Everything about Methotrexate totally explained
| PubChem=126941
| DrugBank=APRD00353
| CAS_number = 59-05-2
| C=20 | H=22 | N=8 | O=5
| molecular_weight = 454.44 g/mol
| bioavailability = 17–90%
| metabolism =
hepatic
| elimination_half-life = 3–15 hours (dose dependent)
| excretion =
renal 48–100%
| pregnancy_AU = D
| pregnancy_US = X
| pregnancy_category =
| legal_AU = S4
| legal_UK =POM
| legal_US =Rx-only
| routes_of_administration =,
IV,
IM,
SC,
intrathecal
}}
Methotrexate (
rINN), abbreviated
MTX and formerly known as
amethopterin, is an
antimetabolite and
antifolate drug used in treatment of
cancer and
autoimmune diseases. It acts by inhibiting the metabolism of
folic acid. Methotrexate replaced the more powerful and toxic antifolate
aminopterin, and the two shouldn't 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
folic acid on acute
leukemic children (severe blood cancer). Inspired, he asked Dr. Y. SubbaRow, then Director of the Research Division of Lederle Labs (part of
American Cyanamid), to synthesize the
anti-folate (methotrexate). Dr. Row, who also happened to be the head of the team which had earlier synthesized folic acid (1946) readily synthesized this anti-folate and handed it over to Dr. Farber, who in turn administered it to a small group of very ill leukemic children. The remarkable clinical improvement that was observed in these patients heralded the era of cancer
chemotherapy in modern medicine. This was reported by Dr. S. Farber in the June 3rd, 1948 issue of NEJM. In 1950 Dr. Farber founded in Boston the world's first Cancer Research Center. Methotrexate gained
Food and Drug Administration (FDA) approval as an oncology drug in 1953.
Uses
In chemotherapy
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.
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
disease-modifying antirheumatic drugs). A parallel use with
TNFα blockers as
infliximab or
etanercept has been shown to markedly improve symptoms.
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 hasn't expelled the fetus, methotrexate may be used to help the body begin the miscarriage process.
It is also sometimes used to treat a rare condition called
Behçet's disease where it's taken weekly, along with folic acid daily.
Pharmacokinetics
Methotrexate is a weak dicarboxylic acid with
pKa 4.8 and 5.5, and thus it's mostly
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's 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 (for example 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's 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's a risk of becoming pregnant, or if they're 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
enzyme that participates in the
tetrahydrofolate synthesis. 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. 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's 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) isn't 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.
Further Information
Get more info on 'Methotrexate'.
|
External Link Exchanges
Do you know how hard it is to get a link from a large encyclopaedia? Well we're different and will prove it. To get a link from us just add the following HTML to your site on a relevant page:
<a href="http://methotrexate.totallyexplained.com">Methotrexate Totally Explained</a>
Then simply click through this link from your web page. Our crawlers will verify your link, extract the title of your web page and instantly add a link back to it. If you like you can remove the words Totally Explained and embed the link in article text.
As long as your link remains in place, we'll keep our link to you right here. Please play fair - our crawlers are watching. Your site must be closely related to this one's topic. Any kind of spamming, dubious practises or removing the link will result in your link from us being dropped and, potentially, your whole site being banned. |
