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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
AlawayNot AvailableNot Available
Ketotifen FumarateNot AvailableNot Available
KetotifeneFrenchINN
Ketotifene fumarateNot AvailableNot Available
KetotifenoSpanishINN
KetotifenumLatinINN
SaltsNot Available
Brand names
NameCompany
TotifenPatron
ZaditenNovartis
ZaditorAlcon
ZastenNovartis
Brand mixturesNot Available
Categories
CAS number34580-14-8
WeightAverage: 309.425
Monoisotopic: 309.118734925
Chemical FormulaC19H19NOS
InChI KeyZCVMWBYGMWKGHF-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
Not Available
Ketotifen-N-glucuronideDetails
Ketotifen
Not Available
10-alpha-hydroxyl KetotifenDetails
Ketotifen
Not Available
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 point152-153U.S. Patents 3,682,930; 3,770,728; and 3,960,894
logP2.2Not Available
pKa8.43Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00787ALOGPS
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 Area20.31 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity101.73 m3·mol-1ChemAxon
Polarizability34.61 Å3ChemAxon
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.

Targets

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

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Drug created on June 13, 2005 07:24 / Updated on May 05, 2014 12:02