Dimethyl fumarate
Synonym(s):Dimethyl fumarate;Fumaric acid dimethyl ester
- CAS NO.:624-49-7
- Empirical Formula: C6H8O4
- Molecular Weight: 144.13
- MDL number: MFCD00064438
- EINECS: 210-849-0
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-03-25 11:48:53
What is Dimethyl fumarate?
Absorption
Once ingested, dimethyl fumarate is rapidly hydrolyzed by esterases to form monomethyl fumarate (MMF). Therefore, there is a negligible amount of dimethyl fumarate in the body, and all pharmacokinetic information is quantified with MMF. The time to maximum concentration (tmax) of MMF ranges between 2 and 2.5 hours. In patients with multiple sclerosis given 240 mg of dimethyl fumarate two times a day with food, the Cmax and AUC were 1.87 mg/L and 8.21 mg?hr/L, respectively. High-fat, high-calorie meals decrease the Cmax of MMF by 40% and cause a tmax delay from 2 hours to 5.5 hours; however, these changes are not considered clinically significant.
Toxicity
Cases of overdose with dimethyl fumarate have been reported, and symptoms were consistent with its adverse event profile. There are no known therapeutic interventions to enhance dimethyl fumarate elimination nor an antidote. The product label of dimethyl fumarate recommends initiating symptomatic supportive treatment as clinically indicated in case of overdose. In vivo carcinogenicity studies found that at doses ranging between 200 and 400 mg/kg/day, mice had a higher incidence of non-glandular stomach and kidney tumors. The highest dose not associated with tumors in mice (75 mg/kg/day) is equivalent to the recommended human dose (RHD) of 480 mg/day. Dimethyl fumarate did not show evidence of mutagenicity in the in vitro bacterial reverse mutation (Ames) assay. Dimethyl fumarate was clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes in the absence of metabolic activation, but not clastogenic in the in vivo micronucleus assay in the rat.
Description
In March 2013, the US FDA approved dimethyl fumarate for the treatment of relapsing forms of multiple sclerosis (MS). Dimethyl fumarate is the newest oral therapeutic for MS. While its mechanism is not completely understood, dimethyl fumarate increases anti-inflammatory cytokines (IL-10, IL-4, and IL-6), decreases proinflammatory cytokines (IL-1β, IL-6, and TNF-α), and activates the Nrf2 pathway to protect neuronal cells. Nrf2 is activated by covalent bond-forming electrophiles such as dimethyl fumarate, a Michael acceptor. Dimethyl fumarate has been used for the treatment of psoriasis in Europe since 1994 and has a favorable long-term safety profile. An exploratory study in patients with relapsing remitting MS showed significant reductions in MS lesions after 18 weeks of treatment with 720 mg/day of dimethyl fumarate. Evaluation of dimethyl fumarate in a mouse experimental autoimmune encephalomyelitis model of MS resulted in reduced spinal cord macrophage inflammation. Dimethyl fumarate is obtained in high purity by esterification of fumaric acid with methanol and catalytic sulfuric acid.
Description
Dimethyl fumarate is an electrophile that chemists often use in Diels–Alder reactions. In the 1950s, German and Swiss physicians found that dimethyl fumarate is an effective topical treatment for psoriasis.?More recently, building on the link between psoriasis and multiple sclerosis (MS), researchers have assessed dimethyl fumarate as a possible MS treatment.
The Uses of Dimethyl fumarate
Dimethyl fumarate acts as an immunomodulator. It is also used in cycloaddition reactions involving ylides, benzenes and amino acids. It is added to food grains,tobacco,leather and preservation. Clothing
Indications
Dimethyl fumarate is indicated for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Background
Dimethyl fumarate is an agent indicated for the treatment of relapsing forms of multiple sclerosis. The mechanism of action of dimethyl fumarate in multiple sclerosis is not well understood. It is thought to involve dimethyl fumarate degradation to its active metabolite monomethyl fumarate (MMF) then MMF up-regulates the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway that is activated in response to oxidative stress. Dimethyl fumarate is marketed under the brand name Tecfidera, and it was the third oral disease-modifying agent for multiple sclerosis approved by the FDA, following fingolimod and teriflunomide. Prior to its FDA approval, dimethyl fumarate had been used in Germany for treatment of psoriasis.
What are the applications of Application
Dimethyl fumarate is an ester used for research purposes
Pharmacokinetics
The physiological effects of dimethyl fumarate on the body are not well understood. It has anti-inflammatory and cytoprotective effects, likely involved in its actions in multiple sclerosis (MS) patients. Dimethyl fumarate does not cause clinically significant QT interval prolongation. However, cases of progressive multifocal leukoencephalopathy, serious opportunistic infections, lymphopenia and liver injury have been reported in MS patients treated with this drug. Dimethyl fumarate may also cause anaphylaxis and angioedema.
Metabolism
Dimethyl fumarate is quickly hydrolyzed by esterases in the gastrointestinal tract, tissues, and blood to form monomethyl fumarate (MMF), its active metabolite. MMF then undergoes subsequent metabolism through the tricarboxylic acid (TCA) cycle. The main metabolites of dimethyl fumarate are MMF, glucose, citric, and fumaric acid. Cytochrome P450 (CYP) enzymes do not participate in the metabolism of dimethyl fumarate.
Properties of Dimethyl fumarate
Melting point: | 102-106 °C (lit.) |
Boiling point: | 192-193 °C (lit.) |
Density | 1,37 g/cm3 |
Flash point: | 192-193°C |
storage temp. | Store below +30°C. |
solubility | 1.6g/l |
form | Liquid |
color | Clear colorless to faintly yellow |
Water Solubility | Soluble in water (1.6 mg/ml at 20°C), methanol (30-36 mg/ml), ethanol (10 mg/ml at 25°C), DMSO (29 mg/ml at 25°C), and DMF (~12 mg/ml). |
Safety information for Dimethyl fumarate
Signal word | Warning |
Pictogram(s) |
Exclamation Mark Irritant GHS07 Environment GHS09 |
GHS Hazard Statements |
H312:Acute toxicity,dermal H315:Skin corrosion/irritation H317:Sensitisation, Skin H335:Specific target organ toxicity, single exposure;Respiratory tract irritation H411:Hazardous to the aquatic environment, long-term hazard |
Precautionary Statement Codes |
P261:Avoid breathing dust/fume/gas/mist/vapours/spray. P264:Wash hands thoroughly after handling. P264:Wash skin thouroughly after handling. P271:Use only outdoors or in a well-ventilated area. P273:Avoid release to the environment. P280:Wear protective gloves/protective clothing/eye protection/face protection. |
Computed Descriptors for Dimethyl fumarate
Abamectin manufacturer
Dr. Reddy's Laboratories Ltd
PANCHSHEEL ORGANICS LTD
Sekhment pharmaventures
Dishman Carbogen Amcis Ltd (Dishman Group)
Honour Lab Limited
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