Naunyn Schmiedebergs Arch Pharmacol. 1992 Jan;345(1):1-6.
Releasing activities of d-fenfluramine and fluoxetine on rat hippocampal synaptosomes preloaded with [3H]serotonin.

Gobbi M, Frittoli E, Mennini T, Garattini S.

Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

Rat hippocampal synaptosomes preloaded with [3H]serotonin and maintained in a superfusion apparatus were exposed for 3 min to d-fenfluramine or fluoxetine. Both drugs evoked a tritium overflow which was reserpine-sensitive requiring the presence of intact synaptic vesicles. However the two drugs displayed different characteristics: 1) the overflow was immediate with d-fenfluramine whereas the releasing activity of fluoxetine showed a delay of about 2 min; 2) d-fenfluramine-induced overflow was already apparent at 0.15 mumol/l whereas the minimal effective concentration of fluoxetine was 2.5 mumol/l. Their concentration-effect curves were differently shaped, the effect of d-fenfluramine being saturable at 5-20 mumol/l (EC50 about 1 mumol/l) while no saturation was observed with fluoxetine up to 10 mumol/l; 3) only 19% of the tritium overflow evoked by fluoxetine (2.5-10 mumol/l) consisted of true [3H]serotonin, compared with 70% when 0.5 mumol/l d-fenfluramine was used; 4) the releasing action of 0.5 mumol/l d-fenfluramine was completely Ca(++)-dependent, while at higher d-fenfluramine concentrations the Ca(++)-independent overflow became more important. The fluoxetine induced overflow was mainly (70%) Ca(++)-independent; 5) the releasing activity of d-fenfluramine was mainly (80%) blocked by the serotonin uptake blockers indalpine, midalcipram and also fluoxetine whereas fluoxetine-induced overflow was insensitive to inhibition of the serotonin carrier. In conclusion, the releasing activity of d-fenfluramine is already present at a very low concentration (0.5 mumol/l) and at this concentration its mechanism of action was Ca(++)-dependent, together with the requirement of a functional serotonin carrier.(ABSTRACT TRUNCATED AT 250 WO




Clin Pharmacol Ther. 1992 Mar;51(3):239-48.
Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction.

Bergstrom RF, Peyton AL, Lemberger L.

Lilly Laboratory for Clinical Research, Eli Lilly and Company, Indianapolis, IN 46285.

Clinical reports of concurrent use of fluoxetine and tricyclic antidepressant agents suggest that tricyclic concentrations increase upon coadministration with fluoxetine. This study was conducted to confirm the clinical reports, to quantify the degree of change in tricyclic kinetics, and to establish the mechanism of interaction. Twelve male subjects were given 50 mg desipramine (six subjects) or 50 mg imipramine (six subjects) on three occasions: alone, after a 60 mg dose of fluoxetine, and after eight daily 60 mg doses of fluoxetine. Fluoxetine significantly reduced oral clearance of both imipramine and desipramine as much as tenfold and prolonged half-life as much as fourfold. Desipramine oral clearance values were 289, 112, and 27 L/hr alone, after a single fluoxetine dose, and after multiple fluoxetine doses, respectively. Correspondingly, imipramine oral clearance values were 181, 87, and 51 L/hr. These kinetic changes resulted in significantly higher plasma tricyclic concentrations after fluoxetine administration. The amount of parent drug excreted unchanged in urine increased and imipramine or desipramine clearance to their respective 2-hydroxy metabolites decreased. Metabolic conversion of imipramine to desipramine appeared to be unaffected. The findings indicate that fluoxetine causes an inhibition of tricyclic 2-hydroxylation and may decrease first-pass and systemic metabolism. When imipramine or desipramine are to be coadministered with fluoxetine, a lower dosage may be needed to maintain steady-state concentrations and to avoid undesirable side effects caused by excessive tricyclic concentrations.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1544284&dopt=Abstract fluoxetine




J Clin Psychiatry. 1992 Apr;53(4):127-9.
Ratio of plasma fluoxetine to norfluoxetine concentrations and associated sedation.

Keck PE Jr, McElroy SL.

Biological Psychiatry Program, University of Cincinnati College of Medicine, University of Cincinnati Hospital, OH 45267-0559.

BACKGROUND: Sedation is an often unanticipated but clinically significant side effect in some patients treated with fluoxetine. To date, no clinical or pharmacokinetic factors have been identified in association with sedation in fluoxetine-treated patients. We hypothesized that patients experiencing sedation might have elevated plasma concentrations of fluoxetine and/or norfluoxetine compared with patients without sedation. METHOD: Plasma samples from eight patients reporting new-onset sedation following initiation of treatment with fluoxetine and from 14 consecutive patients also receiving fluoxetine but who experienced no sedation were analyzed for fluoxetine and norfluoxetine concentrations. RESULTS: Patients in the two groups did not differ significantly in age, sex distribution, diagnoses, mean dose or duration of fluoxetine treatment, or mean combined plasma concentrations of fluoxetine and norfluoxetine. However, the plasma ratio of fluoxetine to norfluoxetine was less than 1.0 in all patients reporting sedation and greater than 1.0 in all patients without sedation. Also, there was a significant difference between the mean +/- SD ratio of fluoxetine-to-norfluoxetine plasma concentrations in the group reporting sedation (0.6 +/- 0.1) and the group without sedation (1.7 +/- 0.8). CONCLUSION: The results of this study suggest an association between sedation and increased plasma concentrations of norfluoxetine compared with fluoxetine. Individuals reporting sedation may metabolize the parent drug differently than patients who do not experience sedation, leading to a relative increase in the proportion of the active metabolite, norfluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1564047&dopt=Abstract fluoxetine




Pharmacotherapy. 1992;12(2):103-6.
A pharmacokinetic evaluation of the combined administration of triazolam and fluoxetine.

Wright CE, Lasher-Sisson TA, Steenwyk RC, Swanson CN.

Clinical Pharmacokinetics Unit, Upjohn Company, Kalamazoo, Michigan 49007.

The influence of fluoxetine on triazolam pharmacokinetics was studied because of changes in diazepam pharmacokinetics reportedly produced by fluoxetine. Twenty-four healthy volunteers received a single 0.25-mg triazolam tablet alone, and another 0.25-mg tablet after 8 days of fluoxetine therapy 60 mg/day. All subjects received these treatments in the same sequence. Several blood samples were drawn from the subjects after the triazolam doses and were assayed by high-performance liquid chromatography (HPLC). Blood samples were drawn immediately before the last three fluoxetine doses to determine the concentration of fluoxetine and its metabolite norfluoxetine, also by HPLC. The pharmacokinetics of triazolam did not change significantly when the tablets were administered after multiple doses of fluoxetine. These results indicate that no pharmacokinetic interaction exists between triazolam and fluoxetine or norfluoxetine. However, each patient's clinical response to therapy should be monitored when triazolam tablets and fluoxetine capsules are administered concomitantly.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1570226&dopt=Abstract fluoxetine




Regul Pept. 1992 Mar 19;38(2):121-8.
Fluoxetine pretreatment potentiates intracisternal TRH analogue-stimulated gastric acid secretion in rats.

Shockley RA, LePard KJ, Stephens RL Jr.

Department of Physiology, Ohio State University, Columbus 43210.

Central injection of TRH or its metabolically stable analogue RX 77368 has been demonstrated to produce a vagal-dependent stimulation in gastric acid secretion. Accumulating evidence exists regarding the interaction of serotonin (5HT) with TRH containing neuronal systems. This study was performed to assess the effect of pretreatment with the 5HT uptake inhibitor fluoxetine on the TRH analogue-induced gastric acid secretory response. Systemic fluoxetine (30 mumol/kg, i.v.) produced a 43-85% increase in the intracisternal RX 77368 (78-780 pmol)-induced gastric acid output, while not affecting the basal acid response. The acid response to a lower dose of RX 77368 (26 pmol) was not altered. In addition, intracisternal fluoxetine (180 nmol) produced a 71% augmentation of the acid secretory response of i.c. RX 77368 (260 pmol). Intracisternal injection of lower doses (60, 120 nmol), or intravenous injection of 180 nmol of fluoxetine was ineffective in altering the intracisternal RX 77368-induced acid response. Pretreatment with the noradrenergic or dopaminergic uptake inhibitor desipramine or GBR 12909 did not alter the RX 77368-stimulated gastric acid secretory response. The results show that fluoxetine pretreatment potentiates the effect of intracisternal RX 77368 on acid secretion. The effect appears to be impulse dependent, and central sites of action are involved. The data suggest an interaction of synaptic serotonin with a RX 77368-elicited event (activation of TRH receptors, second messenger systems and/or firing of the motor vagus) results in potentiation of the RX 77368-induced gastric response.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1574606&dopt=Abstract fluoxetine




Life Sci. 1992;50(26):2125-38.
Fluoxetine-induced inhibition of synaptosomal [3H]5-HT release: possible Ca(2+)-channel inhibition.

Stauderman KA, Gandhi VC, Jones DJ.

Marion Merrell Dow Research Institute, Cincinnati, OH 45215.

Fluoxetine, a selective 5-HT uptake inhibitor, inhibited 15 mM K(+)-induced [3H]5-HT release from rat spinal cord and cortical synaptosomes at concentrations greater than 0.5 uM. This effect reflected a property shared by another selective 5-HT uptake inhibitor paroxetine but not by less selective uptake inhibitors such as amitriptyline, desipramine, imipramine or nortriptyline. Inhibition of release by fluoxetine was inversely related to both the concentration of K+ used to depolarize the synaptosomes and the concentration of external Ca2+. Experiments aimed at determining a mechanism of action revealed that fluoxetine did not inhibit voltage-independent release of [3H]5-HT release induced by the Ca(2+)-ionophore A 23187 or Ca(2+)-independent release induced by fenfluramine. Moreover the 5-HT autoreceptor antagonist methiothepin did not reverse the inhibitory actions of fluoxetine on K(+)-induced release. Further studies examined the effects of fluoxetine on voltage-dependent Ca2+ channels and Ca2+ entry. Whereas fluoxetine and paroxetine inhibited binding of [3H]nitrendipine to the dihydropyridine-sensitive L-type Ca2+ channel, the less selective uptake inhibitors did not alter binding. The dihydropyridine antagonist nimodipine partially blocked fluoxetine-induced inhibition of release. Moreover enhanced K(+)-stimulated release due to the dihydropyridine agonist Bay K 8644 was reversed by fluoxetine. Fluoxetine also inhibited the K(+)-induced increase in intracellular free Ca2+ in fura-2 loaded synaptosomes. These data are consistent with the suggestion that fluoxetine inhibits K(+)-induced [3H]5-HT release by antagonizing voltage-dependent Ca2+ entry into nerve terminals.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1608295&dopt=Abstract fluoxetine




Psychopharmacology (Berl). 1992;107(2-3):359-64.
Partial reversal of fluoxetine anorexia by the 5-HT antagonist metergoline.

Lee MD, Clifton PG.

Laboratory of Experimental Psychology, University of Sussex, Brighton, UK.

Experiment 1 showed that the reduction of intake produced by 5 or 10 mg/kg fluoxetine in rats eating either a solid or a liquid meal was partially antagonised by 1 mg/kg of the 5HT1/5HT2 antagonist metergoline but not by 1 mg/kg of the 5HT2 antagonist ketanserin. Experiment 2 examined the meal patterning of rats given 5 mg/kg fluoxetine and 1 mg/kg metergoline. Fluoxetine alone increased the latency to feed, reduced meal size and shifted the inter-pellet interval (IPI) distribution to the right. Metergoline alone had little immediate effect on food intake or other feeding parameters but partially reversed the reduction of food intake produced by fluoxetine. There was a complete reversal of the increased latency to feed and a partial reversal of the depression of meal size. However, the rightward shift of the IPI distribution caused by fluoxetine, which indicated a depression of feeding rate, was more pronounced after combined treatment. We conclude that fluoxetine reduces food intake by enhancing satiety through a serotonergic dependent mechanism but reduces feeding rate through a separate mechanism, whose neurochemical basis remains to be established.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1615137&dopt=Abstract fluoxetine




J Clin Psychiatry. 1992 Jul;53(7):235-41.
Lack of association between fluoxetine and suicidality in bulimia nervosa.

Wheadon DE, Rampey AH Jr, Thompson VL, Potvin JH, Masica DN, Beasley CM Jr.

Division of Clinical Neurosciences, Eli Lilly and Company, Indianapolis, Ind 46285.

BACKGROUND: The coincidence of major depressive disorder in bulimia nervosa ranges from 35% to 80%. Because of this comorbidity and because suicidality (suicidal acts and ideation) is an inherent part of depression, assessment of the risk of suicide in patients with bulimia nervosa is of considerable interest. METHOD: Data from United States Investigational New Drug double-blind, placebo-controlled fluoxetine clinical trials in bulimia nervosa were analyzed comprehensively to assess the potential association between fluoxetine treatment and suicidality in 785 patients with DSM-III-R bulimia nervosa. Patients were predominantly women (98%), aged 17 to 63 years; of the randomly assigned patients, 16.9% exhibited 17-item Hamilton Rating Scale for Depression (HAM-D) total scores of 17 or greater at baseline (range, 0-31). Incidence of suicidality was analyzed by the incidence difference method. RESULTS: No fatal suicidal acts occurred; 9 (1.15%) of 785 patients made nonfatal attempts; 24 (3.06%) experienced emergent (text-defined) suicidal ideation. No statistically significant increases in the incidence of suicidal acts or suicidal ideation were observed among fluoxetine-treated compared with placebo-treated patients. A smaller percentage of fluoxetine-treated (2.0%) than placebo-treated (3.8%) patients experienced emergence of substantial suicidal ideation (change in baseline HAM-D Item 3 [suicide item] score of 0 or 1 to 3 or 4 during therapy). A statistically significantly greater proportion of fluoxetine-treated than placebo-treated patients experienced improvement in suicidal ideation (decrease in HAM-D Item 3 score) from baseline to endpoint (p = .026). CONCLUSION: Analyses of the incidence of suicidal acts and suicid




J Pharm Pharmacol. 1992 Mar;44(3):250-4.
Anorectic activity of fluoxetine and norfluoxetine in rats: relationship between brain concentrations and in-vitro potencies on monoaminergic mechanisms.

Caccia S, Bizzi A, Coltro G, Fracasso C, Frittoli E, Mennini T, Garattini S.

Istituto di Richerche Farmacologiche Mario Negri, Milan, Italy.

The present study was aimed at establishing the importance of brain monoamine uptake and release mechanisms in the anorectic activity of fluoxetine, relating them to the actual brain concentrations of the parent drug and its metabolite norfluoxetine after anorectic doses in rats. Both compounds showed anorectic activity when administered intraperitoneally, norfluoxetine being slightly more active (ED50 = 22.9 mumol kg-1) than fluoxetine (ED50 = 35.0 mumol kg-1) despite the fact that the metabolite is about ten times less potent than the parent drug in inhibiting 5-hydroxytryptamine (5-HT) uptake. Comparing the brain concentrations of norfluoxetine, in terms of maximum concentrations (Cmax) and area under the curve (AUC), after the ED50 of fluoxetine or synthetic norfluoxetine, it also appeared that the metabolite plays a major role in the anorectic effect of the parent drug in rats. Brain Cmax of fluoxetine (48.7 microM) and norfluoxetine (21.7 and 27.3 microM after metabolite and drug, respectively) were several times those blocking 5-HT uptake in-vitro (0.5 microM), making it unlikely that fluoxetine (directly or through its metabolite) reduces food intake by specifically blocking 5-HT neuronal uptake. Brain Cmax of fluoxetine but particularly norfluoxetine were more compatible with those capable in-vitro of affecting catecholaminergic mechanisms, such as inhibition of dopamine and noradrenaline uptake and enhancement of dopamine release. These results together with recent in-vitro findings that the parent compound and its active metabolite induce tritium release from hippocampal synaptosomes previously loaded with [3H]5-HT suggest that mechanisms other than i