[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Pharmacology](https://durgical.com/en/pharmacology/) › [Antimetabolites](https://durgical.com/en/pharmacology/classes/antimetabolites/) › Methotrexate

[Pharmacology](https://durgical.com/en/pharmacology/) · [Antimetabolites](https://durgical.com/en/pharmacology/classes/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

- Class: [Antimetabolites](https://durgical.com/en/pharmacology/classes/antimetabolites/)
- Enzyme: Dihydrofolate reductase (DHFR)
- ATC code: L01BA01
- WHO Model List of Essential Medicines

Also called: amethopterin

✂**Dihydrofolate reductase (DHFR)**Methotrexate

ⓘ The crystal holds methotrexate bound to human DHFR together with NADPH, the enzyme's cofactor.

**Target in 3D:** Dihydrofolate reductase (DHFR). PDB structure 1U72 (RCSB PDB, public domain). [View the structure at RCSB PDB](https://www.rcsb.org/structure/1U72) · Drag to rotate · pinch to zoom

## 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 →](https://durgical.com/en/conditions/rheumatoid-arthritis/)
- Some other autoimmune diseases, such as systemic lupus erythematosus (off-label use). [Systemic lupus erythematosus →](https://durgical.com/en/conditions/systemic-lupus-erythematosus/)
- Medical treatment of an unruptured ectopic pregnancy, with close follow-up. [Ectopic pregnancy →](https://durgical.com/en/conditions/ectopic-pregnancy/)
- Breast cancer, as part of some combination chemotherapy regimens. [Breast cancer →](https://durgical.com/en/conditions/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

### Serious (rare, important)

- Bone-marrow suppression with infection and bleeding
- Liver fibrosis, cirrhosis or liver failure, worse with alcohol
- Pneumonitis, at any dose
- Kidney damage
- Birth defects and fetal death
- Severe or fatal toxicity when a once-weekly schedule is taken daily by mistake

## 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)

## Memory aid

Methotrexate is a counterfeit key that jams the DHFR lock; folinic acid is a key that has already been cut, so it walks right past the jammed door and the healthy cell carries on.

## 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.

[Add to my cards (4)](https://durgical.app/estudiar/?add=/en/pharmacology/methotrexate/)

## Related drugs

- [Fluorouracil](https://durgical.com/en/pharmacology/fluorouracil/)

## Related conditions

- [Rheumatoid arthritis](https://durgical.com/en/conditions/rheumatoid-arthritis/)
- [Systemic lupus erythematosus](https://durgical.com/en/conditions/systemic-lupus-erythematosus/)
- [Ectopic pregnancy](https://durgical.com/en/conditions/ectopic-pregnancy/)
- [Breast cancer](https://durgical.com/en/conditions/breast-cancer/)

[← Back to the class: Antimetabolites](https://durgical.com/en/pharmacology/classes/antimetabolites/)

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](https://medlineplus.gov/druginfo/meds/a682019.html) (MedlinePlus (U.S. National Library of Medicine), 2025); [METHOTREXATE injection, solution](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a63364d5-4dfa-49d7-8a5e-c8959ae1d37a) (DailyMed (U.S. National Library of Medicine), 2026); [ATCDDD - ATC/DDD Index](https://atcddd.fhi.no/atc_ddd_index/?code=L01BA01) (WHO Collaborating Centre for Drug Statistics Methodology, 2026); [eEML - Electronic Essential Medicines List](https://list.essentialmeds.org/) (World Health Organization, 2025).

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Representative model, for educational purposes only.

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