Prozac
Human cytochromes mediating N-demethylation of fluoxetine in vitro.

von Moltke LL, Greenblatt DJ, Duan SX, Schmider J, Wright CE, Harmatz JS, Shader RI.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA. lvonmolt pearl.edu

Biotransformation of the selective serotonin reuptake inhibitor antidepressant, fluoxetine, to its principal metabolite, norfluoxetine, was evaluated in human liver microsomes and in microsomes from transfected cell lines expressing pure human cytochromes. In human liver microsomes, formation of norfluoxetine from R,S-fluoxetine was consistent with Michaelis-Menten kinetics (mean K(m) = 33 microM), with evidence of substrate inhibition at high substrate concentrations in a number of cases. The reaction was minimally inhibited by coincubation with chemical probes inhibitory for P450-2D6 (quinidine), -1A2 (furafylline, alpha-naphthoflavone), and -2E1 (diethyldithiocarbamate). Substantial inhibition was produced by coincubation with sulfaphenazole (Ki = 2.8 microM), an inhibitory probe for P450-2C9, and by ketoconazole (Ki = 2.5 microM) and fluvoxamine (Ki = 5.2 microM). However, ketoconazole, relatively specific for P450-3A isoforms only at low concentrations, reduced norfluoxetine formation by only 20% at 1 microM, and triacetyloleandomycin (> or = 5 microM) reduced the velocity by only 20-25%. Microsomes from cDNA-transfected human lymphoblastoid cells containing human P450-2C9 produced substantial quantities of norfluoxetine when incubated with 100 microM fluoxetine. Smaller amounts of product were produced by P450-2C19 and -2D6, but no product was produced by P450-1A2, -2E1, or 3A4. Cytochrome P450-2C9 appears to be the principal human cytochrome mediating fluoxetine N-demethylation. P450-2C19 and -3A may make a further small contribution, but P450-2D6 is unlikely to make an important contribution.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9298519&dopt=Abstract fluoxetine Prozac



Prozac
Greater effects of fluoxetine and its combination with (-)-pindolol in elevating hypothalamic serotonin in rats during dark hours.

Dreshfield LJ, Rocco VP, Wong DT.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.

Administration of fluoxetine (10 mg/kg i.p.) caused a significantly greater increase in extracellular 5-HT levels in hypothalamus of rats adapted to a reverse light period (lights off 9:00 am-9:00 pm) than those adapted to the regular cycle (lights off 6:00 pm-6:00 am). Sequential administration of the antagonist 5-HT1A/beta-adrenergic receptors (-)-pindolol at 0.1, 0.3, 1, and 3 mg/kg s.c. significantly enhanced the fluoxetine-induced elevation of 5-HT levels in both groups of rats. (-)-Pindolol at 0.1 mg/kg potentiated the fluoxetine-induced elevation in 5-HT levels significantly higher in rats adapted to the reverse light cycle than in those accustomed to the regular light cycle. The greater effects of fluoxetine and the subsequent administration of (-)-pindolol in the reverse cycle group may relate to the difference in activity of 5-HT neurons in the dorsal raphe of conscious animals adapted to the two light periods.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9303241&dopt=Abstract fluoxetine Prozac



Prozac
Postmortem serum and tissue redistribution of fluoxetine and norfluoxetine in dogs following oral administration of fluoxetine hydrochloride (Prozac).

Pohland RC, Bernhard NR.

Toxicology Research Laboratories, Lilly Research Laboratories, A Division of Eli Lilly and Company, Green-field, IN, USA.

Antemortem serum and postmortem serum and tissues were evaluated to determine if postmortem redistribution of the antidepressant, fluoxetine (Prozac) and its major active metabolite, norfluoxetine, occurred in dogs following oral administration of fluoxetine hydrochloride. Beagle dogs (four males) received daily oral doses of 10 mg fluoxetine/kg for five days. Antemortem serum concentrations of fluoxetine and norfluoxetine were determined 3 and 24 h following administration of the first four daily doses of fluoxetine and 3 h after the fifth dose in order to monitor for steady-state serum concentrations of parent and metabolite prior to postmortem serum concentration determinations. Antemortem serum concentrations of fluoxetine and norfluoxetine 3 h postdose on Day 5 ranged from 530 to 1210 ng/mL and 1460 to 1980 ng/ mL, respectively. Immediately following the 3 h blood sample on Day 5, each dog was euthanized. Serum concentrations of fluoxetine and norfluoxetine were determined from blood samples collected from the vena cava, heart, and clotted blood within the heart at 2 h after death in two dogs and 12 h after death in the remaining two dogs. Similarly, tissue concentrations of fluoxetine and norfluoxetine in heart, liver, and lung were determined 2 and 12 h postmortem. Serum concentrations of fluoxetine and norfluoxetine from the vena cava and heart 2 h postmortem were 2.2- to 6.0-fold and 2.3- to 3.6-fold higher, respectively, than antemortem serum concentrations. Similarly, serum concentrations of fluoxetine and norfluoxetine from vena cava and heart 12 h postmortem were 1.3- to 3.5-fold and 1.7- to 3.3-fold higher, respectively, than antemortem serum concentrations. However, 2-h and 12-h postmortem serum concentrations of fluoxetine and norfluoxetine from clotted blood within the heart were equal to or less than levels determined in antemortem serum. Results from 2-h and 12-h postmortem average tissue concentrations of fluoxetine and norfluoxetine in heart, liver, and lung demonstrated that fluoxetine and norfluoxetine concentrations in myocardium were similar 2 h and 12 h postmortem. However, in liver, fluoxetine concentrations decreased 39% and norfluoxetine concentrations decreased 23% from 2 h to 12 h postmortem. Even greater postmortem decreases in fluoxetine and norfluoxetine concentrations were observed in lung. Fluoxetine and norfluoxetine concentrations in lung decreased 49% and 39%, respectively, from 2 h to 12 h postmortem. In conclusion, this study demonstrated that fluoxetine and norfluoxetine undergo postmortem redistribution in the dog. Furthermore, postmortem serum concentrations appear to be dependent on the sample site and the degree of coagulation of the blood. Finally, postmortem decreases in concentrations of fluoxetine and norfluoxetine in liver and lung may, in part, explain the observed increase in serum concentrations at 2 and 12 h postmortem.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9304827&dopt=Abstract fluoxetine Prozac



Prozac
Influence of anxiolytic drugs on the effects of specific serotonin reuptake inhibitors in the forced swimming test in mice.

Da-Rocha MA Jr, Puech AJ, Thiebot MH.

Department of Pharmacology, Faculty of Medicine Pitie-Salpetriere, Paris, France.

This study aimed at investigating the effect of several selective serotonin reuptake inhibitors (SSRIs), given alone or in combination with anxiolytic drugs, on the time spent immobile in the forced swimming test in mice. The time spent immobile was dose-dependently reduced by acute administration of fluoxetine (4-64 mg/ kg, i.p.), paroxetine (1-32 mg/kg, s.c.) or sertraline (4-32 mg/kg, s.c.), indalpine was active at only one dose (16 mg/kg, i.p.), fluvoxamine (up to 16 mg/kg, i.p.) and citalopram (up to 4 mg/kg, i.p.) were inactive. The anti-immobility effect of fluoxetine (32 mg/kg) was antagonized by an acute co-administration of all anxiolytics tested, the GABAA/BZD receptor agonists, diazepam (2 mg/kg, i.p.), chlordiazepoxide (8 mg/kg, i.p.), lorazepam (0.125 mg/kg, i.p.), triazolam (0.06 mg/kg, i.p.) and alpidem (8 mg/kg, i.p.) and the 5-HT1A receptor partial agonist, buspirone (0.5 mg/kg, s.c.). The sedative neuroleptic, thioridazine (4 mg/kg, i.p.), was also found to counteract the effect of fluoxetine. Lorazepam, triazolam and buspirone also reversed the anti-immobility effect of paroxetine and sertraline, while diazepam and chlordiazepoxide did not. Alpidem reduced the effect of sertraline but not paroxetine, whereas the reverse was found with thioridazine. These data indicate that the influence of anxiolytics on the action of SSRI antidepressants is variable, depending on both the SSRI and the anxiolytic considered. The co-administration of the GABAA/BZD receptor antagonist, flumazenil (16 mg/kg, i.p.), with behaviourally inactive doses of fluoxetine, fluvoxamine and citalopram, resulted in a reduction of immobility. The 5-HT1A receptor antagonist, (+)-WAY 100135 (8 mg/kg, s.c.), combined with a subactive dose of fluoxetine, but not with fluvoxamine, significantly reduced the time spent immobile. The 5-HT2A receptor antagonist, ketanserin (32 mg/kg, s.c.), which reduced immobility when given alone, did not interfere with fluoxetine given at a subactive dose. Although non-specific sedative and/or motor effects cannot be totally ruled out, these results suggest that pharmacodynamic interactions exist between various anxiolytics and SSRIs. These interactions probably involve both serotonergic and GABAergic processes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9305412&dopt=Abstract fluoxetine Prozac



Prozac
Simultaneous identification and quantitation of fluoxetine and its metabolite, norfluoxetine, in biological samples by GC-MS.

Crifasi JA, Le NX, Long C.

St. Louis University, Forensic Toxicology Laboratory, Missouri 63134, USA.

A sensitive method for the quantitation of fluoxetine and norfluoxetine in biological samples was developed. Blood, urine, and tissue samples were alkalinized and extracted with N-butyl chloride. The extracts were derivatized with pentafluoropropionic anhydride before gas chromatography-mass spectrometry (GC-MS). Selected ions were monitored at m/z 117 and 294 for fluoxetine; m/z 117, 176, and 280 for norfluoxetine; and m/z 122 and 299 for the internal standard fluoxetine-d5. The within-run and between-run precision as well as recovery were determined for both analytes. The empirical limit of detection was determined to be 12.5 micrograms/L for both fluoxetine and norfluoxetine, whereas the empirical limit of quantitation was 25 micrograms/L for both drugs. Calibration curves were linear in the range of 50-1000 micrograms/L for both analytes. Some drugs that were known or suspected of interfering with high-performance liquid chromatography and GC methods for fluoxetine and norfluoxetine were tested for interference. This is the only reported method that combines the use of a deuterated internal standard, selected ion monitoring by GC-MS, and derivatization for the identification and quantitation of fluoxetine and norfluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9323519&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine decreases fat and protein intakes but not carbohydrate intake in male rats.

Heisler LK, Kanarek RB, Gerstein A.

Department of Psychology, Tufts University, Medford, MA 02215, USA.

Administration of fluoxetine, a selective serotonin reuptake inhibitor, results in decreases in food intake and body weight. The present study investigated whether the anorectic actions of fluoxetine were due to a general decrease in caloric intake or macronutrient specific. Male Long-Evans rats were maintained on a dietary self-selection regime with separate sources of protein, fat, and carbohydrate. During the acute phase of the experiment, nutrient intakes were measured 2, 4, 6, and 24 h after injections of 0, 5.0, and 10.0 mg/kg fluoxetine hydrochloride. Fluoxetine significantly decreased protein and fat intakes in a dose-related manner at all measurement times. In comparison, fluoxetine had a less pronounced effect on carbohydrate intake. During the chronic phase, rats were divided into two groups, one receiving daily injections of 10.0 mg/kg fluoxetine, and the other, vehicle injections. Drug injections continued for 28 days, and were followed by a 28-day withdrawal period. Rats given fluoxetine on a chronic basis consumed significantly less calories and gained significantly less weight than rats injected with the vehicle. Both caloric intake and body weight returned to control values during the withdrawal period. Fat and protein intakes also were significantly reduced throughout the drug injection period, and were restored to baseline levels during the withdrawal period. In contrast, carbohydrate intake was not reduced on an absolute basis, and actually was increased as percent of total caloric intake during the drug period. The results of this experiment call into question the idea that increased serotoninergic activity is related to selective reductions in carbohydrate intake.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9329071&dopt=Abstract fluoxetine Prozac



Prozac
Trazodone is only slightly faster than fluoxetine in relieving insomnia in adolescents with depressive disorders.

Kallepalli BR, Bhatara VS, Fogas BS, Tervo RC, Misra LK.

Department of Psychiatry, University of South Dakota School of Medicine, Sioux Falls, USA.

This retrospective chart review examined the relative effectiveness of fluoxetine and trazodone in relieving insomnia associated with depressive disorders in adolescents (aged 13-17 years). We reviewed the hospital charts of consecutively admitted adolescents with a depressive disorder and insomnia, who received one of three treatments: fluoxetine (20 +/- 2.2 mg), trazodone (71 +/- 32 mg), or a fluoxetine-trazodone combination (fluoxetine 29 +/- 2.2 mg, trazodone 68 +/- 29 mg). Each treatment was examined in 20 patients. Insomnia was defined as a change in sleep patterns characterized by decreased total sleep time that was sufficient to cause clinical concern, and insomnia resolution was defined as sleep starting by midnight and lasting 6 hours. Mean time to resolution of insomnia was significantly faster in adolescents treated with trazodone rather than fluoxetine (2.5 vs. 5.1 days, p < 0.05). Trazodone seemed to save only about 3 days and insomnia resolved in all subjects by the 11th day of antidepressant treatment. Median time to insomnia resolution was 2 days (range 1-5 days) in the trazodone group and 4 days (range 1-11 days) in the fluoxetine group. This difference between trazodone and fluoxetine, although statistically significant, was generally not clinically significant in the management of insomnia associated with depressive disorders in adolescents. The resolution of insomnia was not faster for treatment with a combination of fluoxetine and trazodone in comparison to fluoxetine monotherapy. Insomnia resolution was slightly later in older children. These clinical findings await confirmation by a controlled study. Both drugs seemed effective in ameliorating sleep symptoms in this sample, although it is likely that they produced these changes by different mechanisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9334895&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine's effects on ethanol's rewarding, aversive and stimulus properties.

Risinger FO.

Portland Alcohol Research Center, Department of Behavioral Neuroscience, Oregon Health Sciences University, 97201, USA. risinger ohsu.edu

These experiments examined the influence of fluoxetine on ethanol-induced conditioned place preference, ethanol-induced conditioned taste aversion, and ethanol discrimination. In the place conditioning experiment, male Swiss-Webster mice received 4 pairings of a distinctive floor cue with 2 g/kg ethanol, 10 mg/kg fluoxetine + ethanol, or fluoxetine alone. A different floor was paired with saline. During conditioning ethanol produced locomotor stimulation. Fluoxetine + ethanol resulted in greater levels of locomotor activity during conditioning trials 2-4. Fluoxetine alone also caused increases in activity. Floor preference testing revealed conditioned place preference in groups receiving ethanol. Fluoxetine did not change the magnitude of ethanol-induced conditioned place preference nor produced place conditioning alone. In the taste conditioning procedure, mice received 1-h access to 0.2 M NaCl solution followed by injections of 0, 5 or 10 mg/kg fluoxetine and 0 or 2.5 g/kg ethanol. Ethanol produced reductions in NaCl intake. Fluoxetine (10 mg/kg) enhanced the development of ethanol-conditioned taste aversion but did not cause taste aversion alone. In the ethanol discrimination experiment, mice were trained to respond for 10% sucrose on an FR20 schedule following injections of either 1 g/kg ethanol or saline. Following acquisition, 10 mg/kg fluoxetine pretreatment enhanced ethanol-appropriate responding at a dose of ethanol (0.5 g/kg) below the training dose. These results indicate enhancement of serotonergic activity influences ethanol aversion and discrimination but not ethanol reward.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9353173&dopt=Abstract fluoxetine Prozac