Fluoxetine Atomoxetine

Atomoxetine (Straterra , originally tomoxetine or tomoxetin, 3) was first described and synthesized by chemists at Eli Lilly in the late 1970s and was one of the few compounds that was known to display meaningful selectivity for the norepinephrine reuptake transporter (NET) versus the serotonin reuptake transporter (SERT) and the dopamine reuptake transporter (DAT) (Barnett, 1986 Molloy and Schmiegel, 1997). Atomoxetine was one of several structurally related and commercially successful monoamine reuptake inhibitors that were developed by Lilly for the treatment of various psychiatric disorders (Eig. 17.4). Fluoxetine (43) and duloxetine (44) have both gained approval in the United States as Prozac and Cymbalta , respectively, and nisoxetine (45) is widely used as a tool in biology. 

D6 Desipramine, dextromethorphan, atomoxetine Paroxetine, quinidine, fluoxetine (use of PM vs. EM subjects) None identified... 

Propranolol Nisoxetine Reboxetine Duloxetine Viloxazine Fluoxetine Atomoxetine... 

SSRIs ATOMOXETINE t plasma concentrations and risk of adverse effects (abdominal pain, vomiting, nausea, fatigue, irritability) Atomoxetine is a selective norepinephrine reuptake inhibitor, t plasma concentrations due to inhibition of CYP2D6 by fluoxetine and paroxetine (potent), fluvoxamine and sertraline (less potent) and escitalopram and citalopram (weak) Avoid concurrent use. The interaction is usually severe with fluoxetine and paroxetine... 

Plasma concentrations of atomoxetine may be increased by drugs that inhibit CYP450 2D6 (e.g., paroxetine, fluoxetine), so atomoxetine dose may need to be reduced if co-administered... 

Bupropion, mirtazapine, reboxetine, or atomoxetine (add with caution and at lower doses since fluoxetine could theoretically raise atomoxetine levels) use combinations of antidepressants with caution as this may activate bipolar disorder and suicidal ideation... 

SSRIs fluoxetine, paroxetine, sertraline Others bupropion, mirtazapine, nefazodone, trazodone, atomoxetine... 

Atomoxetine (CYP2D6) Fluoxetine Paroxetine AUC increase 6- to 8-fold in EM no change PM expected 21... 

In EMs, inhibitors of CYP2D6 increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in PMs. Dosage adjustment of STRATTERA in EMs may be necessary when coadministered with CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine (see Dmg Interactions and PRECAUTIONS). In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine. 

Scientists at Lilly Research Laboratories synthesized more than 50 phenoxypropylamines derived from the antihistamine diphenhydramine (Benadryl) before discovering fluoxetine (21,22) (Fig. 21.2). The first of these compounds was nisoxetine, a potent SNRI (see Fig. 21.8) that was clinically developed but never marketed. Other derivatives that have since been marketed by Lilly include atomoxetine (a SNRI) and duloxetine (a NSRI). 

Paroxetine markedly increases atomoxetine levels in extensive metabolisers of CYP2D6. Fluoxetine also raises atomoxetine levels. There is a possibility that this may increase adverse effects, and a slower titration of atomoxetine dose is su ested for patients taking paroxetine and other CYP2D6 inhibitors. 

Atomoxetine is extensively metabolised by CYP2D6, an isoenzyme that shows polymorphism, with up to 10% of the population lacking an active form (poor metabolisers). Paroxetine inhibits CYP2D6, and thereby increases atomoxetine levels in those with an extensive metaboliser phenotype. It would not be expected to have any effect in poor metabolisers. Fluoxetine can similarly inhibit CYP2D6. 

Kratochviol CJ, Newcom JH, Arnold LE, Duesenberg D, EmsUe GJ, Quintana H, Sarkis EH, Wagner KD, Gao H, Michelson D, Biederman J. Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety s3miptoms. J Am Acad Child Ad-olesc Psychiatry (2005) 44, 915-24. 

Hammond RJ, Poston BW, Ghiviriga I, Feske BD. Biocatalytic synthesis towards both antipodes of 3-hydroxy-3-phenylpropanitrile a precursor to fluoxetine, atomoxetine and nisoxetine. Tetrahedron Lett. 2007 48 1217-1219. 

A nice application in pharmaceutical s)mthesis has been reported. Thus, from the reduction of pentoxifylline a new methylxanthine could be obtained, and a high ee of 98% was observed for this transformation [126, 127]. Since the baker s yeast reduction of 3-oxo-3-phenylpropanenitrile has been difficult to achieve, a library of baker s yeast reductases was screened. As a result, this approach allowed the synthesis of both antipodes of antidepressants fluoxetine, atomoxetine, and nisoxetine [128]. 

This approach was also taken for reduction of 3-oxo-3-phenylpropanenitrile for the synthesis of precursors for both antipodes of fluoxetine, atomoxetine, and nisoxetine, which are popular serotonin/norepinephrine reuptake inhibitors. " Four enzymes were found to reduce this substrate, and by changing the enzyme, both enantiomers of 3-hydroxy-3-phenylpropanitrile could be prepared with a high ee as shown in Scheme 33.1b. 

Minor stmctural modifications to the fluoxetine stmcture may have an impact on selectivity. For example, removal of the trifiuoromethyl group on the para position of the phenoxy ring and attachment of a methoxy group to the ortho position resulted in the discovery of nisoxetine, an effective blocker of the noradrenaline reuptake transport protein NAT (Fig. 18.26). Replacement of the methoxy with a methyl group appears to be tolerated by NAT, which leads to atomoxetine, a selective NAT inhibitor. This derivative has non-stimulant properties and is used in the treatment of ADHD in adults and children. It is available as the hydrochloride salt and dosages can range between 40 and 100 mg. The formulated product only contains the (R)-enantiomer. 

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