The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin

Background: Substrates and inhibitors of the cytochrome P450 isozyme CYP2D6 have overlapping structural characteristics. Two prototype serotonin uptake inhibitors, sertraline and fluoxetine, share these structural criteria and have been identified as potent inhibitors of CYP2D6 in vitro. The current study was undertaken to investigate whether genetically determined CPP2D6 activity alters the disposition of sertraline or fluoxetine or both. Methods: Single doses of sertraline (50 mg) and fluoxetine (20 mg) were administered successively to 20 young men with high (extensive metabolizers; n = 10) and low (poor metabolizers; n = 10) CYP2D6 activity, Blood and urine samples were collected for 5 to 7 half-lives and sertraline, desmethylsertraline, fluoxetine, and norfluoxetine were determined by GC and HPLC techniques. Results: Poor metabolizers had significantly greater fluoxetine peak plasma concentrations (C-max;up arrow 57%), area under the concentration versus time awe (AUC(0-->infinity);up arrow 290%), and terminal elimination half-life (up arrow 216%) compared with extensive metabolizers, The total amount of fluoxetine excreted in the urine during 8 days was almost three times higher in poor metabolizers than in extensive metabolizers (719 versus 225 mu g; P < 0.05), whereas the total amount of norfluoxetine excreted in urine of poor metabolizers was about half of that of extensive metabolizers (524 versus 1047 mu g; P < 0.05). Norfluoxetine C-max and AUG(0-->c) were significantly smaller in poor metabolizers (down arrow 55% and down arrow 53%, respectively), and the partial metabolic clearance of fluoxetine into norfluoxetine was 10 times smaller in this group (4.3 +/- 1.9 versus 0.4 +/- 0.1 L/hr; p < 0.05). No significant differences between extensive and poor metabolizers were found for sertraline and desmethylsertraline pharmacokinetics. Conclusion: These data indicate that poor metabolizers accumulate fluoxetine but not sertraline and that CYP2D6 plays an important role in the demethylation of fluoxetine but not of sertraline.