Pharmacodynamics

The mechanism of action of fluoxetine in premenstrual dysphoric disorder (PMDD) is unknown, but is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in humans have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine.

Antagonism of muscarinic, histaminergic, and α₁-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of certain psychoactive drugs. Fluoxetine has little affinity for these receptors.

Absorption, Distribution, Metabolism, and Excretion

Systemic bioavailability — In humans, following a single oral 40-mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption inconsequentially. Thus, fluoxetine may be administered with or without food.

Protein binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α₁-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important (See PRECAUTIONS).

Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state.

Metabolism — Fluoxetine is extensively metaboli zed in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.

Clinical issues related to metabolism/elimination — The complexity of the metabolism of fluoxetine has several consequences that may potentially affect

Variability in metabolism — A subset (about 7%) of the popul ation has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants (TCAs). In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit.

Because fluoxetine's a number of other compounds including TCAsmetabolism, like and other SSRIs, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (See DRUG INTERACTIONS under PRECAUTIONS).

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