Methotrexate pharmacology and toxicity
How low-dose weekly methotrexate works (polyglutamates and adenosine), its saturable absorption and renal clearance, why trimethoprim and daily dosing errors cause pancytopenia, folate supplementation and folinic acid rescue, and the monitoring and pregnancy rules examiners test.
Tier 1Medical sciences concept
Written with AI assistance and fact-checked against the sources below. For exam study, not clinical decisions. How notes are made
At a glance
- Low-dose methotrexate (7.5 to 25 mg once weekly) is the anchor csDMARD for RA and is used in PsA, psoriasis, vasculitis and as a steroid-sparing agent. Onset takes 6 to 12 weeks.
- At these doses the anti-inflammatory effect comes mainly from adenosine release, not DHFR block. High-dose oncology regimens (grams per m²) work by DHFR inhibition and need folinic acid rescue.
- It is renally cleared. Falling GFR, NSAIDs, trimethoprim and dehydration all push levels up.
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Sources
- Therapeutic Guidelines: RheumatologyAU/NZTherapeutic Guidelines Limited, 2025
- Methotrexate patient and prescriber informationAU/NZAustralian Rheumatology Association, 2023
- Australian Medicines HandbookAU/NZAustralian Medicines Handbook Pty Ltd, 2026
- EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2025 updateAnnals of the Rheumatic Diseases, 2026
- BSR guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory anti-rheumatic drugs and corticosteroidsRheumatology (Russell et al.), 2023
- Splitting high-dose oral methotrexate improves bioavailability: a pharmacokinetic study in patients with rheumatoid arthritisJournal of Rheumatology (Hoekstra et al.), 2006;33:481-5, 2006
- Mechanisms of action of methotrexateBulletin of the Hospital for Joint Diseases (Chan and Cronstein), 2013;71 Suppl 1:S5-8, 2013
- Last updated
- 14 November 2026
What changed
- 14 November 2026 Personal emails, About story and Australian-style copy