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.
In humans, Tecfidera is extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood and tissues, before it reaches the systemic circulation. Further metabolism occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. A single 240 mg (14)C-dimethyl fumarate dose study identified monomethyl fumarate, fumaric and citric acid, and glucose as the major metabolites in plasma. The downstream metabolism of fumaric and citric acid occurs through the TCA cycle, with exhalation of CO2 serving as a primary route of elimination. Less than 0.1% of the dose is excreted as unchanged dimethyl fumarate in urine.
In humans, dimethyl fumarate is extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, before it reaches the systemic circulation. Further metabolism of monomethyl fumarate (MMF) occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. MMF, fumaric and citric acid, and glucose are the major metabolites in plasma.
IDENTIFICATION AND USE: Dimethyl fumarate is a white to off-white powder formulated into delayed release capsules. It is used for the treatment of patients with relapsing forms of multiple sclerosis. Dimethyl fumarate is also used as a biocide to kill molds that may cause products such as furniture or shoes to deteriorate during storage or transportation in a humid climate. Placed in "Desiccant" sachets inside the furniture or footwear boxes, dimethyl fumarate evaporates and impregnates the product, protecting it from molds. HUMAN EXPOSURE AND TOXICITY: When used as a biocide, dimethyl fumarate has caused painful dermatitis. The fact that in serious cases the dermatitis is particularly difficult to treat adds to the damage. Dimethyl fumarate also has toxicity related to its use as a treatment for multiple sclerosis. A patient with multiple sclerosis who was being treated with dimethyl fumarate developed progressive multifocal leukoencephalopathy (PML), and later died. The patient who died was not taking any other drugs that affect the immune system or drugs that are thought to be associated with PML. Patients taking dimethyl fumarate should be advised to contact their clinician if they develop any symptoms that may be suggestive of PML. Treatment with dimethyl fumarate should not be initiated in patients with signs and symptoms of a serious infection. Dimethyl fumarate was clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes in the absence of metabolic activation. ANIMAL STUDIES: Acute toxicity studies were performed in mice and rats using oral and intraperitoneal routes. In mice, reduced motility, ataxia, dyspnea, cyanosis, muscular hypotonia were observed at oral doses as low as 681 mg/kg. Ataxia and hypopnea were observed at i.p. doses as low as 464 mg/kg. In rats, ataxia, muscular hypotonia, inhibited respiratory rate and motility were noted at oral doses as low as 2610 mg/kg. Reduced food intake and decreased body weight gain were seen at 1470 and 2150 mg/kg, respectively. Ataxia, muscular hypotonia, reduced motility and respiratory rate were also observed at intraperitoneal doses as low as 681 mg/kg. Dyspnea (825 mg/kg); tremor, pilo-erection (1000 mg/kg); abdominal positioning (1470 mg/kg) were also noted. In these studies, the kidneys, forestomach and liver were identified as target organs. In mice, oral administration of dimethyl fumarate (25, 75, 200, and 400 mg/kg/day) for up to two years resulted in an increase in nonglandular stomach (forestomach) and kidney tumors: squamous cell carcinomas and papillomas of the forestomach in males and females at 200 and 400 mg/kg/day; leiomyosarcomas of the forestomach at 400 mg/kg/day in males and females; renal tubular adenomas and carcinomas at 200 and 400 mg/kg/day in males; and renal tubule adenomas at 400 mg/kg/day in females. In rats, oral administration of dimethyl fumarate (25, 50, 100, and 150 mg/kg/day) for up to two years resulted in increases in squamous cell carcinomas and papillomas of the forestomach at all doses tested in males and females, and in testicular interstitial (Leydig) cell adenomas at 100 and 150 mg/kg/day. In rats administered dimethyl fumarate orally (25, 100, 250 mg/kg/day) throughout organogenesis, embryo fetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. This dose also produced evidence of maternal toxicity (reduced body weight). Oral administration of dimethyl fumarate (25, 100, and 250 mg/kg/day) to rats throughout organogenesis and lactation resulted in increased lethality, persistent reductions in body weight, delayed sexual maturation (male and female pups), and reduced testicular weight at the highest dose tested. Neurobehavioral impairment was observed at all doses. In rabbits administered dimethyl fumarate orally (25, 75, and 150 mg/kg/day) throughout organogenesis, embryo lethality and decreased maternal body weight were observed at the highest dose tested. In male rats, oral administration of dimethyl fumarate (75, 250, and 375 mg/kg/day) prior to and throughout the mating period had no effect on fertility; however, increases in non-motile sperm were observed at the mid and high doses. In female rats, oral administration of dimethyl fumarate (20, 100, and 250 mg/kg/day) prior to and during mating and continuing to gestation day 7 caused disruption of the estrous cycle and increases in embryo lethality at the highest dose tested. Testicular toxicity (germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia) was observed at clinically relevant doses in mice, rats, and dogs in subchronic and chronic oral toxicity studies of dimethyl fumarate. Dimethyl fumarate was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay, and it was not clastogenic in the in vivo micronucleus assay in the rat.
In large randomized controlled trials of dimethyl fumarate in patients with psoriasis and multiple sclerosis, serum ALT elevations were frequent, occurring in up to 25% of patients. The elevations, however, were generally mild-to-moderate and resolved rapidly even without dose modification. Elevations above 3 times ULN were reported in 6% of dimethyl fumarate compared to 3% to 6% of placebo recipients. The enzyme elevations were usually transient and not associated with symptoms or jaundice, requiring drug discontinuation in less than 1% of patients. No cases of acute hepatitis or clinically apparent liver injury were reported in the preregistration trials of methyl fumarate. Despite this, several cases of clinically apparent liver injury with jaundice were reported within 2 to 3 years of its approval and more widescale use. Most cases occurred within 2 to 3 months of starting dimethyl fumarate but some instances with more prolonged latency were reported. The typical case presented with acute hepatitis like features, marked increases in serum aminotransferase levels, and only modest alkaline phosphatase elevations. Immunoallergic features and autoantibodies were not frequent and all patients recovered upon stopping the medication with no reported instances of chronic injury or hepatic failure.
Cases of clinically apparent liver injury have not been reported with diroximel or monomethyl fumarate but the clinical experience with these agents has been limited. Because the side effect profiles of these three pro-drugs of monomethyl fumarate are similar, it is suspected that all three are rare causes of clinically apparent liver injury.
Likelihood score for dimethyl fumarate: C (probable rare cause of clinically apparent liver injury).
Likelihood score for diroximel fumarate: E* (unproven but suspected rare cause of clinically apparent liver injury).
Likelihood score for monomethyl fumarate: E* (unproven but suspected rare cause of clinically apparent liver injury).
◉ Summary of Use during Lactation:No information is available on the clinical use of dimethyl fumarate during breastfeeding. However, amounts of the active metabolite of dimethyl fumarate, monomethyl fumarate, in breastmilk appear to be low and would not be expected to cause any adverse effects in breastfed infants. Before any data were available, some authors recommend avoiding breastfeeding during dimethyl fumarate therapy, others and the US manufacturer did not. Breastfed infants should be monitored for adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. Some authors also recommend monitoring breastfed infants for flushing, vomiting and diarrhea.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
◈ What is dimethyl fumarate?
Dimethyl fumarate is a prescription medication used to treat a type of multiple sclerosis (MS) with symptoms that flare up from time to time known as relapsing-remitting multiple sclerosis. Dimethyl fumarate is sometime abbreviated as “DMF”. It is sold under the brand name Tecfidera®. It works by lowering inflammation and preventing the nerve damage that causes symptoms of MS. Dimethyl fumarate is also sometimes used to treat plaque psoriasis.For more information on MS and psoriasis, please see our fact sheets at https://mothertobaby.org/fact-sheets/multiple-sclerosis/ and https://mothertobaby.org/fact-sheets/psoriasis-and-pregnancy/.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.
◈ I take dimethyl fumarate. Can it make it harder for me to get pregnant?
It is not known if dimethyl fumarate can make it harder to get pregnant. Animal studies did not find an effect on female fertility.
◈ Does taking dimethyl fumarate increase the chance for miscarriage?
Miscarriage can occur in any pregnancy for many different reasons. Based on the studies reviewed, it is not known if dimethyl fumarate increases the chance for miscarriage. In the few reported cases of pregnancies exposed to dimethyl fumarate, the rate of miscarriage was similar to what is seen in the general population.
◈ Does taking dimethyl fumarate increase the chance of birth defects?
Every pregnancy starts out with a 3%-5% chance of having a birth defect. This is called the background risk. Dimethyl fumarate has not been well studied for use during pregnancy. There are published data on 39 pregnancies and their outcomes with exposure to dimethyl fumarate. In this small group of pregnancies, a higher rate of birth defects was not reported.
◈ Does taking dimethyl fumarate in pregnancy increase the chance of other pregnancy-related problems?
Based on the studies reviewed, it is not known if dimethyl fumarate can cause other pregnancy-related problems, such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).
◈ Does taking dimethyl fumarate in pregnancy affect future behavior or learning for the child?
Based on the studies reviewed, it is not known if dimethyl fumarate increases the chance for behavior or learning issues.In animal studies of dimethyl fumarate there was no difference in the learning or behavior performance of exposed animals compared to non-exposed animals.
◈ Breastfeeding while taking dimethyl fumarate:
Dimethyl fumarate enters breast milk in small amounts. Because dimethyl fumarate is eliminated from the body quickly, it is recommended that people who choose to breastfeed while using this medication consider waiting 4-5 hours after their dose to breast feed to reduce the amount of medication the baby could receive. If you suspect the baby has any symptoms such as poor weight gain, flushing, vomiting, or diarrhea, contact the child’s healthcare provider. Be sure to talk to your healthcare provider about all of your breastfeeding questions.
◈ If a male takes dimethyl fumarate, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Studies have not been done to see if dimethyl fumarate could affect male fertility or increase the chance of birth defects in humans. In animal studies at low and moderate doses, there was no impact on male fertility. At very high doses in male rats, there was a decrease in sperm motility (the sperm’s ability to move) after the drug was given. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet on paternal exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.
来源:Mother To Baby Fact Sheets
毒理性
暴露途径
这种物质可以通过摄入和透过皮肤被吸收进入人体。
The substance can be absorbed into the body by ingestion and through the skin.
来源:ILO-WHO International Chemical Safety Cards (ICSCs)
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.
The main route of elimination of dimethyl fumarate is by CO<sub>2</sub> exhalation, which accounts for 60% of the dose. The other minor routes of elimination are through the kidney (16% of the dose) and feces (1% of the dose). Trace amounts of unchanged monomethyl fumarate (the active metabolite of dimethyl fumarate) are present in urine.
Monomethyl fumarate (MMF), the active metabolite of dimethyl fumarate, has a rapid clearance. Its apparent clearance (Cl/F) appears to be dose-independent.
After oral administration of Tecfidera, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF). Dimethyl fumarate is not quantifiable in plasma following oral administration of Tecfidera. Therefore all pharmacokinetic analyses related to Tecfidera were performed with plasma MMF concentrations. ... The median Tmax of MMF is 2-2.5 hours. The peak plasma concentration (Cmax) and overall exposure (AUC) increased approximately dose proportionally in the dose range studied (120 mg to 360 mg). Following administration of Tecfidera 240 mg twice a day with food, the mean Cmax of MMF was 1.87 mg/L and AUC was 8.21 mg.hr/L in MS patients.
