Pharmacology · Antimetabolites
Methotrexate !
A folate look-alike that blocks DHFR. High doses treat cancers; low once-weekly doses calm rheumatoid arthritis and psoriasis.
Updated 2026-11-01
Also called: amethopterin
The crystal holds methotrexate bound to human DHFR together with NADPH, the enzyme's cofactor.
Mechanism of action
Methotrexate resembles folic acid and binds DHFR far more tightly than its natural substrate, dihydrofolate. Cells run out of tetrahydrofolate, the carrier of one-carbon units needed to make thymidine and purines, so DNA synthesis stops in the S phase. Inside cells it is converted to polyglutamates, which stay in tissues for long periods. How low once-weekly doses calm rheumatoid arthritis is not fully settled; effects on immune cells beyond simple cell killing are thought to matter.
- Mimics folate and binds DHFR very tightly
- Tetrahydrofolate runs out: no thymidine or purines
- DNA synthesis stops in fast-dividing cells
- Tumour cells die; at low doses inflammation settles
Pharmacokinetics
- Absorption
- Oral at low doses; also given subcutaneously, IM, IV and intrathecally.
- Distribution
- Collects in fluid spaces such as ascites or pleural effusions (these are drained before high doses).
- Metabolism
- Converted inside cells to polyglutamates, which persist in tissues.
- Elimination
- Mainly by the kidney, largely unchanged; poor kidney function leads to accumulation and toxicity.
- Half-life
- About 3 to 10 hours at low doses, longer at high doses or with poor kidney function.
Indications
- Rheumatoid arthritis: a cornerstone disease-modifying drug, used once a week at low doses (with folic or folinic acid to reduce side effects). Rheumatoid arthritis →
- Some other autoimmune diseases, such as systemic lupus erythematosus (off-label use). Systemic lupus erythematosus →
- Medical treatment of an unruptured ectopic pregnancy, with close follow-up. Ectopic pregnancy →
- Breast cancer, as part of some combination chemotherapy regimens. Breast cancer →
- Acute lymphoblastic leukaemia, non-Hodgkin lymphoma, osteosarcoma, head and neck cancer and gestational trophoblastic neoplasia; also psoriasis and polyarticular juvenile idiopathic arthritis.
Adverse effects
Common
- Mouth ulcers
- Nausea and tiredness
- Raised liver enzymes
- Hair thinning
Contraindications
- Pregnancy when used for non-cancer diseases (pregnancy testing and contraception are required)
- Severe hypersensitivity to methotrexate
Key interactions
- Sulfonamide antibiotics (such as trimethoprim–sulfamethoxazole) and penicillins
- Reduce methotrexate clearance and increase its toxicity, including marrow suppression.
- NSAIDs and probenecid
- Raise methotrexate levels; severe, even fatal, toxicity has occurred, mainly with high doses.
- Proton pump inhibitors
- May raise methotrexate levels, mainly with high doses.
- Alcohol
- Adds to the risk of liver damage.
What is monitored
- Blood count, liver tests and creatinine at regular intervals
- Pregnancy test before starting
- Methotrexate blood levels after high-dose infusions, to time folinic acid rescue
- New cough or breathlessness (pneumonitis)
Test yourself
Think of the answer, then tap the question to see it.
Why is folinic acid (leucovorin) able to rescue normal cells after high-dose methotrexate?
It is already a reduced folate, so it does not need DHFR, the enzyme methotrexate blocks; it refills the tetrahydrofolate pool.
Why is folic acid often given alongside low-dose methotrexate in rheumatoid arthritis?
It reduces side effects such as mouth ulcers, nausea and liver enzyme rises without removing the benefit for the joints.
A patient on weekly methotrexate is prescribed trimethoprim–sulfamethoxazole. What is the risk?
Higher methotrexate toxicity, especially bone-marrow suppression: sulfonamides reduce its clearance, and trimethoprim is itself a weak DHFR inhibitor.
How does methotrexate work in an unruptured ectopic pregnancy?
Trophoblast cells divide rapidly; blocking DHFR stops their DNA synthesis so the pregnancy tissue stops growing, which is followed with serial β-hCG.
Related drugs
Related conditions
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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Methotrexate: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2025); METHOTREXATE injection, solution (DailyMed (U.S. National Library of Medicine), 2026); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026); eEML - Electronic Essential Medicines List (World Health Organization, 2025).
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Representative model, for educational purposes only.