Methotrexate — Drug Monograph
Brand names: Trexall, Otrexup, Rasuvo, Xatmep
Drug class: Antimetabolite
Mechanism of Action
Folate analog that competitively inhibits dihydrofolate reductase (DHFR), depleting reduced folates required for thymidylate and purine synthesis. At high doses, intracellular polyglutamation prolongs inhibition. Inhibits thymidylate synthase (TS) and aminoimidazole carboxamide ribonucleotide formyltransferase (ATIC) — S-phase specific.
FDA Indications
- Gestational trophoblastic neoplasia (choriocarcinoma, hydatidiform mole)
- Acute lymphocytic leukemia (ALL) — induction, CNS prophylaxis (intrathecal)
- Burkitt lymphoma
- Non-Hodgkin lymphoma
- Breast cancer
- Head and neck carcinoma
- Lung carcinoma
- Osteosarcoma (high-dose regimen)
- Mycosis fungoides
- Rheumatoid arthritis (low-dose anti-inflammatory use)
- Juvenile rheumatoid arthritis
- Psoriasis
Common Side Effects
- Mucositis/stomatitis (dose-limiting at high dose)
- Nausea, vomiting, diarrhea
- Myelosuppression
- Fatigue
- Elevated liver enzymes
- Alopecia
- Rash, photosensitivity
Clinical Pearl
For high-dose MTX, the 72-hour level is the key monitoring point. If >1 μmol/L at 72 hours, increase leucovorin dose and frequency. Glucarpidase (Voraxaze, a carboxypeptidase G2) is the emergency antidote — it rapidly cleaves MTX and is indicated for acute kidney injury with toxic MTX accumulation; give leucovorin ≥2 hours before or after glucarpidase (glucarpidase also degrades leucovorin).
Related Therapies & Mechanisms
- Cyclophosphamide (Cytoxan) — Breast
- Doxorubicin (Adriamycin) — Breast
- Bendamustine (Treanda) — Lymphoma
- Etoposide (VePesid) — Lymphoma