NAT2 polymorphisms as a cause of metamizole-induced agranulocytosis

Area of Science:

• Pharmacogenetics
• Toxicology
• Hematology

Background:

• Metamizole is a widely used nonsteroidal anti-inflammatory drug (NSAID) known for its analgesic and antipyretic effects.
• Despite its efficacy, metamizole is restricted in some regions due to the risk of severe agranulocytosis, a dangerous drop in white blood cells.
• Agranulocytosis is a life-threatening condition characterized by a severe reduction in neutrophils, increasing susceptibility to infections.

Purpose of the Study:

• To investigate the potential role of pharmacogenetics in metamizole-associated agranulocytosis.
• To describe clinical cases of patients who developed agranulocytosis after metamizole use.
• To explore the interaction between genetic predisposition, drug metabolism, and hemolysis in the pathogenesis of metamizole-induced agranulocytosis.

Main Methods:

• Case series describing three patients with metamizole-associated agranulocytosis.
• Pharmacogenetic analysis of genes involved in metamizole metabolism (CYP2C9, CYP2C19, NAT2).
• Assessment of potential contributing factors such as infections and surgical procedures leading to hemolysis.

Main Results:

• All three patients exhibited the NAT2 slow acetylator phenotype.
• Patient #2 was an intermediate metabolizer for CYP2C19, and patient #3 was a poor metabolizer for CYP2C9.
• Impaired metabolism of toxic metabolites, such as 4-methylaminoantipyrine (4-MAA), was observed, potentially leading to bone marrow cytotoxicity when complexed with hemin during hemolysis.

Conclusions:

• Metamizole-induced agranulocytosis is likely linked to genetic predispositions, specifically polymorphisms in NAT2, CYP2C9, and CYP2C19.
• Hemolysis, often associated with infections or surgery, may exacerbate the toxicity of metamizole metabolites in genetically susceptible individuals.
• Pharmacogenetic testing could aid in identifying patients at higher risk for metamizole-associated adverse events.