 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C13H17N3O4S |
| Molecular Weight | 311.36 |
| Exact Mass | 311.094 |
| CAS # | 50567-35-6 |
| PubChem CID | 3111 |
| Appearance | Typically exists as solid at room temperature |
| Density | 1.379g/cm3 |
| Index of Refraction | 1.611 |
| LogP | 1.846 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 21 |
| Complexity | 546 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | CC1=C(C(=O)N(N1C)C2=CC=CC=C2)N(C)CS(=O)(=O)O |
| InChi Key | LVWZTYCIRDMTEY-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C13H17N3O4S/c1-10-12(14(2)9-21(18,19)20)13(17)16(15(10)3)11-7-5-4-6-8-11/h4-8H,9H2,1-3H3,(H,18,19,20) |
| Chemical Name | [(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)-methylamino]methanesulfonic acid |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vivo | Metamizo (Methamizole; 100 mg/kg; ip; once; male Swiss albino mice) increases the activity of the enzyme alanine aminotransferase (ALT) in the serum, a sign of hepatotoxicity[1]. The amount of glutathione (GSH) in the liver of male Swiss albino mice is reduced by metamizo (100 mg/kg; ip; once)[1]. |
| Animal Protocol |
Animal/Disease Models: Male Swiss albino mice (6 weeks old, 25-40 g)[1] Doses: 100 mg/kg Route of Administration: intraperitoneal (ip) injection; once Experimental Results: Increased serum ALT level at 5 hrs (hours) and the maximum serum ALT levels occurred at 5 hrs (hours). Animal/Disease Models: Male Swiss albino mice (6 weeks old, 25-40 g)[1] Doses: 100 mg/kg Route of Administration: intraperitoneal (ip) injection; once Experimental Results: Induced reduction in hepatic glutathione (GSH) content in mice. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Metamizole is hydrolyzed to 4-methyl-amino-antipyrine (MAA) in gastric juice and is mostly absorbed in this form. MAA bioavailability differs based on the administration route. In patients given metamizole tablets, the bioavailability of MAA is 85%, in patients given drops, 89%, in patients given suppositories, 54%, and in patients given an intramuscular injection, 87%. There is a linear relationship between metamizole oral dose and MAA Cmax. After oral doses ranging between 0.75 and 3 g, the tmax is reached at 1.4-2.0 hours. After intravenous or oral administration, 90% of metamizole is recovered in urine, while 10% is recovered in feces. Approximately 60% of four metamizole metabolites (4-methyl-amino-antipyrine, 4-formyl-amino-antipyrine, 4-amino-antipyrine and 4-acetyl-amino-antipyrine) are excreted through urine. Metamizole is quickly metabolized into 4-methyl-amino-antipyrine (MAA), its active metabolite. MAA has a volume of distribution of 1.15 L/kg. The clearance of 4-methyl-amino-antipyrine (MAA), the active metabolite of metamizole, ranges from 110 mL/min to 180 mL/min after oral administration. Metabolism / Metabolites Metamizole undergoes rapid hydrolysis to the active moiety 4-methyl-amino-antipyrine (MAA). MAA is then metabolized to 4-formyl-amino-antipyrine (FAA) via c-oxidation and 4-amino-antipyrine (AA) via N-demethylation. The N-demethylation of MAA is mainly mediated by CYP3A4, although CYP2B6, CYP2C8 and CYP2C9 may also be involved. FAA is an end metabolite, while AA is acetylated by N-acetyl-transferase to form 4-acetyl-amino-antipyrine (AAA). The unchanged drug may be present in plasma following the intravenous administration of metamizole; however, following oral administration, it cannot be detected in plasma or urine. Biological Half-Life _In vitro_, the half-life of metamizole is 16 minutes. The half-life of 4-methyl-amino-antipyrine (MAA), its active metabolite, ranges from 2.6 to 3.5 hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity Cases of liver injury from metamizole were rarely reported before 2019 when two case series of liver injury from its use including fatalities were reported from Germany. Reassessments were conducted by the European Medicines Agency based upon accumulation of more than 40 cases. Within a year or two, reviews of more than 50 cases of clinically apparent liver injury due to metamizole were described. The clinical features of metamizole-associated liver injury have varied greatly, some being hyper-acute with rapid onset of fever, rash, and jaundice after the initial or first several doses. These cases may represent hypersensitivity reactions such as hepatic involvement in DRESS syndrome, toxic epidermal necrolysis, or Stevens-Johnson syndrome. In other instances, metamizole induced liver injury arises during more prolonged therapy after a latency of 2 to 16 weeks, manifested by the gradual onset of fatigue, nausea, anorexia, and right upper quadrant discomfort followed by dark urine and jaundice. The enzyme elevations are typically hepatocellular, but mixed and even cholestatic patterns have been described. The disease is usually self-limited with rapid improvement once metamizole is stopped. Rash, fever, and eosinophilia arise in some cases but are generally transient and mild. Autoantibodies including ANA and AMA are frequently detected, but IgG levels are usually normal and liver histology does not resemble autoimmune hepatitis. Recovery is usually rapid once metamizole is stopped and rarely requires immunosuppressive therapy. As might be expected, the fatality rate appears to be at least 10% in cases with hepatocellular injury and jaundice. There have been reports of fatalities and need for liver transplants due to liver injury caused by the drug. Recurrence upon re-exposure is usually abrupt in onset and more severe in course than the initial episode. Likelihood score: A (well described although rare cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation After ingestion by the mother, dipyrone and its metabolites appear in breastmilk in rather large amounts. It is found in the blood and urine of breastfed infants and can cause pharmacological effects in the breastfed infant. One case of cyanotic episodes in a breastfed infant was attributed to dipyrone in breastmilk. The drug and metabolites are eliminated from the breastmilk by 48 hours after a dose. Dipyrone is not approved for marketing in the United States by the U.S. Food and Drug Administration nor in Canada and many European countries because of its adverse reactions, including agranulocytosis. However, it is widely used in other countries during labor and breastfeeding. The European Medicines Agency recommends that dipyrone not be used in nursing mothers; however, several drug consultation centers in Israel disagree. One manufacturer recommends to withhold breastfeeding for 48 hours after a dose. Safer alternatives are available for analgesia during breastfeeding. ◉ Effects in Breastfed Infants A 42-day-old breastfed infant had 2 cyanotic episodes within 30 minutes after his mother took 3 doses of dipyrone 500 mg orally, 18, 7 and 2 hours before the first episode. A third episode occurred 24 hours after admission to the hospital. Dipyrone was detected in the mother's breastmilk 24 hours after the last dose and in the infant's serum and urine. No explanation could be found for the cyanotic episodes other than dipyrone and after suspending maternal dipyrone intake, no further episodes occurred in the infant up to age 3 years. The reaction is rated as possibly caused by dipyrone in breastmilk. In a blinded study, mothers who were at least 3 days postpartum and requesting analgesia for postpartum uterine pain were given either 1 gram of dipyrone or placebo. The infants of mothers who received dipyrone cried fewer times and for shorter durations in the 14 hours after drug administration than the infants of mothers who received placebo. This effect was more apparent in infants who demand fed than in those who fed on a fixed schedule. Although this study appears to demonstrate a pharmacologic effect in the infants from dipyrone in milk, there is no clear explanation for the change in infant behavior. A multicenter case-control study in Brazil compared 231 children who developed leukemia before 2 years of age with 411 children with various other nonmalignant diseases. Mothers were interviewed to ascertain their analgesic use during pregnancy and lactation. Nursing mothers who took dipyrone during the three months after delivery had a 2-fold risk of having a child with acute lymphocytic leukemia and a 3.87-fold risk in having rearrangement of the MLL gene in infants under one year of age. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding The protein binding of metamizole and its metabolites is low, with an average of 60% for the metabolites 4-methyl-amino-antipyrine, 4-formyl-amino-antipyrine, 4-amino-antipyrine and 4-acetyl-amino-antipyrine. |
| References |
[1]. Effects of Enzyme Induction and/or Glutathione Depletion on Methimazole-Induced Hepatotoxicity in Mice and the Protective Role of N-Acetylcysteine. Adv Pharm Bull. 2014;4(1):21-8. |
| Additional Infomation |
Metamizole is a pyrazole that is antiipyrine substituted at C-4 by a methyl(sulfomethyl)amino group, the sodium salt of which, metamizole sodium, was widely used as a powerful analgesic and antipyretic, but withdrawn from many markets from the 1970s due to a risk of causing risk of causing agranulocytosis. It has a role as an antipyretic, an antirheumatic drug, a non-narcotic analgesic, a peripheral nervous system drug, a prodrug, a cyclooxygenase 3 inhibitor and an anti-inflammatory agent. It is a member of pyrazoles and an amino sulfonic acid. It is functionally related to an antipyrine. It is a conjugate acid of a metamizole(1-). Metamizole (dipyrone) is a pyrazolone derivative that belongs to the group of nonacid nonopioids. It is considered a potent analgesic and antipyretic with favourable gastrointestinal tolerability. Metamizole was formerly marketed in the US as Dimethone tablets and injection, Protemp oral liquid, and other drug products, and was withdrawn due to its association with potentially fatal agranulocytosis. Approvals of the NDA's for metamizole drug products were withdrawn on June 27, 1977 (see the Federal Register of June 17, 1977, 42 FR 30893). In 1963, metamizole was withdrawn from the Canadian market and banned in the UK, France, Sweden, Norway and Australia. Metamizole is still used in certain countries in Europe, Asia and South America. Metamizole, also known as dipyrone, is an oral analgesic that is not available in the United States but is available over-the-counter in many countries of the world. Therapy with metamizole has been associated with rare severe bone marrow and liver adverse events including agranulocytosis, acute hepatitis, and acute liver failure. A drug that has analgesic, anti-inflammatory, and antipyretic properties. It is the sodium sulfonate of AMINOPYRINE. See also: Dipyrone (active moiety of). Drug Indication Metamizole is banned in several countries, where it was previously used as a powerful analgesic and fever reducer. In countries where it is still available, metamizole is indicated for acute severe pain after injuries or surgeries, colic, tumor pain, and acute or severe pain symptoms, as well as high fever if other treatments are unsuccessful. Mechanism of Action The mechanism of action of metamizole is not fully understood. Its active metabolites, 4-methyl-amino-antipyrine (MAA) and 4-amino-antipyrine (AA), inhibit prostaglandin E2 (PGE2)-induced hyperalgesia. It has been suggested that the anti-hyperalgesic effect of MAA is mediated by guanosine 3',5'-cyclic monophosphate (cGMP) activation and ATP-sensitive potassium channel opening, while the effects of AA are associated with the activation of cannabinoid receptor type 1 (CB1). Metamizole is classified in some sources as a weak non-steroidal anti-inflammatory drug (NSAID); however, evidence suggests that its analgesic effects do not depend on its anti-inflammatory properties. Although the inhibition of cyclooxygenase (COX) 2 may play a role in the central nervous system effects of metamizole, reports suggest that metamizole inhibits COX-3 with a higher affinity compared to COX-1 or COX-2. Pharmacodynamics Metamizole is a strong analgesic and antipyretic with spasmolytic properties. It has weak anti-inflammatory or antithrombotic properties and does not follow the same mechanism of action as conventional non-steroidal anti-inflammatory drugs (NSAIDs). Metamizole can lead to agranulocytosis, a life-threatening side effect where a patient’s neutrophil count falls below 500 cells per microliter. It has been shown that metamizole-induced agranulocytosis is caused by the development of drug-dependent anti-neutrophil antibodies requiring covalent binding of neutrophils to metamizole and its metabolites. |
Solubility Data
| Solubility (In Vitro) | 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 |
| Solubility (In Vivo) |
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 Formulations (e.g. IP/IV/IM/SC) 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). 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 Formulations 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). 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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2117 mL | 16.0586 mL | 32.1172 mL | |
| 5 mM | 0.6423 mL | 3.2117 mL | 6.4234 mL | |
| 10 mM | 0.3212 mL | 1.6059 mL | 3.2117 mL |