Methotrexate

Methotrexate (aminopterin, and the two should not be confused with each other.

History

Methotrexate originated in the 1940s when Dr. Sidney Farber at Children's Hospital Boston was testing the effects of Food and Drug Administration (FDA) approval as an oncology drug in 1953.

Uses

In chemotherapy

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

Other uses

More recently it has come into use as a treatment for some autoimmune diseases, including ankylosing spondylitis, Crohn's disease, psoriasis, psoriatic arthritis, and rheumatoid arthritis (see etanercept has been shown to markedly improve symptoms.^[1]

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. This is not a termination, because in this case, the fetus is no longer living.

It is also sometimes used to treat a rare condition called Behcet's Disease where it is taken weekly, along with folic acid daily.

Pharmacokinetics

Methotrexate is a weak dicarboxylic acid with ionized at physiologic pH. Oral absorption is saturatable and thus dose-dependent, with doses less than 40mg/M2 having 42% bioavailability and doses greater than 40mg/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) 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.

Administration

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 folic acid).

Methotrexate is a highly 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.

Mode of action

Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR), an proteins.

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 and psoriasis. In these cases inhibition of dihydrofolate reductase (DHFR) is not thought to be the main mechanism, rather the inhibition of adenosine, or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells.^[2]

References