Methotrexate is a folic acid antagonist that inhibits dihydrofolate reductase, an enzyme essential for the synthesis of purines and pyrimidines. This inhibition blocks DNA synthesis (and also RNA and protein synthesis), mainly during the S-phase of cell division. Its effects on normal tissues can be reduced with appropriately timed leucovorin (folinic acid) rescue. The diagram below shows how the formation of tetrahydrofolate (FH₄) is inhibited by methotrexate and how the administration of folinic acid (leucovorin) can be used to reduce toxicity or act as rescue therapy by bypassing the inhibition of FH₄. Created in BioRender. Boucher, M. (2026) https://BioRender.com/fober0v Fig 1: Mechanism of action of methotrexate and folinic acid Pharmacokinetics The pharmacokinetics of methotrexate is described in the table below: Parameter Methotrexate (oral tablets) Absorption Rapid at low doses (≤30 mg/m²) with high bioavailability (80–100%); Tmax~ 1-2 h; absorption saturates at doses >30 mg/m² and is incomplete >80 mg/m². Distribution ~50% protein bound (reversible); widely distributed to tissues; readily enters intracellular space. Distributes into breastmilk and across the placenta. Metabolism Minimal; minor biliary excretion with pronounced enterohepatic circulation; most remains as unchanged drug. Excretion Mainly renal; ~41% excreted unchanged in urine within 6 hours, 90% within 24 hours; minor biliary excretion. Half-life 3–10 h (low dose), 8–15 h (high dose); accumulation can occur in renal impairment. Indications For Use Methotrexate has several indications for use and dose ranges. Once-weekly Use (non-oncological): Crohn’s disease Rheumatoid arthritis Severe psoriasis It is an NHS never event if patients who are taking methotrexate for a non-cancer treatment are given more than their intended weekly dose. To prevent dosing errors the following steps should be taken: Patients or carers should be clearly informed about the dose and purpose Only one tablet strength should be used Prescriptions and labels must clearly state dose and frequency Patients should be told to report signs of blood, liver, or respiratory toxicity immediately. Methotrexate can also be given once weekly in some cancer therapy regimens, but is more likely to be used at higher doses for the treatment of cancer. Use in Cancer Methotrexate can be used to treat several cancer types including breast cancer, head and neck cancer, lung cancer and acute lymphoblastic leukemia. The Role of Folic / Folinic Acid For non-oncological indications, folic acid 5mg once weekly is usually given alongside methotrexate (on different days of the week) to reduce side effects (particularly mucosal and gastrointestinal) and prevent hepatotoxicity. If folic acid and methotrexate are taken on the same day, the efficacy of methotrexate may be reduced due to decreased absorption. Folinic acid (calcium folinate) can be used in acute toxicity to treat mucositis and myelosuppression Counselling Methotrexate is teratogenic. Females should use effective contraception for at least 6 months after the last dose and males for 3 months. Patients should report symptoms and signs suggestive of infection, especially sore throat, which can also be a sign of blood disorders Cautions Dehydration (increases risk of toxicity) Diarrhoea (may indicate gastrointestinal toxicity) Blood disorders Peptic ulcer disease (avoid in active disease) Ulcerative colitis Renal impairment (decreased clearance) Psychiatric disorders Contraindications Active infection, often held during treatment with antimicrobials Ascites Immunodeficiency syndromes Significant pleural effusion – risk of accumulation due to prolonged t ½ up to 4 times Adverse events Between 7–30% of patients stop methotrexate within the first year because of adverse effects, which also reduce adherence; many side effects are related to its folate antagonism. Regular monitoring is vital due to this; full blood count (FBC) and liver function tests (LFTs) should be taken every 1–2 weeks until stable, then every 2–3 months Phototoxicity Appearing like severe sunburn. Patients should avoid UV exposure, use high-SPF sunscreen and protective clothing, and consult a healthcare professional if any skin reaction occurs. Bone Marrow Suppression: Bone marrow suppression may occur suddenly, especially in older patients, those with renal impairment, or taking other anti-folate drugs; significant drops in white cells (leucopenia) or platelets (thrombocytopenia) require immediate methotrexate withdrawal and supportive treatment. Monitor for sore throat, bruising, mouth ulcers Liver Toxicity Liver cirrhosis has been reported; methotrexate should not be started or should be stopped if liver abnormalities occur, as these may resolve within 2 weeks, allowing possible restart, while persistent transaminase elevations may require dose reduction or discontinuation. Usually associated with chronic hepatic disease Monitor for nausea, vomiting, abdominal discomfort and dark urine Pulmonary Toxicity Pulmonary toxicity can occur, particularly in rheumatoid arthritis; patients should seek care for breathlessness, cough, or fever, be monitored regularly, and stop methotrexate if pneumonitis is suspected. Other Renal damage leading to acute renal failure Opportunistic infections Adverse Effects of Note in Cancer Treatment Alopecia: Rare at standard doses but common with high-dose therapy; usually temporary. Scalp cooling may reduce severity. Tumour lysis syndrome (TLS): May occur early in treatment, affecting renal and cardiac function. Prevention and management include regular blood tests, adequate hydration, allopurinol or rasburicase, and maintaining fluid intake of at least 2 litres daily. Interactions Methotrexate has extensive drug interactions that can increase toxicity or reduce efficacy, mainly by reducing renal clearance, increasing protein binding displacement, or worsening bone marrow, liver, or kidney toxicity. Reduced Renal Excretion → Increased Toxicity: NSAIDs (e.g. aspirin*, ibuprofen, naproxen), PPIs (omeprazole, pantoprazole), diuretics (loop diuretics, thiazides), probenecid, antibiotics (penicillins, sulfonamides, ciprofloxacin, cefalotin), cisplatin, and antiseizure medications (levetiracetam, phenytoin and sodium valproate) can reduce methotrexate clearance. Aspirin given as an antiplatelet can be continued in people taking methotrexate Bone Marrow Suppression Risk: Increased with other antifolate or haematotoxic drugs (trimethoprim, co-trimoxazole, sulfonamides, chloramphenicol, pyrimethamine, azathioprine, leflunomide, metamizole) Bone marrow suppression with trimethoprim/co-trimoxazole and methotrexate has been reported to occur 2 months after giving concomitantly; if given together FBC monitoring should continue during and for at least 2 months after stopping therapy Hepatic Toxicity: Risk increased with alcohol, retinoids & related compounds (acitretin/etretinate/isotretinoin), sulphasalazine, leflunomide, fluconazole, statins, terbinafine and tamoxifen Nephrotoxicity: Increased with nephrotoxic chemotherapy (e.g. cisplatin) and cytotoxic combinations. Reduced Methotrexate Efficacy: Folic acid supplements, caffeine/theophylline, and some antibiotics affecting gut flora may reduce absorption or effects Other Important Interactions: Live vaccines: contraindicated (risk of severe infection) Ciclosporin: excessive immunosuppression and toxicity Mercaptopurine: increased plasma levels (dose adjustment required) Phenytoin and sodium valproate: reduced efficacy reported, monitoring of phenytoin levels recommended Theophylline: decreased clearance, monitoring of theophylline levels recommended References Methotrexate | Drugs | BNF | NICE Accessed 5/2/26 Methotrexate 10 mg Tablets – Summary of Product Characteristics (SmPC) – (emc) | 11723 Accessed 5/2/26 Methotrexate | Macmillan Cancer Support Accessed 5/2/26 Methotrexate Sodium (Cancer Treatment) – NCI Accessed 5/2/26 Managing interactions with methotrexate – NHS SPS – Specialist Pharmacy Service – The first stop for professional medicines advice Accessed 7/2/26 Using folic acid with methotrexate in rheumatoid arthritis – NHS SPS – Specialist Pharmacy Service – The first stop for professional medicines advice Accessed 7/2/26 Methotrexate once-weekly for autoimmune diseases: new measures to reduce risk of fatal overdose due to inadvertent daily instead of weekly dosing – GOV.UK Accessed 7/2/26 Do you think you’re ready? Take the quiz below Pro Feature - Quiz Methotrexate Question 1 of 3 Submitting... Skip Next Rate question: You scored 0% Skipped: 0/3 More Questions Available Upgrade to TeachMePharmacy Pro Challenge yourself with over 200 multiple-choice questions to reinforce learning. Learn More Rate This Article