Methotrexate (rINN) abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug used in treatment of cancer and autoimmune diseases. It acts by inhibiting the metabolism of folic acid. Methotrexate replaced the more powerful and toxic antifolate aminopterin, and the two should not be confused with each other.
Although not indicated for this use, methotrexate is also sometimes used (generally in combination with misoprostol) to terminate early pregnancies, particularly ectopic pregnancies. In the case of early missed miscarriage (particularly a blighted ovum), in which fetal demise has occurred but the body has not expelled the fetus, methotrexate may be used to help the body begin the miscarriage process.
It is also sometimes used to treat a rare condition called Behçet's disease where it is taken weekly, along with folic acid daily. In the case of immune disorders, such as Behcet's disease and rheumatoid disorders, the clinical goal of the low dose methotrexate regimen is to inhibit AICAR transformylase, which leads to increased AICA ribose (AICAR transformylase's substrate). The AICA ribose inhibits adenosine deaminase, resulting in a build-up of extracellular adenosine. Extracellular adenosine inhibits the expression of IL-2 receptors on circulating T-lymphocytes, causing a suppression of the immune system, and thus ameliorating the effects of the immune disorder.
Methotrexate is metabolized by intestinal bacteria to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA) and accounts for less than 5% loss of the oral dose.
Factors that decrease absorption include food, oral non-absorbable antibiotics (e.g. vancomycin, neomycin, and bacitracin), and more rapid transit through the Gastrointestinal (GI) tract such as diarrhea, while slower transit time in the GI tract from constipation will increase absorption.
Possible side effects can include anemia, neutropenia, increased risk of bruising, nausea and vomiting, dermatitis and diarrhea. A small percentage of patients develop hepatitis, and there is an increased risk of pulmonary fibrosis.
The higher doses of methotrexate often used in cancer chemotherapy can cause toxic effects to the rapidly-dividing cells of bone marrow and gastrointestinal mucosa. The resulting myelosuppression and mucositis are often prevented (termed Leucovorin "rescue"- as this is the folic acid based drug used)
Methotrexate is a highly teratogenic drug and categorized in Pregnancy Category X by the FDA. Women must not take the drug during pregnancy, if there is a risk of becoming pregnant, or if they are breastfeeding. Men who are trying to get their partner pregnant must also not take the drug. To engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle and men must wait three months.
There is a risk of a severe adverse reaction if penicillin is prescribed alongside methotrexate.
Interestingly, there have also been some reports of central nervous system reactions to methotrexate especially when given via the intrathecal route which include myelopathies and leucoencephalopathies.
Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle. Logically, it therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI & oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these non-cancerous cells as well causing side effects listed above.
Lower doses of methotrexate have been shown to be very effective for the management of rheumatoid arthritis, Crohn's disease, and psoriasis. In these cases inhibition of dihydrofolate reductase (DHFR) is not thought to be the main mechanism, but rather the inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells.