methotrexate

Methotrexate is a folate antagonist used in the treatment of certain cancers and autoimmune diseases. It inhibits dihydrofolate reductase, leading to reduced production of thymidylate and purines and impaired DNA synthesis. In cells, the drug is polyglutamated, which prolongs activity and enhances potency. Depending on the indication, it is given in low weekly doses or higher doses, with high-dose regimens often requiring leucovorin rescue to limit toxicity.

Medical uses: In oncology, methotrexate is used for acute lymphoblastic leukemia, certain lymphomas, osteosarcoma, choriocarcinoma, and head and neck cancers. It may be given alone or as part of combination regimens and can be administered intrathecally for central nervous system involvement. In autoimmune diseases, low-dose methotrexate is a mainstay for rheumatoid arthritis, psoriatic arthritis, psoriasis, and inflammatory bowel disease.

Administration and safety: It is available in oral, subcutaneous, intramuscular, intravenous, and intrathecal forms. Drug exposure and toxicity are influenced by kidney function; dehydration and drug interactions can raise levels. Important adverse effects include bone marrow suppression, mucositis, hepatotoxicity (including fibrosis and cirrhosis with prolonged use), nephrotoxicity, and rarely pneumonitis. It is teratogenic and contraindicated in pregnancy. Folic acid supplementation reduces toxicity but can diminish efficacy; monitoring of blood counts, liver enzymes, and renal function is required.

Interactions and monitoring: NSAIDs, certain antibiotics, and proton pump inhibitors can increase methotrexate levels by reducing clearance. Alcohol use increases hepatotoxic risk. High-dose methotrexate requires careful monitoring and hydration; leucovorin rescue is used in regimens with potential toxicity.