RiteMED Fluoxetine Mechanism of Action

Antidepressant.
Pharmacology: Pharmacokinetics: Fluoxetine is readily absorbed from the gastrointestinal tract with peak plasma concentrations appearing about 6 to 8 hours after oral dose. Systemic bioavailability does not appear to be affected by food. Fluoxetine is extensively metabolized, by demethylation, in the liver to its primary active metabolite, Norfluoxetine. Excretion is mainly via the urine. Protein binding is reported to be about 95%.
Fluoxetine used clinically is a racemic mixture consisting of R- and S-enantiomers in equal amounts. Both enantiomers are active according to animal studies, but S-Fluoxetine is eliminated more slowly.
Metabolism is believed to be mediated by cytochrome P450 isoenzyme CYP2D6 and leads to R- and S-enantiomers of Norfluoxetine with the S-enantiomer being considered as active as the parent drug, the R-enantiomer is considered to be much less active. This metabolism is subject to genetic polymorphism. While the small proportion of the population known as slow metabolizers do show a different spectrum of parent drug and metabolite, the over-all activity does not appear to be altered.
Fluoxetine is widely distributed throughout the body.
Fluoxetine has a relatively long elimination half-life of about 1 to 3 days after acute use and 4 to 6 days after long-term use; that of its metabolite, Norfluoxetine is even longer being about 4 to 16 days. These long half-lives have clinical implications. Steady-state plasma concentrations will only be attained after several weeks. Additionally, Fluoxetine and its metabolites may persist for a considerable time after treatment, and this has led to precautions concerning the subsequent use of other serotonergic drugs.
Fluoxetine and Norfluoxetine are distributed into breastmilk.
Metabolism: Although Fluoxetine is stated by the manufacturers to be metabolized by the cytochrome P450 isoenzyme CYP2D6, which is supported by studies indicating that its disposition is altered in poor metabolizers of debrisoquine (a substrate for this enzyme), others have suggested that CYP2C19, and perhaps CYP2C9, play an important role.