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QuickView for Duloxetine (compound)

Summary
General Info

PubChem

PubChem Compound 10086118

Name:	duloxetine
PubChem Compound ID:	10086118
Molecular formula:	C₁₈H₁₉NOS
Molecular weight:	299.408 g/mol

DrugBank

Identification

Name:	duloxetine
Name (isomeric):	DB00476
Drug Type:	small molecule
Synonyms:	Duloxetine HCl; (+-)-duloxetine; Duloxetine Hydrochloride
Brand:	Cymbalta, Yentreve
Category:	Dopamine Uptake Inhibitors, Adrenergic Uptake Inhibitors, Serotonin Uptake Inhibitors, Antidepressive Agents
CAS number:	136434-34-9

Pharmacology

Indication:	For the acute and maintenance treatment of major depressive disorder (MDD), as well as acute management of generalized anxiety disorder. Also used for the management of neuropathic pain associated with diabetic peripheral neuropathy, and fibromyalgia. Has been used in the management of moderate to severe stress urinary incontinence (SUI) in women.
Pharmacology:	Duloxetine is in a class of medications called selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) and primarily targets major depressive disorders (MDD) and stress urinary incontinence (SUI). Duloxetine is also used to treat pain and tingling caused by diabetic neuropathy (damage to nerves that can develop in people who have diabet... show more » Duloxetine is in a class of medications called selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) and primarily targets major depressive disorders (MDD) and stress urinary incontinence (SUI). Duloxetine is also used to treat pain and tingling caused by diabetic neuropathy (damage to nerves that can develop in people who have diabetes). Known also as LY248686, it is a potent dual inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake, possessing comparable affinities in binding to NE and 5-HT transport sites. Interestingly, its behavior contrasts to most other dual-reuptake inhibitors. Furthermore, duloxentine lacks affinity for monoamine receptors within the central nervous system. show less «
Mechanism of Action:	Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. The antidepressant and pain inhibitory actions of duloxetine are believed to be r... show more » Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. The antidepressant and pain inhibitory actions of duloxetine are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. The mechanism of action of duloxetine in SUI has not been determined, but is thought to be associated with the potentiation of serotonin and norepinephrine activity in the spinal cord, which increases urethral closure forces and thereby reduces involuntary urine loss. show less «
Absorption:	Orally administered duloxetine hydrochloride is well absorbed.
Protein binding:	Protein binding is greater than 90%.
Biotransformation:	The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP2D6 and CYP1A2 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. The major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.
Route of elimination:	Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces.
Half Life:	12 hours (range 8-17 hours)
Toxicity:	Oral, rat LD₅₀: 491 mg/kg for males and 279 mg/kg for females. Symptoms of overdose include tremors, convulsions, reduced activity, slow pupillary response, intermittent tremors, and rigidity.
Affected organisms:	Humans and other mammals

Interactions

Food interaction:

Food does not affect maximum levels reached, but delays it (from 6 to 10 hours) and total product exposure appears to be reduced by only 10%.

Take without regard to meals.

People taking this product who drink large amounts of alcohol are exposed to a higher risk of liver toxicity.

Drug interaction:

Triprolidine	The CNS depressants, Triprolidine and Duloxetine, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Flecainide	Possible increase in the levels of this agent when used with duloxetine
Nortriptyline	Possible increase in the levels of this agent when used with duloxetine
Phenelzine	Possible severe adverse reaction with this combination
Thioridazine	Increased risk of cardiotoxicity and arrhythmias

Triprolidine	The CNS depressants, Triprolidine and Duloxetine, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Flecainide	Possible increase in the levels of this agent when used with duloxetine
Nortriptyline	Possible increase in the levels of this agent when used with duloxetine
Phenelzine	Possible severe adverse reaction with this combination
Thioridazine	Increased risk of cardiotoxicity and arrhythmias
Trimipramine	Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Tranylcypromine	Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.
Propafenone	Possible increase in the levels of this agent when used with duloxetine
Tamoxifen	Duloxetine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.
Venlafaxine	Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Thiabendazole	The strong CYP1A2 inhibitor, Thiabendazole, may increase the effects and toxicity of Duloxetine by decreasing Duloxetine metabolism and clearance. Monitor for changes in the therapeutic and adverse effects of Duloxetine if Thiabendazole is initiated, discontinued or dose changed.
Isocarboxazid	Possible severe adverse reaction with this combination
Desipramine	Possible increase in the levels of this agent when used with duloxetine
Tramadol	Duloxetine may decrease the effect of Tramadol by decreasing active metabolite production. Increased risk of serotonin syndrome. Monitor for Tramadol efficacy and symptoms of serotonin syndrome.
Zolmitriptan	Use of two serotonin modulators, such as zolmitriptan and duloxetine, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.
Tamsulosin	Duloxetine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Duloxetine is initiated, discontinued, or dose changed.
Amitriptyline	Possible increase in the levels of this agent when used with duloxetine
Rasagiline	Possible severe adverse reaction with this combination
Ciprofloxacin	Ciprofloxacin, a strong CYP1A2 inhibitor, may decrease the metabolism of duloxetine. Monitor for changes in the therapeutic and adverse effects of duloxetine if ciprofloxacin is initiated or discontinued.
Trazodone	Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Terbinafine	Terbinafine may reduce the metabolism and clearance of Duloxetine. Consider alternate therapy or monitor for therapeutic/adverse effects of Duloxetine if Terbinafine is initiated, discontinued or dose changed.
Desvenlafaxine	Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Fluvoxamine	Fluvoxamine increases the effect and toxicity of duloxetine
Imipramine	Possible increase in the levels of this agent when used with duloxetine

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Targets

Sodium-dependent serotonin transporter

Terminates the action of serotonine by its high affinity sodium-dependent reuptake into presynaptic terminals

UniProt ID:

P31645

Gene:

SLC6A4

Actions:

inhibitor

References:

Chen F, Larsen MB, Sanchez C, Wiborg O: The S-enantiomer of R,S-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors. Eur Neuropsychopharmacol. 2005 Mar;15(2):193-8.
View Article

Troelsen KB, Nielsen EO, Mirza NR: Chronic treatment with duloxetine is necessary for an anxiolytic-like response in the mouse zero maze: the role of the serotonin transporter. Psychopharmacology (Berl). 2005 Oct;181(4):741-50. Epub 2005 Sep 29.
View Article

Gould GG, Javors MA, Frazer A: Effect of chronic administration of duloxetine on serotonin and norepinephrine transporter binding sites in rat brain. Biol Psychiatry. 2007 Jan 15;61(2):210-5. Epub 2006 May 2.
View Article

Mirza NR, Nielsen EO, Troelsen KB: Serotonin transporter density and anxiolytic-like effects of antidepressants in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2007 May 9;31(4):858-66. Epub 2007 Jan 30.
View Article

Vaishnavi SN, Nemeroff CB, Plott SJ, Rao SG, Kranzler J, Owens MJ: Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity. Biol Psychiatry. 2004 Feb 1;55(3):320-2.
View Article

Beique JC, Lavoie N, de Montigny C, Debonnel G: Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters. Eur J Pharmacol. 1998 May 15;349(1):129-32.
View Article

Karpa KD, Cavanaugh JE, Lakoski JM: Duloxetine pharmacology: profile of a dual monoamine modulator. CNS Drug Rev. 2002 Winter;8(4):361-76.
View Article

van Groeningen CJ, Peters GJ, Pinedo HM: Lack of effectiveness of combined 5-fluorouracil and leucovorin in patients with 5-fluorouracil-resistant advanced colorectal cancer. Eur J Cancer Clin Oncol. 1989 Jan;25(1):45-9.
View Article

Jost W, Marsalek P: Duloxetine: mechanism of action at the lower urinary tract and Onuf's nucleus. Clin Auton Res. 2004 Aug;14(4):220-7.
View Article

Trivedi MH, Desaiah D, Ossanna MJ, Pritchett YL, Brannan SK, Detke MJ: Clinical evidence for serotonin and norepinephrine reuptake inhibition of duloxetine. Int Clin Psychopharmacol. 2008 May;23(3):161-9.
View Article

Bymaster FP, Lee TC, Knadler MP, Detke MJ, Iyengar S: The dual transporter inhibitor duloxetine: a review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr Pharm Des. 2005;11(12):1475-93.
View Article

Khullar V, Cardozo L, Dmochowski R: Mixed incontinence: current evidence and future perspectives. Neurourol Urodyn. 2010 Apr;29(4):618-22.
View Article

Carter NJ, McCormack PL: Duloxetine: a review of its use in the treatment of generalized anxiety disorder. CNS Drugs. 2009;23(6):523-41.
View Article

Hunziker ME, Suehs BT, Bettinger TL, Crismon ML: Duloxetine hydrochloride: a new dual-acting medication for the treatment of major depressive disorder. Clin Ther. 2005 Aug;27(8):1126-43.
View Article

Sodium-dependent noradrenaline transporter

Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals

UniProt ID:

P23975

Gene:

SLC6A2

Actions:

inhibitor

References:

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.
View Article

Vincent S, Bieck PR, Garland EM, Loghin C, Bymaster FP, Black BK, Gonzales C, Potter WZ, Robertson D: Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacological profiles. Circulation. 2004 Jun 29;109(25):3202-7. Epub 2004 Jun 7.
View Article

Schou M, Halldin C, Pike VW, Mozley PD, Dobson D, Innis RB, Farde L, Hall H: Post-mortem human brain autoradiography of the norepinephrine transporter using (S,S)-[18F]FMeNER-D2. Eur Neuropsychopharmacol. 2005 Oct;15(5):517-20. Epub 2005 Apr 7.
View Article

Karpa KD, Cavanaugh JE, Lakoski JM: Duloxetine pharmacology: profile of a dual monoamine modulator. CNS Drug Rev. 2002 Winter;8(4):361-76.
View Article

Jost W, Marsalek P: Duloxetine: mechanism of action at the lower urinary tract and Onuf's nucleus. Clin Auton Res. 2004 Aug;14(4):220-7.
View Article

Khullar V, Cardozo L, Dmochowski R: Mixed incontinence: current evidence and future perspectives. Neurourol Urodyn. 2010 Apr;29(4):618-22.
View Article

Carter NJ, McCormack PL: Duloxetine: a review of its use in the treatment of generalized anxiety disorder. CNS Drugs. 2009;23(6):523-41.
View Article

Hunziker ME, Suehs BT, Bettinger TL, Crismon ML: Duloxetine hydrochloride: a new dual-acting medication for the treatment of major depressive disorder. Clin Ther. 2005 Aug;27(8):1126-43.
View Article

Sodium-dependent dopamine transporter

Enzymes

Cytochrome P450 1A2

Cytochrome P450 2D6