Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: other immunosuppressants
ATC code: L04AX03
Antirheumatic medicinal product for the treatment of chronic, inflammatory rheumatic diseases and polyarthritic forms of juvenile idiopathic arthritis. Immunomodulating and anti-inflammatory agent for the treatment of Crohn’s disease.

Mechanism of action

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, chronic polyarthritis and Crohn’s disease, 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.

International clinical guidelines reflect the use of methotrexate as a second choice for Crohn’s disease patients that are intolerant or have failed to respond to first-line immunomodulating agents as azathioprine (AZA) or 6-mercaptopurine (6-MP).

The adverse events observed in the studies performed with methotrexate for Crohn’s disease at cumulative doses have not shown a different safety profile of methotrexate than the profile it is already known. Therefore, similar cautions must be taken with the use of methotrexate for the treatment of Crohn’s disease as in other rheumatic and non-rheumatic indications of methotrexate (see sections 4.4 and 4.6).

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Absorption
Following oral administration, methotrexate is absorbed from the gastrointestinal tract. In case of low- dosed administration (dosages between 7.5 mg/m² and 80 mg/m² body surface area), the mean bioavailability is approx. 70%, but considerable interindividual and intraindividual deviations are possible (25–100%). Maximum serum concentrations are achieved after 1–2 hours.

Bioavailability of subcutaneous injection is nearly 100%.

Distribution
Approximately 50% of methotrexate is bound to serum proteins. Upon being distributed into body tissues, high concentrations in the form of polyglutamates are found in the liver, kidneys and spleen in particular, which can be retained for weeks or months. When administered in small doses, methotrexate passes into the cerebrospinal fluid in minimal amounts. The terminal half-life is on average 6–7 hours and demonstrates considerable variation (3–17 hours). The half-life can be prolonged to 4 times the normal length in patients who possess a third distribution space (pleural effusion, ascites).

Biotransformation

Approx. 10% of the administered methotrexate dose is metabolised intrahepatically. The principle metabolite is 7-hydroxymethotrexate.

Elimination

Excretion takes places, mainly in unchanged form, primarily renal via glomerular filtration and active secretion in the proximal tubulus.
Approx. 5–20% methotrexate and 1–5% 7-hydroxymethotrexate are eliminated biliary. There is pronounced enterohepatic circulation.

In the case of renal impairment, elimination is delayed significantly. Impaired elimination with regard to hepatic impairment is not known.