Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic and immunomoduling agents, antineoplastic agents, antimetabolites, folic acid analogues, ATC code: L01BA01

Methotrexate, a derivative of folic acid, belongs to the class of cytotoxic agents known as antimetabolites.
It acts principally during the 'S' phase of cell division, by the competitive inhibition of the enzyme dihydrofolate reductase, thus preventing the reduction of dihydrofolate to tetrahydrofolate, a necessary step in the process of DNA synthesis and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, foetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are generally more sensitive to the effects of methotrexate. When cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues.

The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. Clarification of the effect of methotrexate on immune activity and its relation to rheumatoid immunopathogenesis await further investigation.

In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process.

Pharmacokinetic Properties

5.2. Pharmacokinetic properties

In doses of 0.1mg (of methotrexate) per kg, methotrexate is completely absorbed from the G.I. tract; larger oral doses may be incompletely absorbed. Serum concentrations following oral administration of methotrexate may be slightly lower than those following I.V. injection.

Methotrexate is actively transported across cell membranes. The drug is widely distributed into body tissues with highest concentrations in the kidneys, gall bladder, spleen, liver and skin. Methotrexate is retained for several weeks in the kidneys and for months in the liver. Sustained serum concentrations and tissue accumulation may result from repeated daily doses. Methotrexate crosses the placental barrier and is distributed into breast milk. Approximately 50% of the drug in the blood is bound to serum proteins.

Following oral doses of 0.06mg/kg or more, the drug had a serum half-life of 2-4 hours, but the serum half-life was reported to be increased to 8-10 hours when oral doses of 0.037mg/kg were given.

Methotrexate does not appear to be appreciably metabolised. The drug is excreted primarily by the kidneys via glomerular filtration and active transport. Small amounts are excreted in the faeces, probably via the bile. Methotrexate has a biphasic excretion pattern. If methotrexate excretion is impaired, accumulation will occur more rapidly, e.g., inpatients with impaired renal function. In addition, simultaneous administration of other weak organic acids such as salicylates may suppress methotrexate clearance.