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

Bolo, Nicolas R.; Hodé, Yann; Nédeléc, Jean-François; Lainé, Éric; Wagner, Gabrielle; Mâcher, Jean-Paul

doi:10.1016/s0893-133x(00)00116-0

Cited by 189 publications

(159 citation statements)

References 16 publications

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“…It is of note that the concentrations achieved in the brain of both racemic fluoxetine (25.5 mM) and 80 and 120 mg/day of R-fluoxetine (34.9 and 41.4 mM, respectively (parent drug plus metabolites)) were approximately 20 times those of the parent compound and metabolites in the serum (0.94, 1.10, and 2.02 mM, respectively) for both compounds. This is consistent with earlier studies of racemic fluoxetine, and most likely reflects the fact that the drugs are relatively lipophilic and also accumulate in vesicles on the basis of pH gradients (Bolo et al, 2000;Strauss et al, 2002). It also highlights the fact that these compounds have a large volume of distribution and their pharmacokinetics are dependent on equilibration across multiple compartments.…”

Section: Discussionsupporting

confidence: 89%

“…The MRS signal observed is also dependent on the kinetics of the fluorinated metabolites that are able to enter and accumulate in the brain (Bolo et al, 2000). The primary metabolites of concern are R-and S-norfluoxetine.…”

Section: Discussionmentioning

confidence: 99%

“…As the chemical structure of fluoxetine contains three chemically identical fluorine atoms and clinically efficacious doses of the racemate accumulate in the central nervous system in micromolar concentrations, brain drug levels can be measured using fluorine-19 (19-F) magnetic resonance spectroscopy (MRS) (Bolo et al, 2000;Henry et al, 2000). Data from previous clinical trials of fluoxetine suggest that 20 mg/day is a well-tolerated, efficacious dose of racemic fluoxetine (Beasley et al, 2000;Schmidt et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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A Comparison of Brain and Serum Pharmacokinetics of R-Fluoxetine and Racemic Fluoxetine: A 19-F MRS Study

Henry

Schmidt

Hennen

et al. 2005

Neuropsychopharmacol

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Racemic fluoxetine consists of R-and S-fluoxetine, which are metabolized to R-and S-norfluoxetine, respectively. This study was designed to compare brain levels achieved with R-fluoxetine to those achieved with racemic fluoxetine in healthy subjects using fluorine-19 (19-F) magnetic resonance spectroscopy (MRS). In all, 13 healthy volunteers received study drug for 5 weeks using a dosing schedule designed to achieve steady state for 20 mg/day racemic fluoxetine, 80 mg/day R-fluoxetine, or 120 mg/day R-fluoxetine. The resulting brain drug levels were measured using 19-F MRS. At 5 weeks, the racemate, 80 and 120 mg/day R-fluoxetine groups had mean brain levels of 25.5, 34.9, and 41.4 mM, respectively. In the serum, R-norfluoxetine, which is thought to be an inactive metabolite, accounted for 17, 71, and 63% of the fluoxetine/norfluoxetine concentration, respectively. When the relative proportion of active to total species in serum are taken into account, the data suggest that doses of R-fluoxetine greater than 120 mg/day would be needed to achieve brain levels of active drug comparable to 20 mg/day of racemate. The 120 mg/day R-fluoxetine group experienced a mean increase in QTc interval of 44 ms, with one individual having an increase of 89 ms, which suggests that higher doses may not be tolerable. While these data support the use of MRS to aid in defining the therapeutic dose range for drug development, they also highlight the need for additional studies with concurrent animal models to establish the validity of using serum drug/metabolite ratios to interpret MRS determined brain drug levels.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Comparison of Brain and Serum Pharmacokinetics of R-Fluoxetine and Racemic Fluoxetine: A 19-F MRS Study

Henry

Schmidt

Hennen

et al. 2005

Neuropsychopharmacol

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“…However, micromolar concentration of antidepressants are achieved in the brain of animals treated with the doses used in this and similar studies showing HPA axis changes by antidepressants (Glotzbach and Preskorn, 1982), and, most importantly, are achieved in the brain of patients taking therapeutic doses of antidepressants. In fact, in vivo neuroimaging studies using spectroscopy, which are only possible with antidepressants containing fluorine atoms such as fluoxetine and fluvoxamine, have consistently described steadystate brain concentrations of these drugs in the micromolar range (Bolo et al, 2000). Moreover, brain concentrations of tricyclics in humans, largely derived from postmortem studies following overdoses, have described brain-toplasma concentration ratios ranging from eightfold, at higher plasma concentrations, to 125-fold, at lower plasma concentrations (Sunshine and Baeumler, 1963;Bickel et al, 1967;Avella et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

Yau

Noble

Thomas

et al. 2007

Neuropsychopharmacol

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The mechanisms by which antidepressants regulate the hypothalamic-pituitary-adrenal (HPA) axis are still unknown. The ABCB1-type multiple drug resistance (MDR) p-glycoprotein (PGP) regulates the HPA axis by limiting the access of glucocorticoids to the brain in mice and humans. Previous work in cell cultures has found that antidepressants enhance glucocorticoid receptor (GR) function in vitro by inhibiting MDR PGP, and therefore by increasing the intracellular concentration of glucocorticoidsFbut this model has never been tested directly in animals. Here, the tricyclic antidepressant, desipramine (20 mg/kg/day, i.p., for seven days), was administered to abcb1ab MDR PGP knockout mice (congenic on the FVB/N background strain) and to FVB/N controls. The hippocampal mRNA expression of GR, mineralocorticoid receptor (MR), MDR (Mdr1a) PGP, and 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) were measured, together with plasma corticosterone levels. In FVB/N controls, desipramine induced a significant upregulation of GR mRNA in the CA1 region ( + 31%; p ¼ 0.045); in contrast, in abcb1ab (À/À) mice, desipramine induced a significant downregulation of GR mRNA in the CA1 region (À45%; p ¼ 0.004). MR mRNA expression was unaltered. Desipramine decreased corticosterone levels in both FVB/N controls and in abcb1ab (À/À) mice, but in abcb1ab (À/À) mice the effects were smaller. Specifically, in FVB/N controls (but not in abcb1ab (À/À) mice), desipramine reduced corticosterone levels not only compared with saline-treated mice but also compared with the 'physiological' levels of untreated mice (À39%; p ¼ 0.05). Finally, desipramine reduced Mdr1a mRNA expression across all hippocampus areas (À9 to À23%), but had no effect on 11b-HSD1 mRNA expression. These data support the notion that the MDR PGP is one of the molecular targets through which antidepressants regulate the HPA axis.

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“…Similar concentrations are also needed to enhance proliferation of neural progenitor cells. These concentrations can be easily achieved in the brain at therapeutic dosages since these compounds are preferentially taken up and enriched in brain tissue with 10-20 fold higher concentrations in the human brain compared to plasma [43]. Steady state levels are achieved over several weeks to months [44].…”

Section: Discussionmentioning

confidence: 99%

Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

et al. 2015

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There are severe neurological complications that arise from HIV infection, ranging from peripheral sensory neuropathy to cognitive decline and dementia for which no specific treatments are available. The HIV proteins secreted from infected macrophages, gp120 and Tat, are neurotoxic. The goal of this study was to screen, identify and develop neuroprotective compounds relevant to HIV-associated neurocognitive disorders (HAND). We screened more than 2000 compounds that included FDA approved drugs for protective efficacy against oxidative stress-mediated neurodegeneration and identified selective serotonin reuptake inhibitors (SSRIs) as potential neuroprotectants. Numerous SSRIs were then extensively evaluated as protectants against neurotoxicity as measured by changes in neuronal cell death, mitochondrial potential, and axodendritic degeneration elicited by HIV Tat and gp120 and other mitochondrial toxins. While many SSRIs demonstrated neuroprotective actions, paroxetine was potently neuroprotective (100 nM potency) against these toxins in vitro and in vivo following systemic administration in a gp120 neurotoxicity model. Interestingly, the inhibition of serotonin reuptake by paroxetine was not required for neuroprotection, since depletion of the serotonin transporter had no effect on its neuroprotective properties. We determined that paroxetine interacts selectively and preferentially with brain mitochondrial proteins and blocks calcium-dependent swelling but had less effect on liver mitochondria. Additionally, paroxetine induced proliferation of neural progenitor cells in vitro and in vivo in gp120 transgenic animals. Therefore, SSRIs such as paroxetine may provide a novel adjunctive neuroprotective and neuroregenerative therapy to treat HIVinfected individuals.

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

Cited by 189 publications

References 16 publications

A Comparison of Brain and Serum Pharmacokinetics of R-Fluoxetine and Racemic Fluoxetine: A 19-F MRS Study

A Comparison of Brain and Serum Pharmacokinetics of R-Fluoxetine and Racemic Fluoxetine: A 19-F MRS Study

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

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