Monoamine oxidase a inhibition by fluoxetine: An in vitro and in vivo study

Abstract

Monoamine oxidase A (MAO-A) inhibition was investigated both in vitro and in vivo in rat brains by using the radioligand, 18 F-fluoroclorgyline (N-[3-(2Ј,4Ј-dichlorophenoxy)-2-18 F-fluoropropyl]-N-methylpropargylamine). In vitro binding affinities of six compounds, clorgyline, Ro 41-1049, deprenyl, fluoxetine, norfluoxetine and citalopram, were studied. Fluoxetine and norfluoxetine showed in vitro affinities of 36.5 and 68 µM for MAO-A, respectively. Fluoxetine and norfluoxetine also significantly inhibited (more than 20%) the binding of the radioligand in vivo while citalopram and deprenyl showed very poor affinities in vitro for MAO-A and had no effect in vivo. The in vivo effects of the various drugs were directly comparable to their in vitro affinities for binding to MAO-A as seen in the correlation plot of percent control in vivo binding of 18 F-fluoroclorgyline and binding affinity, -log IC 50 (R 2 ϭ 0.979). An acute dose of 20 mg/kg of fluoxetine inhibited binding of 18 F-fluoroclorgyline by more than 20%, while lower doses had some significant effects. These results provide evidence on the in vitro and in vivo inhibition of monoamine oxidase A by fluoxetine.

T-Type Calcium Channels Are Inhibited by Fluoxetine and Its Metabolite Norfluoxetine

“…The therapeutic action of fluoxetine primarily results from the inhibition of serotonin reuptake (Stark et al, 1985;Wong et al, 1995), thus enhancing serotoninergic neurotransmission. Besides this mechanism, fluoxetine has several other modulatory effects, such as inhibition of G protein-coupled receptors (Stanton et al, 1993;Palvimaki et al, 1996), blockade of monoamine oxidases (Mukherjee and Yang, 1999), and modulation of several ionic channels. Indeed, it has been reported that fluoxetine is a potent blocker of K ϩ channels (Thomas et al, 2002;Choi et al, 2003;Kobayashi et al, 2003;Kennard et al, 2005), Na ϩ channels (Pancrazio et al, 1998), and Ca 2ϩ channels (Deak et al, 2000).…”

Acute Inhibition of Cardiac Monoamine Oxidase A after Tobacco Smoke Inhalation: Validation Study of [11C]Befloxatone in Rats Followed by a Positron Emission Tomography Application in Baboons

“…These discrepant results could be explained by several factors. The affinity of clorgyline for MAO-A is much less than that of befloxatone (Curet et al, 1996;Mukherjee and Yang, 1999). Clorgyline and befloxatone behave differently in vivo.…”

In vitro biotransformation of the selective serotonin reuptake inhibitor citalopram, its enantiomers and demethylated metabolites by monoamine oxidase in rat and human brain preparations

“…However, citalopram was found to have a lower affinity for MAO-A and B compared to fluoxetine and no inhibitory action on the binding of clorgyline and methylpropargylamine to either MAO-A or MAO-B. 24,44 The competing for binding sites depends however on both, the affinity as well as the respective concentrations of the compounds. The extent to which citalopram in a therapeutic setting may interfere with the metabolism of monoamine substrates catalysed by MAO in the brain remains to be investigated.…”

“…23 In general, antidepressants, including those SSRIs examined so far, have only weak, if any, MAO inhibitory activity. [24][25][26] Presumably, the syndrome which appears after combining SSRIs with MAO inhibitors stems from a synergistic action on the levels of serotonin in the synaptic cleft. Whether such effects could arise through mutual inhibition of each drug's inactivation remains an open question.…”