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Identification
Name Ketotifen
Accession Number DB00920 (APRD01061)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Ketotifen Fumarate
Ketotifene [INN-French]
Ketotifene fumarate
Ketotifeno [INN-Spanish]
Ketotifenum [INN-Latin]
Salts Not Available
Brand names
Name Company
Ketotifen
Zaditor
Brand mixtures Not Available
Categories
  • Antipruritics
  • Anti-Allergic Agents
  • Histamine H1 Antagonists
CAS number 34580-14-8
Weight Average: 309.425
Monoisotopic: 309.118734925
Chemical Formula C19H19NOS
InChI Key InChIKey=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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenylpropenes
Substructures
  • Alkanes and Alkenes
  • Phenylpropenes
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Isoprenes
  • Heterocyclic compounds
  • Aromatic compounds
  • Thiophenes
  • Piperidines
  • Ketones
Pharmacology
Indication Indicated 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).
Pharmacodynamics Ketotifen 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 action Ketotifen 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.
Absorption Following oral administration absorption is at least 60%
Volume of distribution Not Available
Protein binding 75%
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.
Route of elimination Not Available
Half life 21 hours (for elimination)
Clearance Not Available
Toxicity Adverse reactions include headaches, conjunctival injection and rhinitis.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Bausch and lomb inc
  • Akorn inc
  • Alcon inc
  • Apotex inc etobicoke site
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
Form Route Strength
Liquid Ophthalmic
Solution Ophthalmic
Syrup Oral
Tablet Oral
Prices
Unit description Cost Unit
Ketotifen fumarate powder 926.63 USD g
Zaditor 0.025% Solution 5ml Bottle 74.96 USD bottle
Ketotifen fum 0.025% eye drops 2.44 USD ml
Refresh 0.025% eye drops 2.2 USD ml
Zaditor 0.025% eye drops 2.15 USD ml
Alaway 0.025% eye drops 0.96 USD ml
Zaditen 1 mg Tablet 0.83 USD tablet
Novo-Ketotifen 1 mg Tablet 0.66 USD tablet
Novo-Ketotifen 0.2 mg/ml Syrup 0.14 USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 191 °C (fumarate salt) Not Available
logP 2.2 Not Available
pKa 8.43 Not Available
Predicted Properties
Property Value Source
water solubility 7.87e-03 g/l ALOGPS
logP 3.49 ALOGPS
logP 3.35 ChemAxon
logS -4.6 ALOGPS
pKa (strongest acidic) 12.3 ChemAxon
pKa (strongest basic) 7.15 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 2 ChemAxon
hydrogen donor count 0 ChemAxon
polar surface area 20.31 ChemAxon
rotatable bond count 0 ChemAxon
refractivity 101.73 ChemAxon
polarizability 34.61 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D01332 Link_out
PubChem Compound 3827 Link_out
PubChem Substance 46508921 Link_out
ChemSpider 3695 Link_out
BindingDB 50002087 Link_out
Therapeutic Targets Database DAP000329 Link_out
PharmGKB PA450152 Link_out
Drug Product Database 2242324 Link_out
RxList http://www.rxlist.com/cgi/generic/ketotifen.htm Link_out
Drugs.com http://www.drugs.com/cdi/ketotifen-drops.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/zad1598.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Ketotifen Link_out
ATC Codes
  • R06AX17
  • S01GX08
AHFS Codes
  • 04:00.00
  • 52:02.00
  • 04:92.00
PDB Entries Not Available
FDA label show (9.05 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Tacrine The 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.
Trimethobenzamide Trimethobenzamide and Ketotifen, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
Triprolidine Triprolidine 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.
Trospium Trospium 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

Pharmacological action: yes
Actions: antagonist

In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system

Organism class: human
UniProt ID: P35367 Link_out
Gene: HRH1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: inhibitor

Adenosine 3',5'-cyclic phosphate + H(2)O = adenosine 5'-phosphate

Organism class: human
UniProt ID: P27815 Link_out
Gene: PDE4A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: inhibitor

May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents

Organism class: human
UniProt ID: Q07343 Link_out
Gene: PDE4B Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: inhibitor

Regulates the levels of cAMP in the cell

Organism class: human
UniProt ID: Q08499 Link_out
Gene: PDE4D Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: inhibitor

Adenosine 3',5'-cyclic phosphate + H(2)O = adenosine 5'-phosphate

Organism class: human
UniProt ID: Q08493 Link_out
Gene: PDE4C Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: inhibitor

Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase is highly specific for cAMP and may have a role in muscle signal transduction

Organism class: human
UniProt ID: Q13946 Link_out
Gene: PDE7A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: inhibitor

May be involved in the control of cAMP-mediated neural activity and cAMP metabolism in the brain

Organism class: human
UniProt ID: Q9NP56 Link_out
Gene: PDE7B Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: inhibitor

Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase, which has a high affinity for cAMP, may be involved in maintaining basal levels of the cyclic nucleotide and/or in the cAMP regulation of germ cell development

Organism class: human
UniProt ID: O60658 Link_out
Gene: PDE8A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: inhibitor

Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase has high affinity for cAMP and may be involved in specific signaling in the thyroid gland

Organism class: human
UniProt ID: O95263 Link_out
Gene: PDE8B Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: inhibitor

6-phospho-D-gluconate + NADP(+) = D-ribulose 5-phosphate + CO(2) + NADPH

Organism class: human
UniProt ID: P52209 Link_out
Gene: PGD Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 February 08, 2013 16:19