Ketotifen (0-100 μM; 2 or 4 days) suppresses SARS-CoV-2 with an EC50 of 48.9 μM; the percentages of SARS-CoV-2 inhibition that increase to 79%, 83%, and 93% when coadministered with 25, 50, and 100 μM indomethacin, respectively[3]. Ketotifen (0-50 μM; 24 h) demonstrates comparatively moderate cytotoxicity in MDCK cells (EC50=291 μM), with inhibitory efficacy against PR8, pH1N1, and H3N2 (EC50 of 5.9 μM, 33.7 μM, and 48.5 μM, respectively) [4].

Ketotifen (80 mg/kg; injectable; given daily for 3 days) lowers end-organ damage and mortality in mice infected with influenza virus [4]. Ketotifen (0.4 mg/kg; intraperitoneally; given daily for 10 days) lowers the prevalence and severity of encephalomyelitis (EAE) [5].

Animal/Disease Models: Female C57BL/6 mice (4-6 weeks; PR8 intranasally infected with 1×103 TCID50 in 30 μL DMEM) [4]
Doses: 80 mg/kg
Route of Administration: ig; one time/day for 3 Day
Experimental Results: diminished end-organ damage and mortality in infected mice.

---

Animal/Disease Models: Female C57BL/6 mice (5-6 weeks old; immunized subcutaneously (sc) (sc) with 150 μg of MOG35-55 peptide containing 4 mg/mL of Mycobacterium tuberculosis) [5]
Doses: 0.4 mg/kg
Route of Administration: intraperitoneal (ip) injection; one time/day for 10 days (starting on day 7 of infection)
Experimental Results: diminished prevalence and severity of EAE; diminished oxidative stress state and inflammasome activation in the central nervous system; diminished T cell activation in the central nervous system numbers, especially Th1; downregulates local mRNA expression of mast cell enzymes and maintains blood-CNS barrier permeability; triggers lymphocyte accumulation in draining lymph nodes.

Absorption, Distribution and Excretion
After oral administration, absorption is relatively rapid (peak time approximately 3 hours), and based on plasma concentrations and urinary excretion levels, absorption is almost complete. Nevertheless, due to a significant first-pass effect in the liver, oral bioavailability is only about 50%. Over 60% of the administered dose is excreted in the urine, primarily as metabolites. Less than 1% is the unchanged drug, while glucuronide and pharmacologically active norketotifen metabolites account for 50% and 10%, respectively. Within 48 hours, 1% of the unchanged drug is excreted in the urine, and 60% to 70% is excreted as metabolites. Clearance is even higher in children. Ketotifen fumarate has an oral absorption rate of at least 60%... rapid absorption rate, with an absorption half-life of 1 hour. Due to a significant first-pass effect, bioavailability is approximately 50%. Food intake does not affect bioavailability. A study involving 15 healthy volunteers showed that twice-daily administration of ketotifen fumarate eye drops to both eyes for 14 days resulted in plasma concentrations typically below the limit of quantification (< 20 pg/mL). It is currently unclear whether ketotifen fumarate eye drops are absorbed in sufficient quantities to be distributed into human breast milk. However, the drug has been detected in the milk of lactating rats following oral administration. /Ketotifen fumarate/
For more complete data on the absorption, distribution, and excretion of ketotifen (7 types), please visit the HSDB record page.

---

Metabolism/Metabolites
Ketotifen is extensively metabolized in the human body, and three distinct metabolites have been detected in human urine. The major metabolite is N-glucuronide, accounting for approximately 50% of the urinary drug product, followed by N-demethylated norketotifen and a 10-hydroxy derivative, accounting for 2% and <1%, respectively. Norketotifen's activity appears to be comparable to its parent drug, but its clinical significance remains unclear given its relatively small proportion in plasma. The formation of the N-glucuronide metabolite is catalyzed by several UGT enzymes, including UGT1A3, UGT1A4, and UGT2B10. The major metabolite in plasma and urine is inactive ketotifen-N-glucuronide. Norketotifen, the N-demethyl metabolite, and the 10-hydroxy derivative are among the few other metabolites detectable in human urine. Both the 10-hydroxy derivative and the N-glucuronide conjugate can be regenerated into the complete product through reversible reactions in vivo. The metabolic pattern in children over 3 years of age is similar to that in adults, but children have higher clearance rates. /Ketotifen Fumarate (Systemic Administration)/
Known metabolites of ketotifen include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[1-methyl-4-(8-oxo-6-thiatricyclo[8.4.0.03,7]tetradec-1(14),3(7),4,10,12-penten-2-ylidene)piperidin-1-onthiol]oxacyclohexane-2-carboxylic acid and ketotifen N-glucuronide.

---

Biological Half-Life
The elimination of ketotifen is biphasic—the half-life of the distribution phase is approximately 3-5 hours, and the half-life of the elimination phase is 22 hours.
Distribution: 3 to 5 hours. Elimination: 21 hours. /Ketotifen Fumarate (Systemic Administration)/
...Absorption is rapid after oral administration, with an absorption half-life of 1 hour.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Due to limited absorption by the eyes, it is not expected that breastfed infants will experience any adverse effects after their mothers use ketotifen eye drops. To significantly reduce the amount of medication that enters breast milk after using the eye drops, press the tear duct near the corner of the eye for at least 1 minute, then wipe away any excess medication with absorbent tissue.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Breastfeeding and Breast Milk
No published information found as of the revision date.

---

Protein Binding
Ketotifen has a 75% protein binding rate in plasma, but the specific proteins it binds to are not yet clear.

---

Drug Interactions
Concomitant use of oral ketotifen with alcohol, antihistamines, hypnotics, or sedatives may enhance the central nervous system depressant effects of these drugs. Ketotifen fumarate
Oral ketotifen combined with oral hypoglycemic agents may cause reversible thrombocytopenia… Ketotifen fumarate
…Ketotifen (4 mg/kg) combined with conventional antiepileptic drugs impaired motor coordination in mice treated with sodium valproate, phenobarbital, or phenytoin sodium.
…Ketotifen reduced the protective effect of carbamazepine and increased the adverse effects of phenytoin sodium, phenobarbital, and sodium valproate in mice.

[1]. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut. 2010 Sep;59(9):1213-21.

[2]. Advances in the discovery of exosome inhibitors in cancer. J Enzyme Inhib Med Chem. 2020;35(1):1322-1330.

[3]. In Vitro Assessment of the Antiviral Activity of Ketotifen, Indomethacin and Naproxen, Alone and in Combination, against SARS-CoV-2. Viruses. 2021 Mar 26;13(4):558.

[4]. Identification and in vivo Efficacy Assessment of Approved Orally Bioavailable Human Host Protein-Targeting Drugs With Broad Anti-influenza A Activity. Front Immunol. 2019 Jun 5;10:1097.

[5]. Calming Down Mast Cells with Ketotifen: A Potential Strategy for Multiple Sclerosis Therapy? Neurotherapeutics. 2020 Jan;17(1):218-234.

Therapeutic Uses
Oral ketotifen is indicated for the chronic treatment of mild atopic asthma in children and may be used as an adjunct therapy. Ketotifen is a preventative medication and requires continuous use; it is ineffective for the prevention or treatment of acute asthma attacks. /Not marketed in the US/
Ophthalmic ketotifen is indicated for the temporary prevention of itchy eyes caused by allergic conjunctivitis. /Included in the US product label/
Drug Warnings Ketotifen should not be used to treat irritation caused by contact lenses. /Ketotifen fumarate/
Pregnancy Risk Class: C/Risk cannot be ruled out. Adequate, well-controlled human studies are lacking, and animal studies have not shown any risk to the fetus or lack relevant data. Use of this drug during pregnancy may cause harm to the fetus; however, the potential benefits may outweigh the potential risks. /
Central nervous system excitation symptoms, such as excitement, irritability, insomnia, and nervousness, have been observed, especially in children. /Ketotifen fumarate (Systemic Use)/
For diabetic patients: Please note that each 5 ml of ketotifen syrup contains 4 grams of carbohydrates; blood glucose levels may be affected. /Ketotifen Fumarate (Systemic Use)/
For more complete data on drug warnings for ketotifen (9 of 9), please visit the HSDB records page.

---

Pharmacodynamics
Ketotifen is a non-competitive histamine antagonist and mast cell stabilizer. After oral administration, it acts as a non-bronchodilator anti-asthmatic by inhibiting the action of endogenous substances known as inflammatory mediators. Although the effects of ketotifen may take 6 to 12 weeks to appear, it has been shown to reduce the frequency, severity, and duration of asthma symptoms and may reduce the use of other asthma therapies.

C19H19NOS

309.426

309.119

34580-13-7

Ketotifen fumarate;34580-14-8;Ketotifen-13C,d3;2748522-40-7

3827

Crystals from ethyl acetate

1.236g/cm3

488.9ºC at 760mmHg

152-153ºC

249.5ºC

3.952

0

3

0

22

476

0

S1C=CC2=C1C(CC1C=CC=CC=1/C/2=C1/CCN(C)CC/1)=O

ZCVMWBYGMWKGHF-UHFFFAOYSA-N

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

2-(1-methylpiperidin-4-ylidene)-6-thiatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),4,10,12-pentaen-8-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

 (Please use freshly prepared in vivo formulations for optimal results.)