Methotrexate, a folate antagonist used in the treatment of cancers, rheumatoid arthritis, and other autoimmune diseases, was first developed in the 1940s and introduced into clinical practice in the 1950s. Its early history is marked by its success as one of the first effective chemotherapy agents for malignancies such as leukemia, followed by its later expansion into low-dose regimens for inflammatory disorders due to its immunosuppressive and anti-inflammatory properties. Methotrexate works by inhibiting dihydrofolate reductase (DHFR), thereby blocking the conversion of folate to its active forms required for DNA synthesis and cell replication, making it particularly effective against rapidly dividing cells. Its widespread clinical use is balanced by significant toxicity risks, including bone marrow suppression, hepatotoxicity, and gastrointestinal adverse effects, which led to the development of strict dosing protocols, folic acid supplementation strategies, and close laboratory monitoring to improve safety during long-term therapy.
BRAND NAMES
Trexall (widely used oral formulation in the U.S.)
Rheumatrex (older brand, especially in oncology/rheumatology use)
Otrexup (subcutaneous auto-injector formulation)
MECHANISM OF ACTION
Methotrexate acts as a folate antagonist by competitively inhibiting the enzyme dihydrofolate reductase (DHFR), which is essential for the conversion of dihydrofolate to tetrahydrofolate. This inhibition leads to depletion of reduced folate cofactors required for the synthesis of purine nucleotides and thymidylate, ultimately suppressing DNA synthesis, repair, and cellular replication.
PHARMACOKINETICS
Absorption
Methotrexate is variably absorbed from the gastrointestinal tract after oral administration, with bioavailability that tends to decrease at higher doses due to saturable absorption. Peak plasma concentrations are generally reached within 1–2 hours.
Distribution
The volume of distribution of methotrexate is approximately 0.4–0.8 L/kg.
For an average adult (≈70 kg), this corresponds to roughly 28–56 liters, though it can vary depending on age, renal function, disease state, and tissue binding.
Metabolism
Methotrexate undergoes limited hepatic metabolism. A small proportion is converted in the liver and intracellularly to 7-hydroxymethotrexate, an active metabolite that is less soluble and can contribute to renal precipitation at high doses.
Elimination
Methotrexate is eliminated primarily through the kidneys by glomerular filtration and active tubular secretion. A significant proportion of the administered dose is excreted unchanged in the urine.
PHARMACODYNAMICS
Methotrexate exerts its effects primarily by inhibiting dihydrofolate reductase (DHFR), leading to depletion of tetrahydrofolate and subsequent suppression of DNA, RNA, and protein synthesis, particularly in rapidly dividing cells. In oncology, this results in inhibition of malignant cell proliferation. In lower doses used for autoimmune conditions, methotrexate promotes accumulation of extracellular adenosine, which has potent anti-inflammatory and immunosuppressive effects.
ADMINISTRATION
Methotrexate can be administered through multiple routes depending on the indication and required dose. It is commonly given orally in tablet form for low-dose therapy in autoimmune conditions. For higher or more reliable systemic exposure, it may be administered subcutaneously, intramuscularly, or intravenously, particularly in oncology settings.
DOSAGE AND STRENGTH
Methotrexate is available in different strengths depending on the formulation. The most common oral tablet strength is 2.5 mg, while the injectable form is commonly available as 25 mg/mL in vials or as prefilled syringes in varying doses. The dosage of methotrexate depends on the medical condition being treated. For rheumatoid arthritis and psoriasis, it is usually prescribed in low doses ranging from 7.5 mg to 25 mg once weekly, either orally or by injection.
DRUG INTERACTIONS
Methotrexate has several important drug interactions that can increase toxicity or reduce its effectiveness. NSAIDs (like ibuprofen, diclofenac) and aspirin in high doses can reduce renal clearance of methotrexate, increasing the risk of bone marrow suppression and kidney toxicity.
FOOD INTERACTIONS
Methotrexate has relatively few direct food interactions, but diet can still influence its safety and tolerability. Alcohol is the most important to avoid or strictly limit because it increases the risk of liver toxicity when combined with methotrexate.
CONTRAINDICATIONS
Methotrexate is contraindicated in patients with known hypersensitivity to the drug or any of its components. It should not be used in pregnancy due to its strong teratogenic effects and risk of fetal loss, and breastfeeding is also contraindicated because the drug can pass into breast milk.
SIDE EFFECTS
Nausea and vomiting
Loss of appetite
Mouth ulcers (stomatitis)
Abdominal discomfort
Fatigue or weakness
Mild hair thinning or hair loss.
OVER DOSE
Methotrexate overdose is a serious medical emergency that can lead to severe toxicity and even death if not treated promptly. It most commonly occurs due to accidental daily intake instead of the prescribed weekly dose or from impaired drug clearance. Symptoms of overdose include severe nausea, vomiting, mouth ulcers, extreme fatigue, fever, and signs of bone marrow suppression such as easy bruising, bleeding, and increased risk of infections.
TOXICITY
Methotrexate toxicity occurs when the drug accumulates in the body, leading to harmful effects on rapidly dividing cells and vital organs. It most commonly affects the bone marrow, gastrointestinal tract, liver, and kidneys. Early signs include mouth ulcers, nausea, vomiting, fatigue, and loss of appetite.
