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Identification
NameKetotifen
Accession NumberDB00920  (APRD01061)
Typesmall molecule
Groupsapproved
Description

A cycloheptathiophene blocker of histamine H1 receptors and release of inflammatory mediators. It has been proposed for the treatment of asthma, rhinitis, skin allergies, and anaphylaxis. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
Ketotifen FumarateNot AvailableNot Available
KetotifeneFrenchINN
Ketotifene fumarateNot AvailableNot Available
KetotifenoSpanishINN
KetotifenumLatinINN
SaltsNot Available
Brand names
NameCompany
KetotifenNot Available
ZaditorNot Available
Brand mixturesNot Available
Categories
CAS number34580-14-8
WeightAverage: 309.425
Monoisotopic: 309.118734925
Chemical FormulaC19H19NOS
InChI KeyInChIKey=ZCVMWBYGMWKGHF-UHFFFAOYSA-N
InChI
InChI=1S/C19H19NOS/c1-20-9-6-13(7-10-20)18-15-5-3-2-4-14(15)12-17(21)19-16(18)8-11-22-19/h2-5,8,11H,6-7,9-10,12H2,1H3
IUPAC Name
2-(1-methylpiperidin-4-ylidene)-6-thiatricyclo[8.4.0.0^{3,7}]tetradeca-1(10),3(7),4,11,13-pentaen-8-one
SMILES
CN1CCC(CC1)=C1C2=C(SC=C2)C(=O)CC2=CC=CC=C12
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassCycloheptathiophenes
SubclassNot Available
Direct parentCycloheptathiophenes
Alternative parentsBenzene and Substituted Derivatives; Piperidines; Thiophenes; Tertiary Amines; Ketones; Polyamines
Substituentsbenzene; piperidine; thiophene; ketone; tertiary amine; polyamine; organonitrogen compound; amine; carbonyl group
Classification descriptionThis compound belongs to the cycloheptathiophenes. These are polycyclic compounds containing a thiophene ring fused to a 7 member carbocyclic moiety.
Pharmacology
IndicationIndicated as an add-on or prophylactic oral medication in the chronic treatment of mild atopic asthmatic children. Also used as self-medication for the temporary relief of itching of the eye due to allergic conjunctivitis (ophthalmic).
PharmacodynamicsKetotifen is a fast acting non-competitive histamine antagonist. It inhibits the release of mediators from mast cells. It is a non-bronchodilator antiasthmatic drug (when taken orally).
Mechanism of actionKetotifen is a relatively selective, non-competitive histamine antagonist (H1-receptor) and mast cell stabilizer. Ketotifen inhibits the release of mediators from mast cells involved in hypersensitivity reactions. Decreased chemotaxis and activation of eosinophils have also been demonstrated. Ketotifen also inhibits cAMP phosphodiesterase. Properties of ketotifen which may contribute to its antiallergic activity and its ability to affect the underlying pathology of asthma include inhibition of the development of airway hyper-reactivity associated with activation of platelets by PAF (Platelet Activating Factor), inhibition of PAF-induced accumulation of eosinophils and platelets in the airways, suppression of the priming of eosinophils by human recombinant cytokines and antagonism of bronchoconstriction due to leukotrienes. Ketotifen inhibits of the release of allergic mediators such as histamine, leukotrienes C4 and D4(SRS-A) and PAF.
AbsorptionFollowing oral administration absorption is at least 60%
Volume of distributionNot Available
Protein binding75%
Metabolism

Primarily hepatic. The main metabolite found in both plasma and urine is the inactive ketotifen-N-glucuronide. Nor-ketotifen, the N-demethylated metabolite, and the 10-alpha-hydroxyl derivative are the only other metabolites detectable in human urine.

SubstrateEnzymesProduct
Ketotifen
    Ketotifen-N-glucuronideDetails
    Ketotifen
      10-alpha-hydroxyl KetotifenDetails
      Ketotifen
        Nor-ketotifenDetails
        Route of eliminationNot Available
        Half life21 hours (for elimination)
        ClearanceNot Available
        ToxicityAdverse reactions include headaches, conjunctival injection and rhinitis.
        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 + 0.9923
        Caco-2 permeable + 0.8867
        P-glycoprotein substrate Substrate 0.87
        P-glycoprotein inhibitor I Inhibitor 0.8564
        P-glycoprotein inhibitor II Non-inhibitor 0.7474
        Renal organic cation transporter Inhibitor 0.8198
        CYP450 2C9 substrate Non-substrate 0.7542
        CYP450 2D6 substrate Non-substrate 0.5638
        CYP450 3A4 substrate Substrate 0.6984
        CYP450 1A2 substrate Non-inhibitor 0.9045
        CYP450 2C9 substrate Non-inhibitor 0.9071
        CYP450 2D6 substrate Inhibitor 0.8931
        CYP450 2C19 substrate Non-inhibitor 0.9026
        CYP450 3A4 substrate Non-inhibitor 0.8607
        CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6414
        Ames test Non AMES toxic 0.7576
        Carcinogenicity Non-carcinogens 0.9649
        Biodegradation Not ready biodegradable 0.9547
        Rat acute toxicity 2.7979 LD50, mol/kg Not applicable
        hERG inhibition (predictor I) Weak inhibitor 0.6336
        hERG inhibition (predictor II) Non-inhibitor 0.5145
        Pharmacoeconomics
        Manufacturers
        • Bausch and lomb inc
        • Akorn inc
        • Alcon inc
        • Apotex inc etobicoke site
        • Novartis pharmaceuticals corp
        Packagers
        Dosage forms
        FormRouteStrength
        LiquidOphthalmic
        SolutionOphthalmic
        SyrupOral
        TabletOral
        Prices
        Unit descriptionCostUnit
        Ketotifen fumarate powder926.63USDg
        Zaditor 0.025% Solution 5ml Bottle74.96USDbottle
        Ketotifen fum 0.025% eye drops2.44USDml
        Refresh 0.025% eye drops2.2USDml
        Zaditor 0.025% eye drops2.15USDml
        Alaway 0.025% eye drops0.96USDml
        Zaditen 1 mg Tablet0.83USDtablet
        Novo-Ketotifen 1 mg Tablet0.66USDtablet
        Novo-Ketotifen 0.2 mg/ml Syrup0.14USDml
        DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
        PatentsNot Available
        Properties
        Statesolid
        Experimental Properties
        PropertyValueSource
        melting point191 °C (fumarate salt)Not Available
        logP2.2Not Available
        pKa8.43Not Available
        Predicted Properties
        PropertyValueSource
        water solubility7.87e-03 g/lALOGPS
        logP3.49ALOGPS
        logP3.35ChemAxon
        logS-4.6ALOGPS
        pKa (strongest acidic)12.3ChemAxon
        pKa (strongest basic)7.15ChemAxon
        physiological charge1ChemAxon
        hydrogen acceptor count2ChemAxon
        hydrogen donor count0ChemAxon
        polar surface area20.31ChemAxon
        rotatable bond count0ChemAxon
        refractivity101.73ChemAxon
        polarizability34.61ChemAxon
        number of rings4ChemAxon
        bioavailability1ChemAxon
        rule of fiveYesChemAxon
        Ghose filterYesChemAxon
        Veber's ruleYesChemAxon
        MDDR-like ruleNoChemAxon
        Spectra
        SpectraNot Available
        References
        Synthesis Reference

        Roy W. Bryant, Ravi Parihar, Thomas Rowe, Susan Caballa, “Methods of Making and Using Stable Pharmaceutical Compositions Comprising Ketotifen and Naphazoline.” U.S. Patent US20110312998, issued December 22, 2011.

        US20110312998
        General ReferenceNot Available
        External Links
        ResourceLink
        KEGG DrugD01332
        PubChem Compound3827
        PubChem Substance46508921
        ChemSpider3695
        BindingDB50002087
        Therapeutic Targets DatabaseDAP000329
        PharmGKBPA450152
        Drug Product Database2242324
        RxListhttp://www.rxlist.com/cgi/generic/ketotifen.htm
        Drugs.comhttp://www.drugs.com/cdi/ketotifen-drops.html
        PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/zad1598.shtml
        WikipediaKetotifen
        ATC CodesR06AX17S01GX08
        AHFS Codes
        • 04:00.00
        • 52:02.00
        • 04:92.00
        PDB EntriesNot Available
        FDA labelshow(9.05 KB)
        MSDSNot Available
        Interactions
        Drug Interactions
        Drug
        TacrineThe therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Ketotifen, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents.
        TrimethobenzamideTrimethobenzamide and Ketotifen, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
        TriprolidineTriprolidine and Ketotifen, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.
        TrospiumTrospium and Ketotifen, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.
        Food Interactions
        • Take without regard to meals.

        1. Histamine H1 receptor

        Kind: protein

        Organism: Human

        Pharmacological action: yes

        Actions: antagonist

        Components

        Name UniProt ID Details
        Histamine H1 receptor P35367 Details

        References:

        1. Mita H, Shida T: Comparison of anti-allergic activities of the histamine H1 receptor antagonists epinastine, ketotifen and oxatomide in human leukocytes. Arzneimittelforschung. 1995 Jan;45(1):36-40. Pubmed
        2. Okabe S, Nakaji S, Tachibana M: Effect of ketotifen on acute gastric lesions and gastric secretion in rats. Jpn J Pharmacol. 1992 Jun;59(2):251-4. Pubmed
        3. Hashimoto T, Ohata H, Honda K: Lysophosphatidic acid (LPA) induces plasma exudation and histamine release in mice via LPA receptors. J Pharmacol Sci. 2006 Jan;100(1):82-7. Epub 2006 Jan 11. Pubmed
        4. Ito K, Sakamoto T, Hayashi Y, Morishita M, Shibata E, Sakai K, Takeuchi Y, Torii S: Role of tachykinin and bradykinin receptors and mast cells in gaseous formaldehyde-induced airway microvascular leakage in rats. Eur J Pharmacol. 1996 Jul 4;307(3):291-8. Pubmed
        5. Yokoyama H, Iinuma K, Yanai K, Watanabe T, Sakurai E, Onodera K: Proconvulsant effect of ketotifen, a histamine H1 antagonist, confirmed by the use of d-chlorpheniramine with monitoring electroencephalography. Methods Find Exp Clin Pharmacol. 1993 Apr;15(3):183-8. Pubmed
        6. Werner-Klein M, Goggel R, Westhof A, Erb KJ: Development and characterisation of a novel and rapid lung eosinophil influx model in the rat. Pulm Pharmacol Ther. 2008 Aug;21(4):648-56. Epub 2008 Apr 7. Pubmed
        7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

        2. cAMP-specific 3',5'-cyclic phosphodiesterase 4A

        Kind: protein

        Organism: Human

        Pharmacological action: yes

        Actions: inhibitor

        Components

        Name UniProt ID Details
        cAMP-specific 3',5'-cyclic phosphodiesterase 4A P27815 Details

        References:

        1. Castillo JG, Gamboa PM, Garcia BE, Oehling A: Effect of ketotifen on phosphodiesterase activity from asthmatic individuals. Allergol Immunopathol (Madr). 1990 Jul-Aug;18(4):197-201. Pubmed
        2. Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K: Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sci. 2006 May 1;78(23):2663-8. Epub 2005 Nov 28. Pubmed

        3. cAMP-specific 3',5'-cyclic phosphodiesterase 4B

        Kind: protein

        Organism: Human

        Pharmacological action: yes

        Actions: inhibitor

        Components

        Name UniProt ID Details
        cAMP-specific 3',5'-cyclic phosphodiesterase 4B Q07343 Details

        References:

        1. Castillo JG, Gamboa PM, Garcia BE, Oehling A: Effect of ketotifen on phosphodiesterase activity from asthmatic individuals. Allergol Immunopathol (Madr). 1990 Jul-Aug;18(4):197-201. Pubmed
        2. Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K: Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sci. 2006 May 1;78(23):2663-8. Epub 2005 Nov 28. Pubmed

        4. cAMP-specific 3',5'-cyclic phosphodiesterase 4D

        Kind: protein

        Organism: Human

        Pharmacological action: yes

        Actions: inhibitor

        Components

        Name UniProt ID Details
        cAMP-specific 3',5'-cyclic phosphodiesterase 4D Q08499 Details

        References:

        1. Castillo JG, Gamboa PM, Garcia BE, Oehling A: Effect of ketotifen on phosphodiesterase activity from asthmatic individuals. Allergol Immunopathol (Madr). 1990 Jul-Aug;18(4):197-201. Pubmed
        2. Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K: Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sci. 2006 May 1;78(23):2663-8. Epub 2005 Nov 28. Pubmed

        5. cAMP-specific 3',5'-cyclic phosphodiesterase 4C

        Kind: protein

        Organism: Human

        Pharmacological action: yes

        Actions: inhibitor

        Components

        Name UniProt ID Details
        cAMP-specific 3',5'-cyclic phosphodiesterase 4C Q08493 Details

        References:

        1. Castillo JG, Gamboa PM, Garcia BE, Oehling A: Effect of ketotifen on phosphodiesterase activity from asthmatic individuals. Allergol Immunopathol (Madr). 1990 Jul-Aug;18(4):197-201. Pubmed
        2. Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K: Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sci. 2006 May 1;78(23):2663-8. Epub 2005 Nov 28. Pubmed

        6. High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A

        Kind: protein

        Organism: Human

        Pharmacological action: yes

        Actions: inhibitor

        Components

        Name UniProt ID Details
        High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A Q13946 Details

        References:

        1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
        2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

        7. cAMP-specific 3',5'-cyclic phosphodiesterase 7B

        Kind: protein

        Organism: Human

        Pharmacological action: yes

        Actions: inhibitor

        Components

        Name UniProt ID Details
        cAMP-specific 3',5'-cyclic phosphodiesterase 7B Q9NP56 Details

        References:

        1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
        2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

        8. High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A

        Kind: protein

        Organism: Human

        Pharmacological action: yes

        Actions: inhibitor

        Components

        Name UniProt ID Details
        High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A O60658 Details

        References:

        1. Castillo JG, Gamboa PM, Garcia BE, Oehling A: Effect of ketotifen on phosphodiesterase activity from asthmatic individuals. Allergol Immunopathol (Madr). 1990 Jul-Aug;18(4):197-201. Pubmed

        9. High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B

        Kind: protein

        Organism: Human

        Pharmacological action: yes

        Actions: inhibitor

        Components

        Name UniProt ID Details
        High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B O95263 Details

        References:

        1. Castillo JG, Gamboa PM, Garcia BE, Oehling A: Effect of ketotifen on phosphodiesterase activity from asthmatic individuals. Allergol Immunopathol (Madr). 1990 Jul-Aug;18(4):197-201. Pubmed

        10. 6-phosphogluconate dehydrogenase, decarboxylating

        Kind: protein

        Organism: Human

        Pharmacological action: unknown

        Actions: inhibitor

        Components

        Name UniProt ID Details
        6-phosphogluconate dehydrogenase, decarboxylating P52209 Details

        References:

        1. Akkemik E, Budak H, Ciftci M: Effects of some drugs on human erythrocyte 6-phosphogluconate dehydrogenase: an in vitro study. J Enzyme Inhib Med Chem. 2010 Mar 17. Pubmed
        2. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed

        Comments
        Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12