Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Other immunosuppressants; Folic acid analogues. ATC-code: L04AX03; L01BA01.
Methotrexate is a folic acid antagonist which belongs to the class of cytotoxic agents known as antimetabolites. It acts by the competitive inhibition of the enzyme dihydrofolate reductase and thus inhibits DNA synthesis. It has not yet been clarified, as to whether the efficacy of methotrexate, in the management of psoriasis, psoriasis arthritis and chronic polyarthritis, is due to an anti-inflammatory or immunosuppressive effect and to which extent a methotrexate-induced increase in extracellular adenosine concentration at inflamed sites contributes to these effects.

Pharmacokinetic Properties

5.2 Pharmacokinetic Properties
After oral application, methotrexate is absorbed from the gastrointestinal tract. When administered in low doses (7.5 mg/m2 to 80 mg/m2 body surface area), methotrexate has a mean bioavailability of approximately 70%, although considerable inter- and intra-subject variations are possible (25–100%). Plasma peak concentrations are attained within 1–2 hours. Subcutaneous, intravenous and intramuscular administration demonstrated similar bioavailability. Approximately 50% of methotrexate is bound to serum proteins. Upon being distributed into body tissues, high concentrations particularly in liver, kidneys and spleen in the form of polyglutamates can be found, which can be retained for weeks or months. When administered in small doses, methotrexate passes into the liquor in minimal amounts; under high doses (300 mg/kg body weight), concentrations between 4 and 7 μg/ml have been measured in the liquor. Average terminal half-life is 6–7 hours and demonstrates considerable variation (3–17 hours). Half-life may be prolonged to 4 times the normal length in patients with third spaces (pleural effusion, ascites). Approximately 10% of the administered methotrexate is metabolised intrahepatically. The major metabolite is 7-hydroxymethotrexate.
Excretion takes place, mainly in unchanged form, primarily renal via glomerular filtration and active secretion in the proximal tubulus. Approx. 5–20% of methotrexate and 1–5% of 7- hydroxymethotrexate are eliminated via the bile. Pronounced enterohepatic blood flow exists.
In case of renal insufficiency, elimination is delayed significantly. Impaired elimination in presence of hepatic insufficiency is not known.
Methotrexate passes the placental barrier in rats and monkeys.