Fundam Clin Pharmacol. 1998;12(2):194-9.
In vitro interactions between fluoxetine or fluvoxamine and methadone or buprenorphine.

Iribarne C, Picart D, Dreano Y, Berthou F.

Laboratoires de Biochimie Nutrition EA-948, Faculte de Medecine, Brest, France.

Methadone and buprenorphine, widely used in the treatment of opioid abuse, are metabolized by cytochrome P450 3A4, while fluoxetine and fluvoxamine, both selective serotonin reuptake inhibitors, are known to be P450 2D6 and 3A4 inhibitors in vitro. This study deals with the in vitro interactions between methadone or buprenorphine and fluoxetine or fluvoxamine. Fluoxetine inhibited methadone N-demethylation (Ki = 55 microM), but conversely did not inhibit buprenorphine dealkylation. Norfluoxetine inhibited the metabolism of both methadone and buprenorphine metabolisms (Ki 13 and 100 microM, respectively). Fluvoxamine inhibited methadone N-demethylation with a Ki of 7 microM and buprenorphine dealkylation, uncompetitively, with a Ki of 260 microM. Finally, these results suggest that care should be taken when selective serotonin reuptake inhibitors are administered in the treatment of drug craving. This is particularly true in the case of fluvoxamine which is more potent than fluoxetine in inhibiting methadone and buprenorphine metabolism.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9565774&dopt=Abstract fluoxetine




Life Sci. 1999;64(9):805-11.
Detection of fluoxetine in brain, blood, liver and hair of rats using gas chromatography-mass spectrometry.

Lefebvre M, Marchand M, Horowitz JM, Torres G.

Centre de Toxicologie du Quebec, Ste-Foy, Canada.

This study reports the measurements of fluoxetine in discrete brain regions, blood, liver and hair of male rats injected with 10 mg/kg fluoxetine HCl for 15 consecutive days. Concentrations of the antidepressant were obtained by gas chromatography-mass spectrometry (GC-MS) methodology. In brain, fluoxetine levels were unevenly distributed, with the raphe nucleus containing the highest amounts relative to the hypothalamus or striatum. Fluoxetine was also measured in blood and liver roughly paralleling those ratios described in previous rodent studies. Of potential interest, fluoxetine was found to accumulate in rat hair after chronic treatment. Detection of fluoxetine in hair by GC-MS could be used as a marker for probative analyses.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10075113&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 1998 May;285(2):579-87.
Differential effects of chronic antidepressant treatment on swim stress- and fluoxetine-induced secretion of corticosterone and progesterone.

Duncan GE, Knapp DJ, Carson SW, Breese GR.

UNC Neuroscience Center, Department of Psychiatry, University of North Carolina at Chapel Hill, USA.

Hypersecretion of cortisol occurs in numerous patients with major depression and normalizes with clinical recovery during the course of chronic antidepressant treatment. These clinical data suggest that investigation of the effects of antidepressant treatments on the regulation of the brain-pituitary-adrenal axis may assist in elucidating the therapeutic basis of antidepressant actions. In the present investigation, both swim stress and acute fluoxetine challenge increased release of corticosterone and progesterone to reflect an activation of the brain pituitary-adrenal axis. The effects of chronic antidepressant treatment (21 days) on corticosterone and progesterone secretion induced by these challenges were investigated. Chronic fluoxetine treatment (5 mg/kg/day) completely blocked the increased secretion of corticosterone and progesterone in response to the acute fluoxetine challenge. Chronic treatment with desipramine, imipramine or amytriptyline (15 mg/kg/day) also markedly attenuated fluoxetine-induced corticosterone and progesterone secretion. However, chronic treatment with the monoamine oxidase inhibitors, phenelzine (5 mg/kg) and tranylcypromine (5 mg/kg), did not affect this hormonal response to acute fluoxetine challenge. Plasma levels of fluoxetine after acute challenge were not significantly different for the various chronic antidepressant treatment conditions from the chronic saline controls; therefore, an increase in the metabolism of fluoxetine can not explain the antagonism of the fluoxetine-induced hormonal response after chronic antidepressant treatment. In contrast to the effects of selected antidepressants on acute fluoxetine-induced steroid release




Am J Psychiatry. 1998 May;155(5):660-5.
Cardiovascular effects of fluoxetine in depressed patients with heart disease.

Roose SP, Glassman AH, Attia E, Woodring S, Giardina EG, Bigger JT Jr.

Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

OBJECTIVE: The purpose of this study was to determine the cardiovascular effects of fluoxetine in depressed patients with cardiac disease. METHOD: Twenty-seven depressed patients (26% of whom were female and whose average age was 73 years) who had congestive heart failure, conduction disease, and/or ventricular arrhythmia were studied in an open medication trial of fluoxetine, up to 60 mg/day, for 7 weeks. The main outcome measures were heart rate and rhythm measured by 24-hour ECG recordings, ejection fraction determined by radionuclide angiography, cardiac conduction intervals, and blood pressure. Baseline values were compared with those at weeks 2 and 7 of fluoxetine treatment. In 60 comparable patients, values of these same cardiovascular measures at baseline and after 3 weeks of treatment with a tricyclic antidepressant, nortriptyline, were also examined. RESULTS: Fluoxetine induced a statistically significant 6% decrease in heart rate, a 2% increase in supine systolic pressure, and a 7% increase in ejection fraction. There was no effect on cardiac conduction, ventricular arrhythmia, or orthostatic blood pressure. Overall, 4% of the fluoxetine patients had an adverse cardiovascular effect. In contrast, nortriptyline treatment caused a significant increase in heart rate and orthostatic hypotension, and 20% of the nortriptyline-treated patients had an adverse cardiovascular effect. CONCLUSIONS: In depressed patients with heart disease, fluoxetine treatment was not associated with the cardiovascular effects documented for the tricyclic antidepressants or with significant adverse cardiac events. However, limited conclusions about fluoxetine's cardiovascular effects and safety can be drawn from this stud




Br J Pharmacol. 1999 Jan;126(2):508-14.
Block by fluoxetine of volume-regulated anion channels.

Maertens C, Wei L, Voets T, Droogmans G, Nilius B.

KU Leuven, Laboratorium voor Fysiologie, LEUVEN, Belgium.

1. We have used the whole-cell patch clamp technique to study the effect of fluoxetine, a commonly used antidepressant drug, on the volume-regulated anion channel (VRAC) in calf pulmonary artery endothelial (CPAE) cells. We also examined its effects on other Cl- channels, i.e. the Ca2(+)-activated Cl- current (I(Cl,Ca) and the cystic fibrosis transmembrane conductance regulator (CFTR) to assess the specificity of this compound for VRAC. 2. At pH 7.4 fluoxetine induced a fast and reversible block of the volume-sensitive chloride current (I(Cl,swell)), with a Ki value of 6.0+/-0.5 microM (n = 6-9). The blocking efficiency increased with increasing extracellular pH (Ki= 0.32+/-0.01 microM at pH 8.8, n = 3-9), indicating that the blockade is mediated by the uncharged form of fluoxetine. 3. Fluoxetine inhibited Ca2(+)-activated Cl(-) currents, I(Cl,Ca), activated by loading CPAE cells via the patch pipette with 1000 nM free Ca2+ (Ki= 10.7+/-1.6 microm at pH 7.4, n=3-5). The CFTR channel, transiently transfected in CPAE cells, was also inhibited with a Ki value of 26.9+/-9.4 microM at pH 7.4 (n = 3). 4. This study describes for the first time the effects of fluoxetine on anion channels. Our data reveal a potent block of VRAC at fluoxetine concentrations close to plasma concentrations. The results suggest a hydrophobic interaction with high affinity between uncharged fluoxetine and volume-activated chloride channels. Ca(2+)-activated Cl- currents and CFTR are also blocked by fluoxetine, revealing a novel characteristic of the drug as a chloride channel modulator.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10077245&dopt=Abstract fluoxetine




J Pharm Pharmacol. 1998 Apr;50(4):419-24.
Kinetic interaction between fluoxetine and imipramine as a function of elevated serum alpha-1-acid glycoprotein levels.

Holladay JW, Dewey MJ, Yoo SD.

College of Pharmacy and Department of Biological Sciences, University of South Carolina, Columbia 29208, USA.

The effect of elevated serum alpha-1-acid glycoprotein (AAG) levels on the pharmacokinetic interaction between imipramine and fluoxetine has been examined by utilizing a novel strain of transgenic mice which express serum AAG levels several times greater than normal. Before fluoxetine treatment, serum imipramine levels were approximately three times greater in transgenic mice than in control mice. Despite higher serum imipramine levels in transgenic mice, brain drug levels were lower than those found in control mice. Fluoxetine pre-treatment (20 mg kg(-1) for 5 days) resulted in an increase in serum imipramine levels in both groups of mice and the extent of the increase was greater in transgenic mice than in control mice (4.5-fold increase compared with 3.1-fold). Similarly, fluoxetine pre-treatment resulted in an increase in brain levels of imipramine in both groups of mice and the extent of the increase was greater in transgenic mice than in control mice (3.0-fold increase compared with 2.0-fold). Similar trends were observed for levels of desipramine in the serum and brain. Serum imipramine and desipramine levels did not correlate with their respective brain levels in the presence of elevated serum AAG levels before and after pre-treatment. These findings indicate that the extent of increases in imipramine and desipramine serum and brain levels are greater during elevated serum AAG states than during normal AAG states when imipramine is co-administered with fluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9625487&dopt=Abstract fluoxetine




Pharmacol Biochem Behav. 1998 Jun;60(2):527-32.
The selective serotonin reuptake inhibitor fluoxetine reduces sexual motivation in male rats.

Vega Matuszcyk J, Larsson K, Eriksson E.

Department of Psychology, University of Goteborg, Sweden.

A male rat put in an open-field arena in which it is free to spend time in the vicinity of--but not in contact with--an estrous female, or in the vicinity of a male, usually spends more time with the female than with the male or elsewhere. Tentatively, the percentage of time spent in the vicinity of the female in this paradigm may be regarded as a measure of sexual motivation. In humans, treatment with selective serotonin reuptake inhibitors (SSRIs) may cause reduced libido. To investigate to what extent serotonin reuptake inhibition influences sexual motivation also in rats, we have tested the effect of subchronic treatment with fluoxetine on the behavior in the sexual motivation test described above; in addition, the effect of fluoxetine on male copulatory behavior was studied. Fluoxetine significantly reduced sexual motivation at subchronic but not at acute administration; moreover, fluoxetine-treated rats displayed an increased ejaculation latency. It is concluded that humans and rats respond similarly to the SSRI fluoxetine with respect to various aspects of sexual behavior.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9632236&dopt=Abstract fluoxetine




Pharmacol Biochem Behav. 1998 Jun;60(2):539-44.
Acute and chronic fluoxetine treatment decreases the sensitivity of rats to rewarding brain stimulation.

Lee K, Kornetsky C.

Boston University School of Medicine, Department of Pharmacology, MA 02118, USA.

The effects of fluoxetine on rewarding brain stimulation were determined in eight Wistar rats using a rate-independent discrete-trial threshold measure. Rats were implanted with bipolar, stainless steel electrodes either into the ventral tegmental area (VTA) or medial forebrain bundle (MFB). Acute administration of fluoxetine significantly raised the reward threshold (decreased sensitivity) at doses of 2.5, 5.0, 10.0, and 20.0 mg/kg, i.p., without altering latency of response. There were no significant differences between VTA and MFB groups. To determine the effects of chronic treatment, daily injections of 5.0 mg/kg fluoxetine were administered to rats for 21 days. Chronic treatment of fluoxetine continued to significantly elevate reward thresholds with no evidence of tolerance. The results of these experiments suggest that fluoxetine does not possess abuse potential and that serotonin produces an inhibitory effect on the mesolimbic dopaminergic reward system. Furthermore, these results suggest that the antidepressant effects of fluoxetine are not the direct result of excitation of brain reward systems, at least in the same manner as abused substances, for example, cocaine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9632238&dopt=Abstract fluoxetine




Int J Neurosci. 1998 Apr;93(3-4):163-79.
Behavioral tolerance to and withdrawal from multiple fluoxetine administration.

Bjork JM, Gaytan O, Patt N, Swann AC, Dafny N.

Department of Neurobiology and Anatomy, University of Texas-Houston, Medical School of Houston, 77025, USA.

The objective of this study was to characterize the lasting effects of fluoxetine on the locomotor behavior of rats using a computerized activity-monitoring system. Challenge dosages (8, 16, and 24 mg/kg i.p.) of fluoxetine 2 h into the dark phase resulted in dose-dependent suppression of locomotor activity for 4 h following injection. Escalating (10-30 mg/kg i.p.) semidaily fluoxetine administration for the next five days resulted in decreasing locomotor activity during the multiple-administration period relative to saline control. Circadian activity patterns at the conclusion of the regimen were unchanged in shape, but featured uniform decreases in locomotor activity at every hour which were more significant during the phase. Upon discontinuation, fluoxetine-treated rats showed a significant increase in activity during the first 4 h following the first "missed" dose which was not seen in subsequent washout. Ninety-six h after the final maintenance dose, the initial three dosages were readministered, and the locomotor activity suppression in response to the rechallenge dose of fluoxetine was significantly lessened compared to initial challenge. These findings suggest that tolerance and withdrawal were obtained.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9639233&dopt=Abstract fluoxetine