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

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 inhibit ors, but R-norfluoxetine is 20-fold less potent in this regard. Racemic flu oxetine and norfluoxetine are potent inhibitors of cytochrome P450 (CYP) 2D 6 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 w as to investigate the stereoselective metabolism of fluoxetine and norfluox etine by CYP2D6 in vivo. A single oral dose of fluoxetine (60 mg) was admin istered to six poor and six extensive metabolizers of sparteine. Blood samp les were collected during 6 weeks for poor metabolizers and 3 weeks for ext ensive metabolizers. Once a week a sparteine test was performed, The R- and S-enantiomers of fluoxetine and norfluoxetine were determined by a stereos elective gas chromatography-mass spectroscopy method. In the poor metaboliz ers, the oral clearance of R- and S-fluoxetine was 3.0 l/h and 17 l/h, resp ectively, 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-l ives 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 s ignificant 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 exte nsive metabolizers were 2.6 and 1.1 days, respectively, Also for this param eter, 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, Pharmaco genetics 9:55-60 (C) 1999 Lippincott Williams & Wilkins.