Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Therakind (Europe) Limited, Paramount Court, Corrig Road, Sandyford Business Park, Dublin 18, D18 R9C7, ฮreland
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antimetabolites, folic acid analogues
ATC code: L01BA01
Methotrexate is a folic acid antagonist that, as an antimetabolite, belongs to the class of cytotoxic active substances. It acts by competitive inhibition of the enzyme dihydrofolate reductase and thus inhibits DNA synthesis.
It has not yet been possible to date to clarify whether the efficacy of methotrexate in the management of psoriasis, psoriatic arthritis and chronic polyarthritis is due either to an anti-inflammatory or immunosuppressive effect, or to what extent a methotrexate-induced increase in extracellular adenosine concentration at inflamed sites contributes to this effect.
Highly proliferating tissue such as malignant cells, bone marrow, foetal cells, skin epithelium and mucosa is generally more sensitive to this effect of methotrexate. Cell proliferation is usually greater in malignant tumours than in normal tissue and methotrexate can therefore exert a sustained effect on malignant growth without causing irreversible damage to normal tissue.
In psoriasis, cell proliferation of the epithelium is markedly increased compared with normal skin. This difference in cell proliferation rate is the starting point for the use of methotrexate in particularly severe, generalised, treatment-resistant psoriasis and psoriatic arthritis.
After oral administration, methotrexate is absorbed from the gastrointestinal tract. When administered in low doses (7.5 mg/mยฒ to 80 mg/mยฒ body surface area), the mean bioavailability of methotrexate is approximately 70%, but considerable inter- and intra-individual variations are possible (25-100%). Peak serum concentrations are attained within 1-2 hours.
Data from a randomised trial in patients with juvenile rheumatoid arthritis (aged 2.8 to 15.1 years) indicated greater oral bioavailability of methotrexate in the fasting state. In children with JIA, the dose normalized area under the plasma concentration versus time-curve (AUC) of methotrexate increased with the age of the children and was lower than that found in adults. The dose normalized AUC of the metabolite 7-hydroxymethotrexate was not dependent on age.
Methotrexate is approximately 50% bound to serum proteins. After distribution, it collects predominantly in the liver, kidneys and spleen in the form of polyglutamates, which can be retained for weeks or months.
The mean terminal half-life is 6-7 hours and demonstrates considerable variations (3-17 hours). The half-life may be prolonged up to four-fold in patients with a third distribution compartment (pleural effusion, ascites).
Approximately 10% of the administered methotrexate dose is metabolised in the liver. The main metabolite is 7-hydroxymethotrexate.
Excretion occurs predominantly in the unchanged form by glomerular filtration and active secretion in the proximal tubule via the kidneys. Approximately 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate is eliminated in the bile. There is a pronounced enterohepatic circulation.
Elimination in patients with impaired renal function is markedly delayed. Impaired elimination in patients with hepatic impairment is not known at present.
Methotrexate crosses the placental barrier in rats and monkeys.
In chronic toxicity studies in mice, rats and dogs, toxic effects were seen in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity.
Long-term studies in rats, mice and hamsters revealed no evidence of a tumorigenic potential of methotrexate. Methotrexate induces gene and chromosomal mutations in vitro and in vivo. There is a suspected mutagenic effect in humans.
Teratogenic effects have been observed in four species (rats, mice, rabbits, cats). In rhesus monkeys, no malformations comparable to those seen in humans occurred.
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