Anorectic activity of fluoxetine and norfluoxetine in mice, rats and guinea-pigs

Abstract

The present study aimed to establish the role of the metabolite norfluoxetine in the anorectic activity of fluoxetine, and to relate the anorectic doses (ED50) to the brain concentrations of the parent drug and its metabolite. Fluoxetine showed anorectic activity at increasing intraperitoneal doses (ED50 = 39.1, 34.7 and 21.7 mumol kg-1 in mouse, rat and guinea-pig, respectively) and norfluoxetine was slightly more active (24.3, 22.9 and 19.1 mumol kg-1, respectively) in all three species. In terms of maximum concentration (Cmax) and area under the curve (AUC) within the experimental period (0-90 min), brain concentrations varied widely and were poorly related to the dose; guinea-pig appeared to be much more sensitive to fluoxetine than was mouse or rat. Administered norfluoxetine was present in the brain of the three species in approximately the same order as fluoxetine, i.e. lower in guinea-pig than in mouse or rat. The Cmax and AUC of norfluoxetine after fluoxetine administration was 50-60% of the values after an equiactive dose of norfluoxetine in mouse and guinea-pig, and more than 80% in rat.

The effects of single and repeated anorectic doses of 5‐hydroxytryptamine uptake inhibitors on indole levels in rat brain

“…Attempts to correlate brain concentrations with the in vitro potency in inhibiting 5-HT uptake (see Dechant & Clissold, 1991;Murdoch & McTavish, 1992 for a comparison of the relative potency) are unfortunately limited by the fact that fluoxetine and sertraline are biotransformed by hepatic N-dealkylation to the nor-derivatives norfluoxetine and nor-sertraline (Schmidt et al, 1988;Tremaine et al, 1989) and these fully retain the parent drug's anorectic activity in animals despite their lower efficacy in inhibiting 5-HT reuptake (Garattini et al, 1991;Caccia et al, 1992a;Anelli et al, 1992). However, metabolites of fluvoxamine and paroxetine do not appear to have significant uptake inhibiting properties in vitro in animals (Benfield & Ward, 1986;Dechant & Clissold, 1991), although their activity in relation to 5-HT mechanisms other than uptake inhibition, and to the anorectic action, is still unknown.…”

“…(Garattini et al, 1991;Caccia et al, 1992a;Anelli et al, 1992 (V. Guardabasso, personal communication) were 34.7 (± 14.9) ltmol kg-' (12.0 mg kg-') for fluoxetine; 59.9 (± 37.8) ymol kg-' (22.2 mg kg-') for fluvoxamine, 20.4 (± 5.7) 1imol kg-' (7.9 mg kg-') for paroxetine and 48.7 (+ 25.4) tLmol kg-' (16.7mgkg-') for sertraline. These doses were then given to other groups of rats which were killed by decapitation 60 min thereafter for determination of the indole content and drug concentrations in selected brain areas (cortex, hippocampus and striatum).…”

Sex Differences in the Cannabinoid Modulation of Appetite, Body Temperature and Neurotransmission at POMC Synapses

“…There has been an appreciable amount of information gathered over the past thirty years on the circadian rhythmicity [27], the effects of fasting [28, 29], and the operant cues [28] associated with guinea pig feeding behavior. Guinea pigs also have proven to be a more sensitive animal model than rats or mice for the study of the anorectic properties of serotonergics such as fenfluramine [30] and fluoxetine [31], and like humans suffer from the inability to manufacture their own vitamin C [27, 32]. In addition, the female guinea pig has an ovulatory cycle that is 14–18 days in length with a true luteal phase, and is nearly identical to the primate female [33,34,35,36].…”

Fluoxetine at anorectic doses does not have properties of a dopamine uptake inhibitor

“…Therefore fluoxetine does not inhibit dopamine uptake in mice at the dose used by Melamed etlal. (1985), which was 25 mg/kg i.p.-well above the anorectic EDs0 dose reported by Anelli et al (1992) and over 50 times the EDs0 dose that blocks serotonin depletion by p-chloroamphetamine in mice (Fuller et al, 1974).…”

“…For inhibition of serotonin uptake, a 10mg/kg dose of fluoxetine is commonly used in rats, and even very high doses of fluoxetine (100mg/kg) have been reported to have no effect or only a small effect on norepinephrine uptake (Maitre et al, 1980). Fluoxetine reduces food intake in rats and other species (Goudie et al, 1976;Rowland etal., 1982;Wong etal., 1988;Fuller and Wong, 1989;Clifton etal., 1989;Cooper etal., 1990;Anelli et al, 1992), as do other direct-and indirectacting serotonin agonists, findings that are part of a large body of evidence that brain serotonin is an important neurotransmitter in regulating caloric intake (Blundell, 1984;Carruba etal., 1985;Leibowitz, 1990;Dourish, 1992). The anorectic action of fluoxetine has generally been attributed to its inhibition of serotonin uptake.…”