Article: Methotrexate

Methotrexate
Systematic (IUPAC) name
(S)-2-(4-(((2,4-diaminopteridin-6-yl) methyl)methylamino)benzamido) pentanedioic acid
Identifiers
CAS number	59-05-2
ATC code	L01BA01 L04AX03
PubChem	126941
DrugBank	APRD00353
Chemical data
Formula	C20H22N8O5
Mol. weight	454.44 g/mol
Pharmacokinetic data
Bioavailability	17–90%
Metabolism	hepatic
Half life	3–15 hours (dose dependent)
Excretion	renal 48–100%
Therapeutic considerations
Pregnancy cat.	D(AU) X(US)
Legal status	S4(AU) POM(UK) ℞-only(US)
Routes	oral, IV, IM, SC, intrathecal

Methotrexate (rINN) (IPA: [mɛθəˈtrɛkseɪt]), abbreviated MTX and formerly known as amethopterin, is an antimetabolite drug used in treatment of cancer and autoimmune diseases. It acts by inhibiting the metabolism of folic acid.

History

Methotrexate originated in the 1940s when Sidney Farber at Children's Hospital Boston was testing the effects of folic acid on cancer. That inspired chemists at the drug company Lederle to start looking for antimetabolites resembling folate. The result was methotrexate, which was developed in 1948. Methotrexate gained Food and Drug Administration (FDA) approval as an oncology drug in 1953.

Uses

Methotrexate was originally used, as part of combination chemotherapy regimens, to treat many kinds of cancers. It is still the mainstay for the treatment of many neoplastic disorders including acute lymphoblastic leukemia.

More recently it has come into use as a treatment for some autoimmune diseases, including psoriasis, psoriatic arthritis, rheumatoid arthritis (see disease-modifying antirheumatic drugs), and Crohn's disease. In the case of rheumatoid arthritis, parallel use with infliximab or etanercept has been shown to markedly improve symptoms. (Klareskog, et al., 2004)

Although not licensed for this indication, methotrexate is also sometimes used (generally in combination with misoprostol) to terminate early pregnancies, particularly ectopic pregnancies.

It can be taken orally or administered by injection (subcutaneous, intramuscular, intravenous or intrathecal). Although daily preparations are occasionally used, most patients take weekly doses, which decreases the risk of certain side-effects.

Adverse effects

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 methotrexate "rescue") by using folinic acid supplements (not to be confused with folic acid).

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.

Mode of action

Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR), an enzyme that is part of the folate synthesis metabolic pathway. The affinity of methotrexate for DHFR is about one thousand-fold that of folate for DHFR. Dihydrofolate reductase 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. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.

Methotrexate is cell cycle S-phase selective, and has a greater negative effect on rapidly dividing cells (such as malignant and myeloid cells), which are replicating their DNA, and thus inhibits the growth and proliferation of these cells.

Lower doses of methotrexate have been shown to be very effective for the management of rheumatoid arthritis and psoriasis. In these cases inhibition of dihydrofolate reductase (DHFR) is not thought to be the main mechanism, 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 (Johnston et al., 2005).