|Systematic (IUPAC) name|
|Pregnancy cat.||D (AU) X (US)|
|Legal status||Prescription Only (S4) (AU) POM (UK) ℞-only (US)|
|Routes||oral, IV, IM, SC, intrathecal|
|Half-life||15 hours (dose dependent)|
|ATC code||L01 L04|
|Mol. mass||454.44 g/mol|
| (what is this?)
Methotrexate (rINN) (pron.: //), abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate began to replace the more toxic antifolate aminopterin starting in the 1950s. The drug was developed by Yellapragada Subbarao.
Medical uses 
Methotrexate was originally developed and continues to be used for chemotherapy either alone or in combination with other agents. It is effective for the treatment of a number of cancers including: breast, head and neck, leukemia, lymphoma, lung, osteosarcoma, bladder, and trophoblastic neoplasms.
Autoimmune disorders 
It is used as a treatment for some autoimmune diseases, including rheumatoid arthritis, Juvenile dermatomyositis, psoriasis, psoriatic arthritis, lupus, Crohn's disease, and many forms of vasculitis, to name a few. Although methotrexate was originally designed as a chemotherapy drug (in high doses), in low doses methotrexate is a generally safe and well tolerated drug in the treatment of certain autoimmune diseases. Because of its effectiveness, low-dose methotrexate is now first-line therapy for the treatment of rheumatoid arthritis. Though methotrexate for autoimmune diseases is taken in lower doses than it is for cancer, side effects such as hair loss, nausea, headaches, and skin pigmentation are still common. Though not everybody is responsive to treatment with methotrexate, multiple studies and reviews showed that the majority of patients receiving methotrexate for up to one year had less pain, functioned better, had fewer swollen and tender joints, and had less disease activity overall as reported by themselves and their doctors. X-rays also showed that the progress of the disease slowed or stopped in many patients receiving methotrexate.
Methotrexate is commonly used (generally in combination with misoprostol) to terminate pregnancies during the early stages (i.e., as an abortifacient). It is also used to treat ectopic pregnancies.
It can be taken orally or administered by injection (intramuscular, intravenous, subcutaneous, or intrathecal). Oral doses are taken weekly not daily. Routine monitoring of the complete blood count, liver function tests, and creatinine are recommended. Measurements of creatinine are recommended at least every 2 months.
Adverse effects 
The most common adverse effects include: ulcerative stomatitis, low white blood cell count and thus predisposition to infection, nausea, abdominal pain, fatigue, fever, dizziness, acute pneumonitis and rarely pulmonary fibrosis.
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. To engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle.
Central nervous system reactions to methotrexate have been reported, especially when given via the intrathecal route which include myelopathies and leucoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses.
Generally, the more "nonspecific" action a pharmacological substance has, the more possible side effects can be expected. Methotrexate has, like all cytotoxic substances, a broad array of possible adverse effects. Care should always be taken to read the manufacturer's original instructions for the preparation in question.
Drug interactions 
Penicillins may decrease the elimination of methotrexate and thus increase the risk of toxicity. While they may be used together increased monitoring is recommended. Probenecid inhibits methotrexate excretion, which increases the risk of methotrexate toxicity. Additionally, methotrexate neurotoxicity—which may cause seizures—is known to be induced by phenobarbital and carbamazepine, which are antiepileptic drugs. Its effects can be reversed by folinic acid (leucovorin) in a process known as "leucovorin rescue."
Mechanism of action 
Methotrexate is thought to affect cancer and rheumatoid arthritis by two different pathways. For cancer, methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about one thousand-fold that of folate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.
Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle. It therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and gastrointestinal and oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these noncancerous cells, as well as causing the listed side effects. Facing a scarcity of dTMP, rapidly dividing cancerous cells undergo cell death via thymineless death.
For the treatment of rheumatoid arthritis, inhibition of 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. In these cases, patients should supplement their diets with folate.
In its low-dose regimen methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells.
Methotrexate is a weak dicarboxylic acid with pKa 4.8 and 5.5, and thus it is mostly ionized at physiologic pH. Oral absorption is saturatable and thus dose-dependent, with doses less than 40 mg/m2 having 42% bioavailability and doses greater than 40 mg/m2 only 18%. Mean oral bioavailability is 33% (13-76% range), and there is no clear benefit to subdividing an oral dose. Mean intramuscular bioavailability is 76%.
Methotrexate is metabolized by intestinal bacteria to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA), which accounts for less than 5% loss of the oral dose.
Factors that decrease absorption include food, oral nonabsorbable antibiotics (e.g. vancomycin, neomycin, and bacitracin), and more rapid transit through the gastrointestinal tract (GI) tract, such as diarrhea, while slower transit time in the GI tract from constipation will increase absorption. Methotrexate is also administered in the placenta accreta, inhibiting the blood circulation to the target site.
In 1947, a team of researchers led by Sidney Farber showed aminopterin, a chemical analogue of folic acid developed by Yellapragada Subbarao of Lederle, could induce remission in children with acute lymphoblastic leukemia. The development of folic acid analogues had been prompted by the discovery that the administration of folic acid worsened leukemia, and that a diet deficient in folic acid could, conversely, produce improvement; the mechanism of action behind these effects was still unknown at the time. Other analogues of folic acid were in development, and by 1950, methotrexate (then known as amethopterin) was being proposed as a treatment for leukemia. Animal studies published in 1956 showed the therapeutic index of methotrexate was better than that of aminopterin, and clinical use of aminopterin was thus abandoned in favor of methotrexate.
In 1951, Jane C. Wright demonstrated the use of methotrexate in solid tumors, showing remission in breast cancer. Wright's group were the first to demonstrate use of the drug in solid tumors, as opposed to leukemias, which are a cancer of the marrow. Min Chiu Li et al then demonstrated complete remission in women with choriocarcinoma and chorioadenoma in 1956, and in 1960 Wright et al produced remissions in mycosis fungoides.
The drug was then investigated as a treatment for many other cancers, alone or in combination with other drugs, and was studied for other, noncancer indications in the 1970s. In 1988, it was approved by the U.S. Food and Drug Administration (FDA) to treat rheumatoid arthritis.
In 2011, Ben Venue Laboratories shut down their production of injectable preservative-free methotrexate, leading to a shortage of the form of the drug commonly used to treat childhood Acute lymphoblastic leukemia.
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- National Rheumatoid Arthritis Society (NRAS) article on Methotrexate
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