Brands, Medical Use, Clinical Data
- Antirheumatic Agents
- Immunosuppressive Agents
- Dermatologic Agents
- Abortifacient Agents
- Antineoplastic Agents
- Powder for solution
- Tablet (oral, in 5 mg, 7.5 mg, or 10 mg)
Brands / Synonyms
Abitrexate; Amethopterin; Amethopterine; Antifolan; Arbitrexate; Emtexate; Folex; Folex Pfs; HDMTX; L-Amethopterin; Ledertrexate; Metatrexan; Methopterin; Methotextrate; Methotrate; Methotrexat; Methotrexate; Methotrexate for Injection; Methotrexate Lpf; Methotrexate Preservative Free; Methotrexate Sodium; Methotrexate, Usp Grade; Methylaminopterin; Methylaminopterinum; Mexate; Mexate-Aq; Mexate-Aq Preserved; MTX; N-Bismethylpteroylglutamic Acid; Rheumatrex; Rheumatrex Dose Pack; Trexall
For the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. Also for the treatment of severe psoriasis and severe, active, classical or definite rheumatoid arthritis.
Methotrexate is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Methotrexate inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid. At two stages in the biosynthesis of purines and at one stage in the synthesis of pyrimidines, one-carbon transfer reactions occur which require specific coenzymes synthesized in the cell from tetrahydrofolic acid. Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Methotrexate selectively affects the most rapidly dividing cells (neoplastic and psoriatic cells). Methotrexate is also indicated in the management of severe, active, classical, or definite rheumatoid arthritis.
Mechanism of Action
Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.
Generally well absorbed with a mean bioavailability of about 60%.
Symptoms of overdose include bone marrow suppression and gastrointestinal toxicity. LD50=43mg/kg(orally in rat).
Biotrnasformation / Drug Metabolism
Methotrexate can cause fetal death or teratogenic effects when administered to a pregnant woman. Methotrexate is
contraindicated in pregnant women with psoriasis or rheumatoid arthritis and should be used in the treatment of
neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Women of childbearing potential
should not be started on methotrexate until pregnancy is excluded and should be fully counseled on the serious risk
to the fetus should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is
receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for
at least one ovulatory cycle after therapy for female patients.
Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is
contraindicated in nursing mothers.
Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver
disease should not receive methotrexate.
Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency
syndromes should not receive methotrexate.
Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow
hypoplasia, leukopenia, thrombocytopenia or significant anemia, should not receive methotrexate.
Patients with a known hypersensitivity to methotrexate should not receive the drug.
Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and
prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity.
Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of
methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and
may enhance its toxicity.
Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually
included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated,
however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in
psoriasis and that larger doses could lead to unexpected toxicity.
Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain
drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished
by probenecid; use of methotrexate with this drug should be carefully monitored.
Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease
intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and
suppressing metabolism of the drug by bacteria.
Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with
concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of
methotrexate with penicillins should be carefully monitored.
The potential for increased hepatotoxicity when methotrexate is administered with other
hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore,
patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g., azathioprine,
retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.
Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used
concurrently with methotrexate.
Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered
methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered
leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and in humans, remain 1 - 3 orders of magnitude lower
than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin
may reduce the efficacy of intrathecally administered methotrexate.
Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been reported
rarely to increase bone marrow suppression in patients receiving methotrexate, probably by an additive antifolate