|Systematic (IUPAC) name|
|Licence data||US FDA:|
|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 (INN, BAN and USAN) //, 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 Subbarow.
- 1 History
- 2 Medical uses
- 3 Adverse effects
- 4 Mechanism of action
- 5 Pharmacokinetics
- 6 References
- 7 External links
In 1947, a team of researchers led by Sidney Farber showed aminopterin, a chemical analogue of folic acid developed by Yellapragada Subbarow 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.
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.
It is used as a treatment for some autoimmune diseases, including rheumatoid arthritis, Juvenile dermatomyositis, psoriasis, psoriatic arthritis, lupus, sarcoidosis, Crohn's disease, eczema, and many forms of vasculitis. 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.
There are no reports of toxicity following acute oral ingestions and most cases with severe effects are from dosing interval errors (dose administered daily instead of weekly). High-dose intravenous methotrexate chemotherapy with acute kidney failure can result in severe toxicity. Inadvertent intrathecal overdose can result in severe and life-threatening CNS toxicity.
Single acute oral ingestion
Ingestion of less than 500 mg methotrexate in adults, or less than 5 mg/kg methotrexate in children, is unlikely to cause toxicity.
Repeat oral ingestion
Oral methotrexate is most toxic when the dosing interval is decreased, most commonly as an error from weekly to daily, especially if weekly doses are taken for more than 3 consecutive days.
Intravenous administration (chemotherapeutic use)
Intravenous methotrexate doses more than 400 mg/m2 generally require rescue calcium folinate therapy. Such high doses should be monitored by an oncologist. In rare cases, high-dose intravenous methotrexate can cause acute kidney failure. This is a life threatening toxicity and immediate treatment with antidotal therapy is indicated.
A clinical error where an intravenous preparation is given intrathecally will result in over administration. Whilst an uncommon error, it can rapidly develop into a life-threatening neurotoxicity.
Systemic effects of methotrexate poisoning include:
- Gastrointestinal effects—dose-related nausea and vomiting; gastrointestinal epithelial damage with severe stomatitis, diarrhoea and gastrointestinal bleeding. Hepatotoxicity occurs in severe cases
- Bone marrow toxicity—myelosuppression is worst 7 to 14 days after onset of toxicity
- CNS toxicity (particularly with intrathecal overdose)—seizures, coma, chemical meningitis.
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.
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.
- "Methotrexate". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
- Bertino JR (2000). "Methotrexate: historical aspects". In Cronstein BN, Bertino JR. Methotrexate. Basel: Birkhäuser. ISBN 978-3-7643-5959-1. Retrieved November 21, 2009.[page needed]
- Meyer, Leo M.; Miller, Franklin R.; Rowen, Manuel J.; Bock, George; Rutzky, Julius (1950). "Treatment of Acute Leukemia with Amethopterin (4-amino, 10-methyl pteroyl glutamic acid)". Acta Haematologica 4 (3): 157–67. doi:10.1159/000203749. PMID 14777272.
- Wright, Jane C.; Prigot, A.; Wright, B.P.; Weintraub, S; Wright, LT (1951). "An evaluation of folic acid antagonists in adults with neoplastic diseases. A study of 93 patients with incurable neoplasms". J Natl Med Assoc 43 (4): 211–240. PMC 2616951. PMID 14850976.
- Li, MC; Li, R; Spencer, DB (1956). "Effect of methotrexate upon choriocarcinoma". Proc Soc Exp Biol Med 93 (2): 361–366. doi:10.3181/00379727-93-22757. PMID 13379512.
- Wright, JC; Gumport, SL; Golomb, FM (1960). "Remissions produced with the use of methotrexate in patients with mycosis fungoides". Cancer Chemother Rep 9: 11–20. PMID 13786791.
- Wright, JC; Lyons, M; Walker, DG; Golomb, FM; Gumport, SL; Medrek, TJ (1964). "Observations on the use of cancer chemotherapeutic agents in patients with mycosis fungoides". Cancer 17 (8): 1045–1062. doi:10.1002/1097-0142(196408)17:8<1045::AID-CNCR2820170811>3.0.CO;2-S. PMID 14202592.
- Harris, Gardiner. "Supply of a Cancer Drug May Run Out Within Weeks." New York Times. February 10, 2012.
- Cronstein, B. N. (2005). "Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis". Pharmacological Reviews 57 (2): 163–172. doi:10.1124/pr.57.2.3. PMID 15914465.
- American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines (2002) Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum 46: 328-346.
- Based on Suarez-Almazor M, Osiri M, Emery P, Ottawa Methods Group. Rheumatoid arthritis. In Evidence-based Rheumatology. London: BMJ Books, 2003.
- Mol, F.; Mol, B.W.; Ankum, W.M.; Van Der Veen, F.; Hajenius, P.J. (2008). "Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis". Human Reproduction Update 14 (4): 309–19. doi:10.1093/humupd/dmn012. PMID 18522946.
- eTG complete [internet]. Melbourne: Therapeutic Guidelines Limited; 2013 Mar.
- Scheinfeld, N (2006). "Three cases of toxic skin eruptions associated with methotrexate and a compilation of methotrexate-induced skin eruptions". Dermatology online journal 12 (7): 15. PMID 17459301.
- Maytal J, Grossman R, Yusuf FH, Shende AC, Karayalycin G, Lanzkowsky P, Schaul N, Eviatar L. 1995. Prognosis and treatment of seizures in children with acute lymphoblastic leukemia. Epilepsia 36(8): 831-6.
- Halwachs S, Lakoma C, Schafer I, et al. 2011. The antiepileptic drugs phenobarbital and carbamazepine reduce transport of methotrexate in rat choroid plexus by down-regulation of the reduced folate carrier. Molecular pharmacology 80(4): 621-9.
- Rajagopalan, P. T. Ravi; Zhang, Zhiquan; McCourt, Lynn; Dwyer, Mary; Benkovic, Stephen J.; Hammes, Gordon G. (2002). "Interaction of dihydrofolate reductase with methotrexate: Ensemble and single-molecule kinetics". Proceedings of the National Academy of Sciences 99 (21): 13481–6. doi:10.1073/pnas.172501499. PMC 129699. PMID 12359872.
- David S. Goodsell (August 1999). "The Molecular Perspective: Methotrexate". The Oncologist 4 (4): 340–341. PMID 10476546.
- Johnston, Andrew; Gudjonsson, Johann Eli; Sigmundsdottir, Hekla; Ludviksson, Björn; Valdimarsson, Helgi (2005). "The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules". Clinical Immunology 114 (2): 154–63. doi:10.1016/j.clim.2004.09.001. PMID 15639649.
- Brody, M.; Böhm, I.; Bauer, R. (1993). "Mechanism of action of methotrexate: Experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells". European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies 31 (10): 667–674. PMID 8292668.
- National Rheumatoid Arthritis Society (NRAS) article on Methotrexate
- Chembank entry on methotrexate
- Methotrexate general article from NIH
- Methotrexate Injection MedlinePlus article from NIH
- Patient Education - Methotrexate from American College of Rheumatology
- U.S. National Library of Medicine: Drug Information Portal - Methotrexate