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.

Chemical properties

fine white crystalline powder

Originator

Biogen Idec (United States)

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

Definition

ChEBI: Dimethyl fumarate is an enoate ester resulting from the formal condensation of both carboxy groups of fumaric acid with methanol. Used for treatment of adults with relapsing forms of multiple sclerosis. It has a role as an immunomodulator and an antipsoriatic. It is an enoate ester, a methyl ester and a diester. It is functionally related to a methanol and a fumaric acid.

brand name

Tecfidera

Synthesis Reference(s)

Synthetic Communications, 21, p. 223, 1991 DOI: 10.1080/00397919108020815
The Journal of Organic Chemistry, 55, p. 329, 1990 DOI: 10.1021/jo00288a056

General Description

Dimethyl fumarate is a novel oral therapeutic agent, which can be used for patients suffering from relapsing-remitting multiple sclerosis. It shows an effective inhibition of mould in bread and can also serve as a potential candidate for the treatment of psoriasis, a chronic autoimmune condition.

Contact allergens

Dimethylfumarate, a strong irritant, is used as an industrial wide spectrum biocide in Asia and mainly in China, for textiles, leather, seeds, food, and cosmetic ingredients. It provoked a worldwide epidemic of severe contact dermatitis, initially from Chinese sofas sold in Finland, Great Britain, and France. It also induced severe burning and contact allergy due to shoes, and to contaminated clothing as well. This chemical, presents as is (white powder) or as tablets contained in little bags disposed in/or around the materials to protect, progressively evaporates and contaminates the environment. It is forbidden in the European Union since 2008

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.

Clinical Use

Treatment of relapsing-remitting multiple sclerosis
Treatment of moderate to severe plaque psoriasis

Drug interactions

Potentially hazardous interactions with other drugs
Aminophylline and theophylline: enhanced effect of aminophylline and theophylline.
Anaesthetics: enhanced hypotensive effect.
Anti-arrhythmics: increased risk of bradycardia, AV block and myocardial depression with amiodarone; increased risk of bradycardia and myocardial depression with dronedarone.
Antibacterials: metabolism increased by rifampicin; metabolism possibly inhibited by clarithromycin, erythromycin and telithromycin.
Antidepressants: enhanced hypotensive effect with MAOIs; concentration of imipramine and possibly other trycyclics increased
Antiepileptics: effect probably reduced by barbiturates, fosphenytoin, phenytoin, and primidone; enhanced effect of carbamazepine; increased levels of fosphenytoin and phenytoin.
Antifungals: negative inotropic effect possibly increased with itraconazole.
Antihypertensives: enhanced hypotensive effect; increased risk of first dose hypotensive effect of postsynaptic alpha-blockers
Antipsychotics: concentration of lurasidone increased.
Antivirals: concentration increased by atazanavir and ritonavir - reduce dose of diltiazem with atazanavir; concentration reduced by efavirenz; use telaprevir with caution.
Avanafil: possibly increases avanafil concentration.
Beta-blockers: risk of bradycardia and AV block if co-prescribed with beta-blockers.
Cardiac glycosides: increased digoxin concentration.
Ciclosporin: increased ciclosporin concentrations.
Cilostazol: increased cilostazol concentration - avoid.
Colchicine: possibly increased risk of colchicine toxicity - suspend or reduce colchicine, avoid concomitant use in renal or hepatic failure.
Cytotoxics: concentration of bosutinib, ibrutinib and olaparib possibly increased - avoid or reduce dose; possibly increased risk of bradycardia with crizotinib.
Fingolimod: increased risk of bradycardia.
Ivabradine: concentration of ivabradine increased - avoid.
Lipid lowering drugs: concentration of lomitapide possibly increased - avoid.
Sirolimus: sirolimus concentration increased.

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.

Metabolism

Diltiazem is almost completely absorbed from the gastrointestinal tract after oral doses, but undergoes extensive first-pass hepatic metabolism resulting in a bioavailability of about 40%. It is extensively metabolised in the liver, mainly by the cytochrome P450 isoenzyme CYP3A4; one of the metabolites, desacetyldiltiazem, has been reported to have 25-50% of the activity of the parent compound.
About 2-4% of a dose is excreted in urine as unchanged diltiazem with the remainder excreted as metabolites in bile and urine.