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

Clinical Pharmacology and Therapeutics
B A HamelinM LeBel

Abstract

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 CYP2D6 activity alters the disposition of sertraline or fluoxetine or both. 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. Poor metabolizers had significantly greater fluoxetine peak plasma concentrations (Cmax; increases 57%), area under the concentration versus time curve (AUCzero-->infinity; increases 290%), and terminal elimination half-life (increases 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 22...Continue Reading

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