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.

Structure
Thumb
Synonyms
  • Ketotifene
  • Ketotifeno
  • Ketotifenum
Product Ingredients
IngredientUNIICASInChI Key
Ketotifen fumarateHBD503WORO34580-14-8YNQQEYBLVYAWNX-WLHGVMLRSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Ketotifen Ophthalmic SolutionSolution0.25 mgOphthalmicSterimax Inc2013-03-07Not applicableCanada
Novo-ketotifen - Syr 1mg/5mlSyrup1 mgOralNovopharm Limited1995-12-312015-10-26Canada
Novo-ketotifen Tab 1mgTablet1 mgOralNovopharm Limited1997-07-292013-02-11Canada
Nu-ketotifen Syrup - 1mg/5mlSyrup1 mgOralNu Pharm Inc1996-12-092012-09-04Canada
PMS-ketotifenSyrup1 mgOralPharmascience Inc1998-08-312013-02-07Canada
PMS-ketotifenTablet1 mgOralPharmascience Inc1998-08-312013-02-07Canada
ZaditenTablet1 mgOralTeva1990-12-31Not applicableCanada
ZaditenSyrup1 mgOralTeva1990-12-31Not applicableCanada
Zaditen - Dps 1mg/mlSolution / drops1 mgOralNovartisNot applicableNot applicableCanada
ZaditorSolution0.25 mgOphthalmicNovartis2006-08-032012-01-17Canada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-ketotifen - Syr 1mg/5mlSyrup1 mgOralApotex Corporation1996-11-07Not applicableCanada
Over the Counter Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AlawaySolution / drops.25 mg/mLOphthalmicBauch & Lomb Incorporated2006-12-01Not applicableUs
AlawayKitBauch & Lomb Incorporated2006-12-01Not applicableUs
Allergy EyeSolution / drops.25 mg/mLOphthalmicH.E.B.2010-09-15Not applicableUs
Allergy EyeSolution / drops.25 mg/mLOphthalmicCvs Health2011-01-07Not applicableUs
Allergy Eye DropsSolution / drops.35 mg/mLOphthalmicH.E.B.2014-02-25Not applicableUs
Allergy Eye DropsSolution / drops.35 mg/mLOphthalmicAdvanced Vision Research (Subsidiary of Akorn, Inc.)2013-11-14Not applicableUs
Allergy Eye DropsSolution / drops.35 mg/mLOphthalmicCardinal Health2014-01-13Not applicableUs
Allergy Eye Original Prescription StrengthSolution / drops.25 mg/mLOphthalmicMeijer Distribution1995-12-12Not applicableUs
Allergy Relief EyeSolution / drops.25 mg/mLOphthalmicWestern Family Foods2011-05-25Not applicableUs
Allergy Relief Eye DropsSolution / drops.35 mg/mLOphthalmicKinray2014-03-18Not applicableUs
International/Other Brands
Totifen (Patron) / Zasten (Novartis)
Categories
UNII
X49220T18G
CAS number
34580-13-7
Weight
Average: 309.425
Monoisotopic: 309.118734925
Chemical Formula
C19H19NOS
InChI Key
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[8.4.0.0³,⁷]tetradeca-1(14),3(7),4,10,12-pentaen-8-one
SMILES
CN1CCC(CC1)=C1C2=C(SC=C2)C(=O)CC2=CC=CC=C12

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).

Structured Indications
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.

TargetActionsOrganism
AHistamine H1 receptor
antagonist
Human
U6-phosphogluconate dehydrogenase, decarboxylating
inhibitor
Human
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
PathwayCategory
Ketotifen H1-Antihistamine ActionDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
2,5-Dimethoxy-4-ethylamphetamine2,5-Dimethoxy-4-ethylamphetamine may decrease the sedative activities of Ketotifen.Experimental, Illicit
3,4-Methylenedioxyamphetamine3,4-Methylenedioxyamphetamine may decrease the sedative activities of Ketotifen.Experimental, Illicit
4-Bromo-2,5-dimethoxyamphetamine4-Bromo-2,5-dimethoxyamphetamine may decrease the sedative activities of Ketotifen.Experimental, Illicit
AmphetamineAmphetamine may decrease the sedative activities of Ketotifen.Approved, Illicit
BenzphetamineBenzphetamine may decrease the sedative activities of Ketotifen.Approved, Illicit
Benzylpenicilloyl PolylysineKetotifen may decrease effectiveness of Benzylpenicilloyl Polylysine as a diagnostic agent.Approved
BetahistineThe therapeutic efficacy of Betahistine can be decreased when used in combination with Ketotifen.Approved
ChlorphentermineChlorphentermine may decrease the sedative activities of Ketotifen.Illicit, Withdrawn
DextroamphetamineDextroamphetamine may decrease the sedative activities of Ketotifen.Approved, Illicit
DiethylpropionDiethylpropion may decrease the sedative activities of Ketotifen.Approved, Illicit
GepefrineGepefrine may decrease the sedative activities of Ketotifen.Experimental
HyaluronidaseThe therapeutic efficacy of Hyaluronidase can be decreased when used in combination with Ketotifen.Approved, Investigational
HydroxyamphetamineHydroxyamphetamine may decrease the sedative activities of Ketotifen.Approved
Iofetamine I-123Iofetamine I-123 may decrease the sedative activities of Ketotifen.Approved
LisdexamfetamineLisdexamfetamine may decrease the sedative activities of Ketotifen.Approved, Investigational
MephedroneMephedrone may decrease the sedative activities of Ketotifen.Investigational
MephentermineMephentermine may decrease the sedative activities of Ketotifen.Approved
MethamphetamineMethamphetamine may decrease the sedative activities of Ketotifen.Approved, Illicit
MethoxyphenamineMethoxyphenamine may decrease the sedative activities of Ketotifen.Experimental
Midomafetamine3,4-Methylenedioxymethamphetamine may decrease the sedative activities of Ketotifen.Experimental, Illicit
MMDAMMDA may decrease the sedative activities of Ketotifen.Experimental, Illicit
PhenterminePhentermine may decrease the sedative activities of Ketotifen.Approved, Illicit
PseudoephedrinePseudoephedrine may decrease the sedative activities of Ketotifen.Approved
RitobegronRitobegron may decrease the sedative activities of Ketotifen.Investigational
Food Interactions
  • Take without regard to meals.

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 References
Not Available
External Links
Human Metabolome Database
HMDB15056
KEGG Drug
D01332
PubChem Compound
3827
PubChem Substance
46508921
ChemSpider
3695
BindingDB
94597
ChEBI
92511
ChEMBL
CHEMBL534
Therapeutic Targets Database
DAP000329
PharmGKB
PA450152
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Ketotifen
ATC Codes
S01GX08 — KetotifenR06AX17 — Ketotifen
AHFS Codes
  • 04:00.00
  • 04:92.00
  • 52:02.00
PDB Entries
Not Available
FDA label
Download (9.05 KB)
MSDS
Not Available

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableConjunctivitis, Seasonal Allergic1
1, 2RecruitingTreatmentWidespread Chronic Pain1
2CompletedTreatmentConjunctivitis, Seasonal Allergic1
2Unknown StatusTreatmentPeanut Allergies in Children1
2WithdrawnNot AvailableConjunctivitis, Seasonal Allergic1
3Active Not RecruitingPreventionJoint Contractures1
3CompletedBasic ScienceFibromyalgia1
3CompletedTreatmentAtopics / Skin Inflammation1
3CompletedTreatmentConjunctivitis, Seasonal Allergic2
3CompletedTreatmentRhinitis, Allergic, Perennial1
3Not Yet RecruitingTreatmentFunctional Dyspepsia1
4CompletedTreatmentConjunctivitis, Seasonal Allergic1
4RecruitingTreatmentDengue Fever / Pleural Effusions1

Pharmacoeconomics

Manufacturers
  • Bausch and lomb inc
  • Akorn inc
  • Alcon inc
  • Apotex inc etobicoke site
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
Kit
SolutionOphthalmic.25 g/mL
Solution / dropsOphthalmic.35 mg/mL
Solution / dropsOphthalmic.25 mg/mL
SolutionOphthalmic.25 mg/mL
Solution / dropsOphthalmic.345 mg/mL
SyrupOral1 mg
TabletOral1 mg
Solution / dropsOral1 mg
SolutionOphthalmic.35 mg/mL
SolutionOphthalmic0.25 mg
Prices
Unit descriptionCostUnit
Ketotifen fumarate powder926.63USD g
Zaditor 0.025% Solution 5ml Bottle74.96USD bottle
Ketotifen fum 0.025% eye drops2.44USD ml
Refresh 0.025% eye drops2.2USD ml
Zaditor 0.025% eye drops2.15USD ml
Alaway 0.025% eye drops0.96USD ml
Zaditen 1 mg Tablet0.83USD tablet
Novo-Ketotifen 1 mg Tablet0.66USD tablet
Novo-Ketotifen 0.2 mg/ml Syrup0.14USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)152-153U.S. Patents 3,682,930; 3,770,728; and 3,960,894
logP2.2Not Available
pKa8.43Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00787 mg/mLALOGPS
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
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9923
Caco-2 permeable+0.8867
P-glycoprotein substrateSubstrate0.87
P-glycoprotein inhibitor IInhibitor0.8564
P-glycoprotein inhibitor IINon-inhibitor0.7474
Renal organic cation transporterInhibitor0.8198
CYP450 2C9 substrateNon-substrate0.7542
CYP450 2D6 substrateNon-substrate0.5638
CYP450 3A4 substrateSubstrate0.6984
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorInhibitor0.8931
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8607
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6414
Ames testNon AMES toxic0.7576
CarcinogenicityNon-carcinogens0.9649
BiodegradationNot ready biodegradable0.9547
Rat acute toxicity2.7979 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6336
hERG inhibition (predictor II)Non-inhibitor0.5145
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as cycloheptathiophenes. These are polycyclic compounds containing a thiophene ring fused to a 7 member carbocyclic moiety. Thiophene is 5-membered ring consisting of four carbon atoms and one sulfur atom.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Cycloheptathiophenes
Sub Class
Not Available
Direct Parent
Cycloheptathiophenes
Alternative Parents
Aryl alkyl ketones / Piperidines / Benzenoids / Thiophenes / Heteroaromatic compounds / Trialkylamines / Azacyclic compounds / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Cycloheptathiophene / Aryl alkyl ketone / Aryl ketone / Piperidine / Benzenoid / Thiophene / Heteroaromatic compound / Ketone / Tertiary amine / Tertiary aliphatic amine
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Details
1. Histamine H1 receptor
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Histamine receptor activity
Specific Function
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 catecholamin...
Gene Name
HRH1
Uniprot ID
P35367
Uniprot Name
Histamine H1 receptor
Molecular Weight
55783.61 Da
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:7893266]
  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:1434122]
  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:16404130]
  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:8836617]
  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:8101246]
  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. doi: 10.1016/j.pupt.2008.03.002. Epub 2008 Apr 7. [PubMed:18490184]
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Phosphogluconate dehydrogenase (decarboxylating) activity
Specific Function
Catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate and CO(2), with concomitant reduction of NADP to NADPH.
Gene Name
PGD
Uniprot ID
P52209
Uniprot Name
6-phosphogluconate dehydrogenase, decarboxylating
Molecular Weight
53139.56 Da
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 Aug;25(4):476-9. doi: 10.3109/14756360903257900. [PubMed:20235752]
  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:10592235]

Drug created on June 13, 2005 07:24 / Updated on October 02, 2017 04:48