Disease relevance of NSC675448

• Thus, at steady state both fluoxetine and norfluoxetine concentrations will be higher in patients with cirrhosis, unless the dosage is reduced [1].
• FLX was 2-fold higher and NORFLX was 1.7-fold higher in children relative to adolescents; however, when normalized to body weight, FLX and NORFLX were similar for both age groups [2].
• Dyskinesia with fluoxetine: tardive or late-onset persistent, acute norfluoxetine dyskinesia [3]?
• Drug-induced long QT syndrome: hERG K(+) channel block and disruption of protein trafficking by fluoxetine and norfluoxetine [4].
• These data further suggest that renal failure and the process of hemodialysis do not materially alter the pharmacokinetics of fluoxetine or its major metabolite norfluoxetine [5].

Psychiatry related information on NSC675448

• CONCLUSIONS: Steady state plasma levels of fluoxetine and norfluoxetine are not related to clinical outcome in patients with obsessive-compulsive disorder [6].
• Based on these findings, it could be inferred that the increase of brain Allo content elicited by fluoxetine and norfluoxetine, rather than the inhibition selective of 5-HT reuptake, may be operative in the fluoxetine-induced remission of the behavioral abnormalities associated with mood disorders [7].

High impact information on NSC675448

• Fluoxetine and norfluoxetine plasma concentrations in major depression: a multicenter study [8].
• First, the pharmacokinetics of sertraline are the same in both elderly and younger patients, whereas elderly, in comparison with younger, patients develop higher plasma levels of fluoxetine (and its active metabolite, norfluoxetine) or paroxetine, when given the same dose [9].
• Indeed, fluoxetine and norfluoxetine at 1 microM strongly inhibited cloned T currents (approximately 50 and approximately 75%, respectively) in action potential clamp experiments performed with firing activities of thalamocortical relay neurons [10].
• BACKGROUND: The aim of this prospective clinical trial was to investigate the pharmacokinetics of fluoxetine and its active metabolite, norfluoxetine, during pregnancy, delivery, and lactation in mothers and their infants [11].
• Fluoxetine and norfluoxetine concentrations in nursing infants and breast milk [12].

Biological context of NSC675448

• The PSG changes were correlated with daily dose, cumulative dosage, single serum concentrations, and the total area under the serum concentration curve (AUC) of both FLU and NFLU [13].
• The relative rectal bioavailability was determined for norfluoxetine and total (fluoxetine + norfluoxetine) in each individual [14].
• Fluvoxamine has a much shorter elimination half-life than fluoxetine and its active metabolite, norfluoxetine, and therefore a reduced potential for drug interactions [15].
• 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 [16].
• 3. Norfluoxetine was a more potent inhibitor of TREK-1 currents with an IC50 of 9 microM [17].

Anatomical context of NSC675448

• Peak breast milk concentrations occurred approximately 8 hours after maternal dosing and predicted norfluoxetine concentrations in infant serum [12].
• 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 [16].
• The results show that fluoxetine (as well as norfluoxetine) has multiple effects on the energy metabolism of rat liver mitochondria, being potentially toxic in high doses [18].
• The recovery of firing did not correlate with either plasma or cerebrospinal fluid levels of fluoxetine or norfluoxetine [19].
• In the pig choroid plexus in vitro, fluoxetine and norfluoxetine inhibited specific [3H] mesulergine binding with pKI's (+/- S.E.M.) of 6.45 +/- 0.09 (n = 4) and 6.05 +/- 0.05 (n = 3), and slope factors (+/- S.E.M.) of 1.06 +/- 0.14 and 0.99 +/- 0.13, respectively [20].

Associations of NSC675448 with other chemical compounds

• The extended half-life of fluoxetine (4-6 days) and its active metabolite, norfluoxetine (4-16 days), results in an extended time to steady-state and a prolonged washout period when dosing is discontinued [21].
• The present data provide evidence that fluoxetine, norfluoxetine and citalopram, along with many other antidepressant compounds, interact directly with the 5-HT2C receptor [22].
• Fluorine-19 NMR spectroscopy was used to monitor the anti-depressant drug fluoxetine (and its metabolite norfluoxetine) in vivo in human brain [23].
• Fluoxetine and norfluoxetine are potent inhibitors of P450IID6--the source of the sparteine/debrisoquine oxidation polymorphism [24].
• Fluoxetine and norfluoxetine also significantly inhibited (more than 20%) the binding of the radioligand in vivo while citalopram and deprenyl showed very poor affinities in vitro for MAO-A and had no effect in vivo [25].

Gene context of NSC675448

• Since the enantiomers of fluoxetine and norfluoxetine are inhibitors of CYP2D6, upon chronic dosing, the CYP2D6-mediated metabolism of the fluoxetine enantiomers would likely be inhibited, resulting in R-norfluoxetine formation being mediated by CYP2C9 and S-norfluoxetine formation being mediated by multiple high K(m) enzymes [26].
• CYP3A4 is the most abundant human cytochrome P450, but most of the SSRIs with the exception of norfluoxetine do not inhibit this enzyme, and interactions with SSRIs and CYP3A4 appear not to be a significant [27].
• 2. None of the drugs showed potent inhibition of CYP2A6 (coumarin 7-hydroxylase) or CYP2E1 (chlorzoxazone 6-hydroxylase), while norfluoxetine was the only potent inhibitor of CYP3A having IC50 values of 11 microM and 19 microM for testosterone 6 beta-hydroxylase and cortisol 6 beta-hydroxylase, respectively [28].
• Fluoxetine metabolism involves CYP2D6 and CYP2C9 in the formation of its major metabolite, norfluoxetine [29].
• METHODS: The kinetics of Ne formation of norfluoxetine was determined in human liver microsomes from six genotyped CYP2C19 extensive metabolizers (EM) [30].

Analytical, diagnostic and therapeutic context of NSC675448

• Breast milk, maternal and infant serum concentrations of fluoxetine and norfluoxetine were determined with high-performance liquid chromatography [12].
• Plasma concentrations of fluoxetine and norfluoxetine were not significantly changed by hemodialysis [31].
• Using the whole-cell patch-clamp technique, we have examined the effects of fluoxetine and norfluoxetine, its major active metabolite, on cloned low-voltage-activated T-type calcium channels (T channels) expressed in tsA 201 cells [10].
• Fluoxetine, an antidepressant, and norfluoxetine, its metabolite, determined by HPLC with a C8 column and ultraviolet detection [32].
• Determination of fluoxetine and norfluoxetine in plasma by gas chromatography with electron-capture detection [33].

References