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Methotrexate (MTX)

Clinical data

Trade names MTX
AHFS/Drugs.com monograph
Medline Plus a682019
Pregnancy cat. D (AU) X (US)
Legal status Prescription Only (S4) (AU)POM (UK) ℞-only (US)
Routes oral

Pharmacokinetic data

Bioavailability 17–90%
Metabolism hepatic
Half-life 15 hours (dose dependent)
Excretion renal 48–100%

Identifiers

CAS number 59-05-2
ATC code L01BA01 L04AX03
PubChem CID 126941
Drug Bank DB00563
ChemSpider 112728
UNII YL5FZ2Y5U1
KEGG D00142
ChEBI CHEBI:44185
ChEMBL CHEMBL34259

Chemical data

Formula C20H22N8O5
Mol. mass 454.44 g/mol
SMILES[show]
InChI[show]

Methotrexate

Methotrexate (rINN) /mɛθɵˈtrɛkseɪt/, abbreviated MTX and formerly known asamethopterin, is an ant metabolite 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.

History

Methotrexate (MTX)

Medical uses

Chemotherapy

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, sarcoidosis, Crohn’s disease, and many forms of vacuities. 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.

It has also been used for multiple sclerosis but is not approved by the Food and Drug Administration.

Abortion

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.

Administration

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.

Toxicity

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:

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 foliate 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.

Intrathecal overdose

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.

Clinical presentation

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.

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.[citation needed]

Central nervous system reactions to methotrexate have been reported, especially when given via the intrathecal route which includes 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.

Drug interactions

Penicillin’s 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

Mechanism of action

The similar structure of dihydrofolic acid (top) and methotrexate (bottom) suggests that methotrexate is a competitive inhibitor

Mechanism

Methotrexate is thought to affect cancer and rheumatoid arthritis by two different pathways. For cancer, methotrexate competitively inhibitsdihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolatesynthesis. The affinity of methotrexate for DHFR is about one thousand-fold that of foliate. DHFR catalyses the conversion of dihydrofolateto the active tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Also, foliate 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 thymine less 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 foliate.

In its low-dose regimen methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells.

Pharmacokinetics

Methotrexate is a weak dicarboxylic acid with plan 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 no absorbable 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 accrete, inhibiting the blood circulation to the target site

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