Fluoxetine metabolism

Several compounds affecting various 5-HT functional parameters (uptake inhibition (fluoxetine), metabolism (tranylcypromine) or synthesis (5-OH tryptophan, 5-HTP)) had no effect on subemetic doses of cisplatin [110]. In fact, tranylcypromine and 5-HTP antagonized emesis of cisplatin. Thus these results would favour an inhibitory role of 5-HT instead of emetogenic. It is conceivable that an excess of 5-HT may desensitize 5-HT3 receptors that may result in a reduced sensitivity to emetogenic stimuli. 

Hamelin, B. A., Turgeon, J., Vallee, F. etal. (1996). The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin. Clin. Pharmacol. Ther., 60, 512-21. 

Tolterodine undergoes hepatic metabolism involving CYP450 2D6 and 3A4 isoenzymes. Therefore, elimination can be impaired by CYP450 3A4 inhibitors including fluoxetine, sertraline, fluvoxamine, macrolide antibiotics, imidazoles, and grapefruit juice. 

Use of a hERG blocker in a patient also taking CYP3A4 inhibitors (e.g. antibacterial macrolides, azole antifungals, HIV protease inhibitors) or CYP2D6 inhibitors (quinidine, halofantrine, fluoxetine, paroxetine, thioridazine, terbinafine) the hERG blocker, if mostly metabolized by these CYP isoforms, may accumulate because... 

The most damning evidence of APIs impact on wildlife comes from smdies on fish. Fluoxetine has been detected in tissues of fish species living in a municipal effluent at levels of 0.1 ng g Redox properties of some medicinal products can influence the oxidative metabolism in hepatocytes of rainbow trout leading to oxidative damage [115]. 

Serotonin mediates many central and peripheral physiological functions, including contraction of smooth muscle, vasoconstriction, food intake, sleep, pain perception, and memory, a consequence of it acting on several distinct receptor types. Although 5-HT may be metabolized by monoamine oxidase, platelets and neurons possess a high-affinity mechanism for reuptake of 5-HT. This mechanism may be inhibited by the widely prescribed antidepressant drugs termed selective serotonin re-uptake inhibitors (SSRl), e.g. fluoxetine (Prozac ), thereby increasing levels of 5-HT in the central nervous system. 

Special populations Use a starting dose of 6 mg/25 mg for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine/fluoxetine (eg, female gender, elderly, nonsmoking status). When indicated, perform dose escalation with caution in these patients. Olanzapine/fluoxetine has not been systemically studied in patients older than 65 years of age or in patients younger than 18 years of age. 

Bertelsen, K.M., Venkatakrishnan, K., Von Moltke, L.L., Obach, R.S. and Greenblatt, D.J. (2003) Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine comparison with fluoxetine and quinidine. Drug Metabolism and Disposition The Biolo cal Fate of Chemicals, 31, 289-293. 

Serotonin re-uptake inhibitors are readily absorbed after oral administration and widely distributed throughout the body. Elimination is mainly by hepatic metabolism. Fluoxetine, sertraline and venlafaxine are demethylated to active metabolites. 

Venlafaxine, although its re-uptake inhibitory activity is not restricted to serotonin, is often classified as an SSRI because of its similar spectrum of adverse reactions. It has a short elimination half-life in contrast to the other serotonin re-uptake inhibitors. Fluoxetine, norfluoxetine and paroxetine are inhibitors of their own metabolism by CYP2D6 resulting in non-linear pharmacokinetic behavior. 

Most benzodiazepines undergo oxidative metabolism in the liver that may be enhanced by enzyme inducers (e.g. carbamazepine, phenytoin) or slowed by inhibitors (sodium valproate, fluoxetine, fluvoxamine). Oxazepam, lorazepam and temazepam are directly conjugated and are not subject to these interactions. 

Fluoxetine is a secondary amine, which is demethy-lated to norfluoxetine. Norfluoxetine is clinically active. Both compounds have S- and R- enantiomers (Wong et ah, 1990, 1993). Unlike citalopram, S- and R-fluoxetine and S-norfluoxetine are active forms. R-fluoxetine is much less potent than the other two compounds. In addition, it appears that R-fluoxetine and R-norfluoxetine are metabolized more rapidly than the S-enantiomers (Torok-Both et ah, 1992). 

Fluoxetine s most notable side effect is nervousness (>10% in adults) (Preskorn, 2000), which may be more common in the pediatric population (Teicher and Baldessarini, 1987). Fluvoxamine is less stimulating than fluoxetine but is a significant inhibitor of CYP3A4, which metabolizes common pediatric medications (Michalets and Williams, 2000). Fluvoxamine is most likely to cause constipation in adults (>10%) (Preskorn, 2000). This is an important consideration in children, given the often comorbid symptoms of en-copresis from overflow constipation. 

SSRIs—fluvoxamine, fluoxetine, and paroxetine, more than sertraline and citalopram Inhibition of metabolism at CYP2D6 isoenzyme TCA toxicity due to up to 10-fold increase in TCA levels with coadministration Lower TCA dose Baumann, 1996... 

There are several antipsychotics that are substrates to CYP2D6 (von Bahr et ah, 1991 Jerling et ah, 1996 Ring et ah, 1996 (Fang and Gorrod, 1999 Flockhart and Oesterheld, 2000) (Table 26.3). Moreover, several antipsychotics may act as inhibitors of CYP2D6-mediated biotransformation. These include thioridazine, chlorpromazine, haloperidol, fluphenazine, and pimozide (Desta et ah, 1998 Shin et ah, 1999). Of particular salience is the fact that the serotonin selective reuptake inhibitors (SSRIs) fluoxetine and paroxetine are metabolized to a significant extent by this isoenzyme. 

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