[(2,3-Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)methylamino]methansulfonsure

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Listed in ZINC15

Breast Feeding; Lactation; Milk, Human; Analgesic Agents; Anti-inflammatory Agents, Nonsteroidal

Pharmaceuticals

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.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

METAMIZOLE

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

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.

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.

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.

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.