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Identification
NameAtomoxetine
Accession NumberDB00289  (APRD00614)
Typesmall molecule
Groupsapproved
Description

Atomoxetine is the first non-stimulant drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). It is sold in the form of the hydrochloride salt of atomoxetine. This chemical is manufactured and marketed under the brand name Strattera; by Eli Lilly and Company and as a generic Attentin by Torrent Pharmaceuticals. There is currently no generic available within the United States due to patent restrictions. [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
(-)-TomoxetineNot AvailableNot Available
TomoxetinaSpanishNot Available
TomoxetineNot AvailableINN
TomoxetinumLatinNot Available
SaltsNot Available
Brand names
NameCompany
AttentinNot Available
StratteraEli Lilly and Company
TomoxetinNot Available
Brand mixturesNot Available
Categories
CAS number82248-59-7
WeightAverage: 255.3547
Monoisotopic: 255.162314299
Chemical FormulaC17H21NO
InChI KeyInChIKey=VHGCDTVCOLNTBX-QGZVFWFLSA-N
InChI
InChI=1S/C17H21NO/c1-14-8-6-7-11-16(14)19-17(12-13-18-2)15-9-4-3-5-10-15/h3-11,17-18H,12-13H2,1-2H3/t17-/m1/s1
IUPAC Name
methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine
SMILES
CNCC[C@@H](OC1=CC=CC=C1C)C1=CC=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassPhenylpropylamines
Direct parentPhenylpropylamines
Alternative parentsBenzylethers; Phenol Ethers; Toluenes; Alkyl Aryl Ethers; Polyamines; Dialkylamines
Substituentsphenol ether; alkyl aryl ether; toluene; secondary amine; secondary aliphatic amine; ether; polyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the phenylpropylamines. These are compounds containing a phenylpropylamine moiety, which consists of a phenyl group substituted at the third carbon by an propan-1-amine.
Pharmacology
IndicationFor the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) alone or in combination with behavioral treatment, as an adjunct to psychological, educational, social, and other remedial measures.
PharmacodynamicsAtomoxetine is the first non-stimulant drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). Atomoxetine is classified as a norepinephrine reuptake inhibitor, and is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six years old. Its advantage over stimulants for the treatment of ADHD is that it has less abuse potential than stimulants, is not scheduled as a controlled substance and has proven in clinical trials to offer 24 hour coverage of symptoms associated with ADHD in adults and children.
Mechanism of actionThe precise mechanism by which atomoxetine produces its therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined through in-vitro studies. Atomoxetine appears to have minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors.
AbsorptionAtomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in EMs and 94% in PMs. Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) have no effect on atomoxetine bioavailability. Absorption is minimally affected by food.
Volume of distribution
  • 0.85 L/kg
Protein bindingAt therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily albumin.
Metabolism

Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs).

SubstrateEnzymesProduct
Atomoxetine
    4-hydroxyatomoxetineDetails
    Route of eliminationNot Available
    Half life5 hours
    Clearance
    • 0.35 L/hr/kg [after oral administration in adult extensive metabolizers]
    • 0.03 L/hr/kg [administration of atomoxetine to poor metabolizers]
    ToxicityThe most commonly reported symptoms accompanying acute and chronic overdoses are somnolence, agitation, hyperactivity, abnormal behavior, and gastrointestinal symptoms.
    Affected organisms
    • Humans and other mammals
    PathwaysNot Available
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 1.0
    Blood Brain Barrier + 0.964
    Caco-2 permeable + 0.852
    P-glycoprotein substrate Substrate 0.6133
    P-glycoprotein inhibitor I Inhibitor 0.7771
    P-glycoprotein inhibitor II Non-inhibitor 0.8003
    Renal organic cation transporter Inhibitor 0.5929
    CYP450 2C9 substrate Non-substrate 0.7443
    CYP450 2D6 substrate Substrate 0.8919
    CYP450 3A4 substrate Substrate 0.6216
    CYP450 1A2 substrate Inhibitor 0.9324
    CYP450 2C9 substrate Non-inhibitor 0.957
    CYP450 2D6 substrate Inhibitor 0.9037
    CYP450 2C19 substrate Non-inhibitor 0.9025
    CYP450 3A4 substrate Non-inhibitor 0.8122
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7371
    Ames test Non AMES toxic 0.7738
    Carcinogenicity Non-carcinogens 0.8493
    Biodegradation Not ready biodegradable 0.8013
    Rat acute toxicity 2.5166 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Strong inhibitor 0.7132
    hERG inhibition (predictor II) Inhibitor 0.7974
    Pharmacoeconomics
    Manufacturers
    • Eli lilly and co
    Packagers
    Dosage forms
    FormRouteStrength
    CapsuleOral
    CapsuleOral10 mg
    CapsuleOral18 mg
    CapsuleOral25 mg
    CapsuleOral40 mg
    CapsuleOral60 mg
    Prices
    Unit descriptionCostUnit
    Strattera 80 mg capsule6.94USDcapsule
    Strattera 100 mg capsule6.83USDcapsule
    Strattera 40 mg capsule6.43USDcapsule
    Strattera 60 mg capsule6.43USDcapsule
    Strattera 18 mg capsule6.03USDcapsule
    Strattera 25 mg capsule5.85USDcapsule
    Strattera 10 mg capsule5.84USDcapsule
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    CountryPatent NumberApprovedExpires (estimated)
    United States56585901997-05-262017-05-26
    Canada22097352002-10-012016-01-04
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    water solubility27.8 mg/mLNot Available
    logP3.9Not Available
    Predicted Properties
    PropertyValueSource
    water solubility3.90e-03 g/lALOGPS
    logP3.95ALOGPS
    logP3.81ChemAxon
    logS-4.8ALOGPS
    pKa (strongest basic)9.8ChemAxon
    physiological charge1ChemAxon
    hydrogen acceptor count2ChemAxon
    hydrogen donor count1ChemAxon
    polar surface area21.26ChemAxon
    rotatable bond count6ChemAxon
    refractivity79.44ChemAxon
    polarizability29.79ChemAxon
    number of rings2ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleYesChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    Judith Aronhime, Stefano Bianchi, Eugenio Castelli, Paola Daverio, Silvia Mantovani, Adrienne Kovacsne-Mezei, “Processes for the preparation of atomoxetine hydrochloride.” U.S. Patent US20060211772, issued September 21, 2006.

    US20060211772
    General Reference
    1. Spencer TJ, Faraone SV, Michelson D, Adler LA, Reimherr FW, Glatt SJ, Biederman J: Atomoxetine and adult attention-deficit/hyperactivity disorder: the effects of comorbidity. J Clin Psychiatry. 2006 Mar;67(3):415-20. Pubmed
    2. Pilhatsch MK, Burghardt R, Wandinger KP, Bauer M, Adli M: Augmentation with atomoxetine in treatment-resistant depression with psychotic features. A case report. Pharmacopsychiatry. 2006 Mar;39(2):79-80. Pubmed
    3. Carpenter LL, Milosavljevic N, Schecter JM, Tyrka AR, Price LH: Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants. J Clin Psychiatry. 2005 Oct;66(10):1234-8. Pubmed
    4. Kratochvil CJ, Newcorn JH, Arnold LE, Duesenberg D, Emslie 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 symptoms. J Am Acad Child Adolesc Psychiatry. 2005 Sep;44(9):915-24. Pubmed
    5. McElroy SL, Guerdjikova A, Kotwal R, Welge JA, Nelson EB, Lake KA, Keck PE Jr, Hudson JI: Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial. J Clin Psychiatry. 2007 Mar;68(3):390-8. Pubmed
    6. Purper-Ouakil D, Fourneret P, Wohl M, Reneric JP: [Atomoxetine: a new treatment for Attention Deficit/Hyperactivity Disorder (ADHD) in children and adolescents] Encephale. 2005 May-Jun;31(3):337-48. Pubmed# Simpson D, Plosker GL: Atomoxetine: a review of its use in adults with attention deficit hyperactivity disorder. Drugs. 2004;64(2):205-22. Pubmed
    7. Montoya A, Hervas A, Cardo E, Artigas J, Mardomingo MJ, Alda JA, Gastaminza X, Garcia-Polavieja MJ, Gilaberte I, Escobar R: Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naive children and adolescents with attention deficit/hyperactivity disorder. Curr Med Res Opin. 2009 Nov;25(11):2745-54. Pubmed
    8. Gaillez C, Sorbara F, Perrin E: [Atomoxetine (Strattera), an alternative in the treatment of attention-deficit/hyperactivity disorder (ADHD) in children] Encephale. 2007 Sep;33(4 Pt 1):621-8. Pubmed
    External Links
    ResourceLink
    KEGG DrugD02574
    PubChem Compound54841
    PubChem Substance46506160
    ChemSpider49516
    BindingDB50133749
    ChEBI127342
    ChEMBLCHEMBL641
    Therapeutic Targets DatabaseDAP000721
    PharmGKBPA134688071
    Drug Product Database2262800
    RxListhttp://www.rxlist.com/cgi/generic3/strattera.htm
    Drugs.comhttp://www.drugs.com/cdi/atomoxetine.html
    WikipediaAtomoxetine
    ATC CodesN06BA09
    AHFS Codes
    • 28:92.00
    PDB EntriesNot Available
    FDA labelshow(72.8 KB)
    MSDSNot Available
    Interactions
    Drug Interactions
    Drug
    AmiodaroneThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    ChloroquineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    CocaineCYP2D6 Inhibitors (Strong) such as cocaine may increase the serum concentration of atomoxetine. Initiate atomoxetine at a reduced dose (patients up to 70kg: 0.5mg/kg/day; patients 70kg or more: 40mg/day) in patients receiving a strong CYP2D6 inhibitor. The dose should only be increased to usual doses if symptoms fail to improve after 4 weeks. Patients established on atomoxetine therapy may require dosage reductions and should be monitored for increased levels/adverse effects with initiation/dose increase of a strong CYP2D6 inhibitor.
    DextropropoxypheneThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    DiphenhydramineDiphenhydramine, a moderate CYP2D6 inhibitor, may increase the therapeutic and adverse effects of atomoxetine by decreasing its metabolism.
    FluoxetineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    FluphenazineRisk of additive CNS depressant effects. Monitor for increased CNS depression during concomitant therapy.
    HaloperidolThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    IsocarboxazidPossible severe adverse reaction with this combination
    LomustineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    MibefradilThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    ParoxetineThe CYP2D6 inhibitor, paroxetine, may increase the effect and toxicity of atomoxetine.
    PerphenazineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    PhenelzinePossible severe adverse reaction with this combination
    QuinacrineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    QuinidineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    Quinidine barbiturateThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    QuinineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    RasagilinePossible severe adverse reaction with this combination
    RitonavirThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    TerbinafineTerbinafine, a CYP2D6 inhibitor, may reduce the metabolism and clearance of Atomoxetine. Consider alternate therapy or monitor for therapeutic/adverse effects of Atomoxetine if Terbinafine is initiated, discontinued or dose changed.
    ThioridazineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    TranylcypromineThe MAO inhibitor, Tranylcypromine, may increase the central neurotoxic effects of the Atomoxetine. These agents should not be administered within 14 days of each other.
    TriprolidineThe CNS depressants, Triprolidine and Atomoxetine, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
    VinorelbineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    YohimbineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
    Food Interactions
    • In the presence of food, the absorption rate is reduced, without the quantity absorbed being affected.
    • Take without regard to meals.

    1. Sodium-dependent noradrenaline transporter

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Components

    Name UniProt ID Details
    Sodium-dependent noradrenaline transporter P23975 Details

    References:

    1. Biederman J, Heiligenstein JH, Faries DE, Galil N, Dittmann R, Emslie GJ, Kratochvil CJ, Laws HF, Schuh KJ: Efficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder. Pediatrics. 2002 Dec;110(6):e75. Pubmed
    2. Spencer T, Heiligenstein JH, Biederman J, Faries DE, Kratochvil CJ, Conners CK, Potter WZ: Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2002 Dec;63(12):1140-7. Pubmed
    3. Michelson D, Adler L, Spencer T, Reimherr FW, West SA, Allen AJ, Kelsey D, Wernicke J, Dietrich A, Milton D: Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry. 2003 Jan 15;53(2):112-20. Pubmed
    4. Wernicke JF, Faries D, Girod D, Brown J, Gao H, Kelsey D, Quintana H, Lipetz R, Michelson D, Heiligenstein J: Cardiovascular effects of atomoxetine in children, adolescents, and adults. Drug Saf. 2003;26(10):729-40. Pubmed
    5. Wernicke JF, Adler L, Spencer T, West SA, Allen AJ, Heiligenstein J, Milton D, Ruff D, Brown WJ, Kelsey D, Michelson D: Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: a prospective, placebo-controlled assessment. J Clin Psychopharmacol. 2004 Feb;24(1):30-5. Pubmed
    6. Garnock-Jones KP, Keating GM: Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. Paediatr Drugs. 2009;11(3):203-26. Pubmed
    7. Kaplan S, Heiligenstein J, West S, Busner J, Harder D, Dittmann R, Casat C, Wernicke JF: Efficacy and safety of atomoxetine in childhood attention-deficit/hyperactivity disorder with comorbid oppositional defiant disorder. J Atten Disord. 2004 Oct;8(2):45-52. Pubmed
    8. Purper-Ouakil D, Fourneret P, Wohl M, Reneric JP: [Atomoxetine: a new treatment for Attention Deficit/Hyperactivity Disorder (ADHD) in children and adolescents] Encephale. 2005 May-Jun;31(3):337-48. Pubmed
    9. Gaillez C, Sorbara F, Perrin E: [Atomoxetine (Strattera), an alternative in the treatment of attention-deficit/hyperactivity disorder (ADHD) in children] Encephale. 2007 Sep;33(4 Pt 1):621-8. Pubmed
    10. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. Pubmed

    2. Sodium-dependent serotonin transporter

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Components

    Name UniProt ID Details
    Sodium-dependent serotonin transporter P31645 Details

    References:

    1. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. Pubmed

    1. Cytochrome P450 2D6

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate inhibitor

    Components

    Name UniProt ID Details
    Cytochrome P450 2D6 P10635 Details

    References:

    1. Purper-Ouakil D, Fourneret P, Wohl M, Reneric JP: [Atomoxetine: a new treatment for Attention Deficit/Hyperactivity Disorder (ADHD) in children and adolescents] Encephale. 2005 May-Jun;31(3):337-48. Pubmed
    2. Garnock-Jones KP, Keating GM: Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. Paediatr Drugs. 2009;11(3):203-26. Pubmed
    3. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
    4. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
    5. Lexicomp

    2. Cytochrome P450 2C19

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Cytochrome P450 2C19 P33261 Details

    References:

    1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

    3. Cytochrome P450 3A4

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Cytochrome P450 3A4 P08684 Details

    References:

    1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
    2. Lexicomp

    Comments
    Drug created on June 13, 2005 07:24 / Updated on September 25, 2013 18:51