Fluoxetine is a selective serotonin reuptake inhibitor (SSRI). It has been prescribed for the treatment of depression and has shown also efficacy in the treatment of bulimia nervosa and obsessive-compulsive disorder (3501993, 2787123). Fluoxetine is almost completely absorbed after oral administration. However, its systemic availability is reduced because of first-pass metabolism in the liver. Due to its lipophilic character, fluoxetine has a large volume of distribution and accumulates in several tissues (8861776). The brain to plasma ratio is 2.6:1, which is lower than for other SSRIs (9090339).
Fluoxetine is extensively metabolized in the liver. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. Fluoxetine is a racemic mixture of two enantiomers. S-fluoxetine is slightly more potent in the inhibition of serotonin reuptake than R-fluoxetine (7935707). The difference is much more pronounced for the active metabolite. S-norfluoxetine has about 20 times higher reuptake blocking potency than the R-norfluoxetine (1279447). These four compounds differ also in their kinetics. After several weeks of treatment, the plasma concentration of both S-enantiomers is about two times higher than the concentration of the R-enantiomers (7935707).
The primary route of elimination is largely through oxidative metabolism and conjugation, but more than half of the metabolic end products are unknown (7935707). Fluoxetine is mainly excreted in urine with less than 10% excreted unchanged or as fluoxetine glucuronide (2878798).
Evidence from several in vitro and in vivo studies indicates the involvement, at least in part, of CYP2D6, CYP2C19, CYP2C9, CYP3A4, and CYP3A5 in the biotransformation of R- and S-fluoxetine to their N-desmethyl metabolites (11356927, 10997938). The cytochrome P450 isoforms exhibit genetic polymorphisms which affect their catalytic activity. Results from studies on patients with different CYP2D6 and CYP2C9 genotypes showed that CYP2C9 preferentially catalyzes R-fluoxetine demethylation, whereas the formation of S-norfluoxetine is highly dependent on CYP2D6 (11356927, 10208643). At the same time, enantiomers of fluoxetine and norfluoxetine are inhibitors of CYP2D6 mediated reactions. Therefore, the influence of CYP2C19, CYP2C9, CYP3A4, and CYP3A5 in the fluoxetine metabolism becomes more important during chronic dosing when the contribution of CYP2D6 is diminished by the inhibition through fluoxetine and norfluoxentine.
Additionally, fluoxetine has demonstrated inhibitory potency toward CYP2C19, CYP2C9, and CYP3A4 in in vitro studies (9298519, 9384467, 8703653). All of these CYP isoenzymes are involved in the metabolism of numerous drugs; therefore, fluoxetine and norfluoxetine have the potential to alter metabolism and pharmacokinetics of coadministered drugs. Due specifically to the inhibitory effect of fluoxetine and norfluoxentine on the isoenzyme CYP2D6, clinically relevant drug interactions have been reported with tricyclic antidepressants and neuroleptics (10674711).
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
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Entities in the Pathway
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|Arrow From||Arrow To||Controllers||PMID|
|fluoxetine||Fluoxetine glucuronide||10674711, 2878798, 7935707|
|fluoxetine||Inactive metabolites||10674711, 2878798, 7935707|
|fluoxetine||R-Norfluoxetine||CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5||10208643, 10997938, 11356927, 8355218, 9298519|
|fluoxetine||S-Norfluoxetine||CYP2C19, CYP2D6, CYP3A4, CYP3A5||10208643, 10997938, 11356927, 8355218, 9298519|
|R-Norfluoxetine||Inactive metabolites||10674711, 2878798, 7935707|
|R-Norfluoxetine||Norfluoxetine glucuronide||10674711, 2878798, 7935707|
|S-Norfluoxetine||Inactive metabolites||10674711, 2878798, 7935707|
|S-Norfluoxetine||Norfluoxetine glucuronide||10674711, 2878798, 7935707|
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