Clin Pharmacol Ther. 1988 Sep;44(3):353-9.
Fluoxetine disposition and elimination in cirrhosis.

Schenker S, Bergstrom RF, Wolen RL, Lemberger L.

Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7878.

Fluoxetine is a specific and potent inhibitor of presynaptic serotonin reuptake and has been shown to be a clinically effective antidepressant. Elimination of the drug depends primarily on hepatic metabolism, with formation of a pharmacologically active demethylated product, norfluoxetine. The present study assesses for the first time the effect of chronic liver disease on these processes. Our data show that in stable alcoholic cirrhosis, the elimination of fluoxetine is significantly reduced. The mean t1/2 was 6.6 vs. 2.2 days and plasma clearance was 4.2 vs. 9.6 ml/min/kg for patients with cirrhosis vs. normal volunteers, respectively. In addition, the formation of norfluoxetine was decreased and its clearance was also reduced. Thus, at steady state both fluoxetine and norfluoxetine concentrations will be higher in patients with cirrhosis, unless the dosage is reduced. Conventional liver tests and indocyanine green clearance in cirrhosis did not correlate in a predictive manner with individual patients' elimination of fluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3262026&dopt=Abstract fluoxetine




Alcohol. 1988 Jul-Aug;5(4):283-6.
Effects of fluoxetine on the intragastric self-administration of ethanol in the alcohol preferring P line of rats.

Murphy JM, Waller MB, Gatto GJ, McBride WJ, Lumeng L, Li TK.

Department of Psychiatry, Indiana University School of Medicine, Indianapolis 46223.

Rats of the alcohol-preferring P line (n = 7) were trained to self-administer ethanol (20% v/v) and water via an intragastric IG catheter. Food was available ad lib. Ethanol intakes averaged approximately 5-6 g/kg body wt./day. Treatment with the serotonin (5-HT) uptake inhibitor fluoxetine (10 mg/kg/day; IG) for seven consecutive days produced a marked decrease in ethanol self-administration on the first day, which was sustained throughout the seven days of treatment to values as low as 1 g/kg/day. Concomitant with the decrease in ethanol intake, the self-infusion of water gradually increased during the period of fluoxetine treatment. Total caloric intake (ethanol plus food) was moderately reduced during fluoxetine treatment; the decrease in food consumption was consistent but not statistically significant. When fluoxetine treatment was terminated, ethanol self-administration quickly returned to the prefluoxetine levels, while water intake began to decrease. Since no ethanol was consumed orally, the IG ethanol was not self-administered for its taste or smell, but apparently for its postingestive pharmacological effects. The robust reduction of ethanol self-infusion that occurred with fluoxetine treatment suggests that the 5-HT systems are involved in the reinforcing effects of ethanol in the P line of rats.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3265874&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 1990 Dec;255(3):976-9.
Ineffectiveness of parenteral fluoxetine or RU-486 to alter long-term food intake, body weight or body composition of genetically obese mice.

Dubuc PU, Peterson CM.

Sansum Medical Research Foundation, Santa Barbara, California.

The effects of 3 weeks of daily subcutaneous injections of a serotonin agonist (fluoxetine, 20 mg/kg) or agent having antiglucocorticoid properties (RU-486, 20 mg/kg) on food intake and body growth were examined in C57BL/6 ob/ob and lean mice. Fluoxetine injections during ad libitum feeding led to depressed food intake and body weight in both obese and lean mice over the initial 10 days of treatment with full recovery of both intake and weight by the end of the study. Fluoxetine treatment of mice restricted to 3.2 g of laboratory diet per day caused small but persistent depressions of body weight in both phenotypes. RU-486 did not affect food intake weight or weight gain in either phenotype or feeding condition and neither drug affected carcass composition. Insulin levels were also unaffected by treatment but final corticosterone concentrations were consistently higher in fluoxetine-treated mice and lower in RU-486-treated mice. Although transient benefits on feeding and weight gain were observed with fluoxetine administration, the present results show that neither fluoxetine nor RU-486 administered parenterally provides significant long-term improvement in the metabolic, growth or behavioral disturbances that characterize ob/ob mice.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2124625&dopt=Abstract fluoxetine




Brain Res. 1990 Oct 8;529(1-2):294-301.
Effects of fluoxetine or D-fenfluramine on serotonin release from, and levels in, rat frontal cortex.

Sarkissian CF, Wurtman RJ, Morse AN, Gleason R.

Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge 02139.

Using in vivo microdialysis of frontal cortex in anesthetized rats, as well as analysis of frontal cortex homogenates, we examined the effects of chronic administration of fluoxetine (30 mg/kg, i.p.) or D-fenfluramine (7.5 mg/kg, i.p.), administered daily for 3 days, on serotonin and 5-HIAA levels a day later. Measurements were also taken after 3-, 7- , and 21-day recovery periods. Neither chronic fluoxetine nor D-fenfluramine changed basal serotonin release. Both treatments, however, transiently decreased the release of serotonin evoked by an acute dose of D-fenfluramine (10 mg/kg, i.p.). Release initially was completely suppressed in fluoxetine-pretreated animals but returned to normal by the 21st day of washout; following D-fenfluramine pretreatment, normal release was attained by the 7th day of washout. Both fluoxetine and D-fenfluramine transiently decreased 5-HIAA levels in the dialysates and tissues. Both drugs also caused prolonged changes in frontal cortex serotonin levels, D-fenfluramine lowering them but fluoxetine elevating them. These results suggest that, at comparable dosage levels relative to their ED50s, fluoxetine and D-fenfluramine cause comparable reversible effects on brain serotonin release. The drugs also cause prolonged but opposite changes in brain serotonin levels, probably reflecting differences in the extents to which they or their principal metabolites release serotonin and block its reuptake.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1704283&dopt=Abstract fluoxetine




Biochem Pharmacol. 1990 Nov 1;40(9):2161-7.
Interaction of fluoxetine with the human placental serotonin transporter.

Cool DR, Liebach FH, Ganapathy V.

Department of Cell and Molecular Biology, Medical College of Georgia, Augusta 30912-2100.

The interaction of fluoxetine, a non-tricyclic antidepressant, with the human placental serotonin transporter was investigated by studying its influence on [3H]paroxetine binding to the transporter and on [3H]serotonin uptake via the transporter. These studies were done using brush-border membrane vesicles purified from normal term human placentas. Fluoxetine inhibited binding of paroxetine to the membrane vesicles in a concentration-dependent manner, with a Ki value of 3 nM. Kinetic analysis revealed that the inhibition was competitive because the presence of 10 nM fluoxetine increased the Kd for paroxetine from 72 to 461 pM, but had no effect on the Bmax. Fluoxetine also caused a time-dependent dissociation of paroxetine already bound to the transporter. The dissociation followed first-order kinetics. Uptake of serotonin in these membrane vesicles was also inhibited by fluoxetine. The inhibition was concentration dependent with a Ki value of 66 nM at pH 7.5 and 80 nM at pH 6.5. The effect of fluoxetine on the uptake kinetics was to increase the apparent dissociation constant (Kt) for serotonin without influencing the maximal transport capacity (Vmax). The results demonstrate that fluoxetine is a high-affinity ligand and a potent inhibitor of the serotonin transporter found in the human placental brush-border membrane.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2146964&dopt=Abstract fluoxetine




Toxicol Appl Pharmacol. 1986 Jan;82(1):70-9.
Hemodynamic and electrocardiographic effects of fluoxetine and its major metabolite, norfluoxetine, in anesthetized dogs.

Steinberg MI, Smallwood JK, Holland DR, Bymaster FP, Bemis KG.

The cardiovascular effects of the selective serotonin uptake inhibitor, fluoxetine, and its N-desmethyl metabolite, norfluoxetine, were studied in anesthetized dogs during constant iv infusion of supratherapeutic doses (0.1 mg/kg/min for 50 min). Fluoxetine and norfluoxetine did not significantly affect mean blood pressure, pulmonary artery wedge pressure, or heart rate compared to a corresponding vehicle group. Cardiac output fell 15 to 20% during fluoxetine infusion due to nonsignificant decreases in both heart rate (10%) and stroke volume (5 to 10%). In contrast, the tricyclic antidepressant agent, amitriptyline, infused at the same dose, decreased both mean pressure and systemic vascular resistance (20%) and increased heart rate (20%). Pulmonary wedge pressure rose by 35%, and stroke volume fell by 20% suggesting impaired ventricular contractility. Both intramyocardial and infranodal conduction was slowed during amitriptyline infusion as indicated by increases in the QRS duration, and the PQ and HV interval. Fluoxetine and norfluoxetine had no influence on cardiac impulse conduction velocity as assessed by either surface or intracardiac conduction indices. Plasma concentrations of fluoxetine, norfluoxetine, and amitriptyline reached during infusion ranged from 1.0 to 2.5 micrograms/ml. Platelet [3H]serotonin uptake was inhibited by 95% during infusion of fluoxetine and about 75% during infusion of norfluoxetine or amitriptyline. These observations indicate that large iv doses of fluoxetine or norfluoxetine lack prominent cardiodepressant effects in dogs, suggesting a greater margin of safety for fluoxetine compared to tricyclic antidepressant drugs.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3484846&dopt=Abstract fluoxetine




Pharmacol Biochem Behav. 1986 Feb;24(2):281-4.
Fluoxetine enantiomers as antagonists of p-chloroamphetamine effects in rats.

Fuller RW, Snoddy HD.

The dextrorotatory enantiomer of fluoxetine was slightly more potent than the levorotatory enantiomer in antagonizing the depletion of brain serotonin by p-chloroamphetamine in rats. The time course of the depletion of brain serotonin at times out to 24 hr after the injection of p-chloroamphetamine was determined with or without simultaneous administration of one of the fluoxetine enantiomers. The dextrorotatory enantiomer prevented the depletion of brain serotonin at any time after p-chloroamphetamine. The levorotatory enantiomer prevented the initial depletion of brain serotonin at 2 and 4 hr, but by 8 hr brain serotonin concentration was decreased and by 24 hr the depletion of serotonin was almost as great as in rats treated with p-chloroamphetamine alone. The elevation of serum corticosterone that occurred acutely after injection of a low dose of p-chloroamphetamine was significantly antagonized by both enantiomers of fluoxetine, the dextrorotatory enantiomer being slightly more potent. In contrast, the lowering of DOPAC (3,4-dihydroxyphenylacetic acid) concentration in rat brain by p-chloroamphetamine was not antagonized by either enantiomer of fluoxetine, indicating this effect is not secondary to serotonin release by p-chloroamphetamine. The results are consistent with other evidence that both enantiomers of fluoxetine are potent inhibitors of serotonin uptake, the dextrorotatory enantiomer being longer-acting than the levorotatory enantiomer in rats.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3485293&dopt=Abstract fluoxetine




J Clin Psychopharmacol. 1987 Oct;7(5):329-32.
An open trial of fluoxetine in the treatment of panic attacks.

Gorman JM, Liebowitz MR, Fyer AJ, Goetz D, Campeas RB, Fyer MR, Davies SO, Klein DF.

Anxiety Disorders Clinic, New York State Psychiatric Institute, New York.

Fluoxetine is a new antidepressant with pharmacologic effects apparently limited to blockade of neuronal serotonin reuptake. We entered 20 patients who met DSM-III criteria for either panic disorder or agoraphobia with panic attacks into an open, uncontrolled pilot study of fluoxetine. Four responded to placebo in the week before fluoxetine administration and were dropped from the study. Of the remaining 16 patients, nine were nonresponders and seven were responders, with complete cessation of their panic attacks. Eight of the nine nonresponders were unable to tolerate the side effects of fluoxetine. In contrast, all of the responders (and one nonresponder) experienced minimal side effects. Fluoxetine may be effective in the treatment of panic attacks, perhaps implicating the serotonergic system in the pathophysiology of panic disorder. Future studies should use very low doses of fluoxetine to initiate treatment.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3500189&dopt=Abstract fluoxetine




Brain Res. 1987 Dec 8;436(1):92-102.
Short-term effects of fluoxetine and trifluoromethylphenylpiperazine on electroencephalographic sleep in the rat.

Pastel RH, Fernstrom JD.

Department of Psychiatry, University of Pittsburgh, PA.

Fluoxetine and trifluoromethylphenylpiperazine (TFMPP) were studied for their short-term effects on electroencephalographic sleep in male rats. Following single injection, each drug produced a sizeable, dose-related suppression of rapid-eye-movement (REM) sleep that persisted for 4-5 h (fluoxetine, 0.625-5 mg/kg; TFMPP, 0.10-1.25 mg/kg). TFMPP also consistently increased non-REM (NREM) sleep during the second hour after drug injection, though this effect was not dose-related (it was seen at all doses tested). Fluoxetine produced small effects on NREM sleep that varied non-systematically with dose and time after drug injection. TFMPP, but not fluoxetine, also increased at all doses the number of delta waves per minute of NREM sleep in the second hour. A structural analog of TFMPP that is inactive at serotonin (5-HT) receptors [4-(m-trifluoromethylphenyl)piperadine; LY97117] was also tested, and found to be devoid of effects on NREM and REM sleep. Both fluoxetine (a 5-HT reuptake blocker) and TFMPP (a 5-HT agonist) enhance transmission across 5-HT synapses, though by different mechanisms. Because they have the common effect of suppressing REM sleep, and in a dose-related manner, the data support the notion that 5-HT neurons in the brain, when active, can suppress REM sleep.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3500757&dopt=Abstract fluoxetine