Pharmacology: The exact mechanism of fluoxetine's psychotropic actions (antidepressant, anti-obsessive-compulsive and anti-bulimic) remains unclear but is presumed to be linked to its selective inhibition of the central nervous system (CNS) neuronal uptake of serotonin. Fluoxetine-induced inhibition of the CNS neuronal uptake of serotonin causes increased synaptic concentrations of serotonin in the CNS, resulting in numerous functional changes associated with enhanced serotonergic neurotransmission.
Clinical studies have shown that at clinically relevant doses, fluoxetine blocks the uptake of serotonin into human platelets. Preclinical studies also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine.
Fluoxetine has practically no affinity to other receptors such as α1-, α2-, and β-adrenergic; serotonergic; dopaminergic; histaminergic; muscarinic; and GABA receptors.
Pharmacokinetics: Fluoxetine is well absorbed from the gastrointestinal tract after oral administration. The oral bioavailability of fluoxetine is estimated to be about 60 to 80%. Food may delay absorption by approximately 1 to 2 hours but generally does not affect the amount of drug that reaches the circulation. Peak fluoxetine plasma concentrations of 15 to 55 ng/mL are achieved within 6 to 8 hours after oral administration of a 40 mg dose.
Fluoxetine has high affinity for plasma proteins which is independent of plasma concentration and is approximately 94.5% protein-bound at plasma concentrations of 200 to 1,000 ng/mL. The apparent volume of distribution of fluoxetine and norfluoxetine (active metabolite) in healthy adults is an average of 20 to 45 L/kg.
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 the predominant enantiomer present in plasma at steady state. Fluoxetine is extensively metabolized in the liver to norfluoxetine, the only identified active metabolite formed by demethylation of fluoxetine, and a number of other unidentified metabolites. 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. Fluoxetine and norfluoxetine are slowly cleared from the circulation. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.
A subset (about 7%) of the population, referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants (TCAs), has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). A study involving labeled and unlabeled enantiomers given as a racemate showed that 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. The total sum at steady state of the plasma concentrations of the four active enantiomers was not significantly greater among poor metabolizers compared with normal metabolizers. Therefore, the net pharmacodynamic activities were essentially the same. In addition, nonsaturable pathways (non-2D6) contribute to the metabolism of fluoxetine. This is the reason why fluoxetine achieves a steady-state concentration rather than increasing without limit.
Like other SSRIs, the metabolism of fluoxetine involves the CYP2D6 system. Thus, concomitant administration with drugs also metabolized by this enzyme system (such as TCAs) may lead to drug interactions.
Even when a fixed dose is used, the relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration) results to significant accumulation of these active species with chronic use and delayed attainment of steady state concentration. Plasma concentrations were in the range of 91 to 302 ng/mL for fluoxetine and 72 to 258 ng/mL for norfluoxetine after 30 days of dosing at 40 mg per day. Fluoxetine's plasma concentrations were higher than those predicted by single dose-studies since metabolism of fluoxetine is not proportional to dose. Norfluoxetine, on the other hand, appears to have linear pharmacokinetics with a mean terminal half-life of 8.6 days after a single dose and 9.3 days after multiple dosing. Steady-state levels after prolonged dosing are similar to levels at 4 to 5 weeks.
Even after discontinuation of fluoxetine therapy, the parent drug and its metabolites will remain in the circulation for several weeks, depending on individual patient characteristics, previous dosage regimen and length of previous therapy at discontinuation, due to the long elimination half-lives of fluoxetine and norfluoxetine. This may be clinically significant particularly when drug discontinuation is required or when new drugs are to be prescribed that might interact with fluoxetine and norfluoxetine after recent fluoxetine withdrawal.
Special Population: Hepatic disease: Fluoxetine's elimination half-life was prolonged in cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. Exercise caution when giving fluoxetine to patients with liver disease; a lower or less frequent dose should be used.
Renal disease: Fluoxetine 20 mg given once a day for two months in depressed patients on dialysis produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose may not be necessary in these patients.
Elderly: The disposition of single doses of fluoxetine in healthy elderly subjects (>65 years old) did not differ significantly from that in younger normal subjects. A study involving healthy depressed elderly patients (≥60 years old) who received fluoxetine 20 mg for six weeks was done to determine the effects of age on the metabolism of fluoxetine. It showed that combined fluoxetine plus norfluoxetine plasma concentrations was 209.3±85.7 ng/mL at the end of six weeks.
Children and adolescents: A pharmacokinetic study involving pediatric patients (children: ages 6 to <13; adolescents: 13 to <18) with major depressive disorder or obsessive disorder who received fluoxetine 20 mg per day for 62 days showed that the average steady-state concentrations of fluoxetine in children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in children were 1.5 fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences may be due to differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Higher average steady-state fluoxetine and norfluoxetine concentrations were shown in children relative to adults; however, these concentrations were within the range of concentrations seen in the adult population. Similar in adults, fluoxetine and norfluoxetine accumulated extensively after multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing.