Toxicology – Methotrexate (MTX) Toxicity

Source

Methotrexate is a folate-antagonist medication used in conditions such as rheumatoid arthritis, psoriasis, certain cancers, and ectopic pregnancy. Toxicity commonly occurs from dosing errors, particularly when a weekly regimen is accidentally taken every day.

Typical Presentation

A patient taking methotrexate develops painful mouth ulcers, nausea, vomiting, abdominal discomfort, and abnormal liver tests after receiving excessive or overly frequent doses.

Clinical Features

Oral methotrexate toxicity may cause:

• Nausea and vomiting
• Stomatitis and oral ulceration
• Bone marrow suppression
• Hepatitis and elevated liver enzymes

High-dose or intravenous exposure may additionally cause:

• Acute kidney injury
• Neurological dysfunction

Risk is increased in older adults, patients with impaired kidney function, those taking other nephrotoxic drugs, and patients with significant third-space fluid collections.

Mechanism of Action

Methotrexate inhibits dihydrofolate reductase (DHFR), reducing formation of biologically active folate. This interferes with DNA synthesis and particularly affects rapidly dividing tissues such as bone marrow and gastrointestinal mucosa.

Management

• Leucovorin (folinic acid rescue) should be started promptly when clinically significant toxicity is suspected.
• Supportive care includes fluids, monitoring of blood counts, kidney function, and liver function.
• Urinary alkalinization and hydration can improve methotrexate elimination in appropriate high-dose toxicity.
• Specialized therapy such as glucarpidase (carboxypeptidase G2) may be used in severe toxicity with delayed clearance, particularly when kidney function is impaired.
• Gastrointestinal decontamination may be considered in selected recent oral exposures.

Key Points

• Accidental daily administration of a medication intended to be taken weekly is a classic cause of methotrexate toxicity.
• Oral ulcers and bone marrow suppression are important warning signs.
• Reduced kidney function increases the risk of severe toxicity because methotrexate is primarily eliminated through the kidneys.
• Leucovorin is the main rescue therapy for significant methotrexate toxicity.