Clinical Pharmacokinetics of Fluoxetine

Abstract

Fluoxetine is well absorbed after oral intake, is highly protein bound, and has a large volume of distribution. The elimination half-life of fluoxetine is about 1 to 4 days, while that of its metabolite norfluoxetine ranges from 7 to 15 days. Fluoxetine has a nonlinear pharmacokinetic profile. Therefore, the drug should be used with caution in patients with a reduced metabolic capability (i.e. hepatic dysfunction). In contrast with its effect on the pharmacokinetics of other antidepressants, age does not affect fluoxetine pharmacokinetics. This finding together with the better tolerability profile of fluoxetine (compared with tricyclic antidepressants) makes this drug particularly suitable for use in elderly patients with depression. Furthermore, the pharmacokinetics of fluoxetine are not affected by either obesity or renal impairment. On the basis of results of plasma concentration-clinical response relationship studies, there appears to be a therapeutic window for fluoxetine. Concentrations of fluoxetine plus norfluoxetine above 500 micrograms/L appear to be associated with a poorer clinical response than lower concentrations. Fluoxetine interacts with some other drugs. Concomitant administration of fluoxetine increased the blood concentrations of antipsychotics or antidepressants. The interactions between fluoxetine and lithium, tryptophan and monoamine oxidase inhibitors, in particular, are potentially serious, and can lead to the 'serotonergic syndrome'. This is because of synergistic pharmacodynamic effects and the influence of fluoxetine on the bioavailability of these compounds.

Brain Pharmacokinetics and Tissue Distribution In Vivo of Fluvoxamine and Fluoxetine by Fluorine Magnetic Resonance Spectroscopy

“…Our finding that the steady state brain SSRI concentrations were about 10 times higher than plasma concentrations is compatible with its pharmacokinetic profile, with a reported apparent distribution volume of approximately 20 in humans for fluvoxamine (Palmer and Benfield 1994;Wilde et al 1993) and 12 to 43 for fluoxetine (Altamura et al 1994), indicating considerable uptake of the drug into tissue spaces. The result that no correlation was found between the steady state brain or plasma concentrations and the daily dose indicates that there can be a considerable variability of plasmatic levels relative to treatment dose.…”

“…In this study, plasma steady state concentrations obtained were found to be somewhat higher than the values from the literature for fluvoxamine (Palmer and Benfield 1994;De Vries et al 1993) and fluoxetine (Altamura et al 1994) studies. The discrepancies can be accounted for by the difference between single dose and long term multiple dose studies (Kelly et al 1989) for which the values are comparable.…”

“…An obvious shortcoming of the kinetic data is that the reported values result from the combination of fluoxetine and norfluoxetine data which are not separable under these conditions. As the two compounds have different plasma half-lives: 24 to 96 hours for fluoxetine vs. 168 to 360 hours for norfluoxetine, respectively (Altamura et al 1994), their brain half-lives could as well present such a large discrepancy. A relatively large variability was found between the two subjects for which the brain fluoxetine-norfluoxetine half-life ranged from 349 to 416 hours.…”

Pharmacologically Diverse Antidepressants Rapidly Activate Brain-Derived Neurotrophic Factor Receptor TrkB and Induce Phospholipase-Cγ Signaling Pathways in Mouse Brain

“…Given the importance of prolonged antidepressant treatment for clinical recovery from depression, association of PLCg1 with Trk was also analyzed after long-term FLX (0.08 mg/ml FLX in drinking solution, 21 days) and water administration (n ¼ 8-9/ group). In the drug treatment group, average plasma FLX levels were clinically relevant being 268733 ng/ml (Altamura et al, 1994) at the time of brain tissue dissection. This FLX administration protocol has been previously shown to produce long-term alterations in neuroplasticity and animal behavior (Santarelli et al, 2003).…”

Inhibition of K+ currents of outer hair cells in guinea pig cochlea by fluoxetine

“…Since therapeutic doses of fluoxetine result in a plasma concentration of approximately 1 AM (Altamura et al, 1994), we examined the effects of 1 AM fluoxetine on the (Fig. 1C).…”