - Nov 2005

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Enantiomers
Fluoxetine
Genetic Polymorphisms
Polymorphism
Plasmas
Cytochrome P-450 CYP2D6
Genotype
norfluoxetine
Cytochrome P-450 CYP2C9
Serotonin Uptake Inhibitors
Metabolites
Metabolism
Cytochrome P-450 Enzyme System
Antidepressive Agents
Isoenzymes
Serotonin
Pharmacology

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Influence of CYP2C9, 2C19 and 2D6 genetic polymorphisms on the steady-state plasma concentrations of the enantiomers of fluoxetine and norfluoxetine. / Scordo, Maria Gabriella; Spina, Edoardo; Dahl, Marja Liisa; Gatti, Giuliana; Perucca, Emilio.

In: Basic and Clinical Pharmacology and Toxicology, Vol. 97, No. 5, 11.2005, p. 296-301.

Research output: Contribution to journalArticle

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