Clinical Significance

Methotrexate [N-[4[[(2,4-diamino-6-pteridinyl) methyl] methylamino]benzoyl]-L-glutamic acid], formerly Amethopterin, is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Methotrexate has the potential for serious toxicity. Patients undergoing methotrexate therapy should be closely monitored so that toxic effects are detected promptly. Guidelines for methotrexate therapy with leucovorin rescue should be consulted. Intermediate to high doses of methotrexate (approximately 35 mg/m2 - 12 g/m2) with leucovorin (citrovorum-factor) rescue have been used with favorable results in the treatment of osteogenic sarcoma, leukemia, non-Hodgkin’s lymphoma, lung and breast cancer.

No precise relationship between methotrexate serum levels and antineoplastic efficacy has been established, although levels below approximately 2 x 10-8 M were seen as necessary for resumption of DNA synthesis. Following a 4-6 hour intravenous methotrexate infusion, a patient with a 24-hour serum concentration of greater than 50µmol/L, a 48-hour level greater than 10µmol/L , and a 72-hour level greater than 0.5µmol/L is at an increased risk of toxicity if conventional low-dose leucovorin rescue is given. In this case, high-dose leucovorin rescue would be indicated. Guidelines for methotrexate therapy with leucovorin rescue usually recommend continuance of leucovorin until the methotrexate level falls below 0.05 μmol/L. Toxicity typically presents in the form of myelosuppression, stomatitis, nausea, vomiting, convulsions, and liver and renal abnormalities. Anemia, leukopenia, thrombocytopenia, and skin and mucosa involvement with a fatal outcome have also been reported. Neurotoxicity and leukoencephalopathy are also reported as toxic effects involving methotrexate.