Methotrexat Ebewe Mechanism of Action

ATC Code: L 01 BA 01.
Pharmacology: Pharmacodynamics: 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 more 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.
Pharmacokinetics: Following oral administration of Methotrexat "Ebewe", 2 x 2.5mg tablets, methotrexate is rapidly absorbed achieving T_max at 0.83h. The mean maximum serum concentration was 170 ng/mL.
Methotrexate is generally completely absorbed from parenteral routes of administration. Peak serum concentrations following intramuscular administration are achieved in 30 to 60 minutes. After intravenous administration the initial volume of distribution is approximately 0.18L/kg (18% of body weight) and steady-state volume of distribution if approximately 0.4 to 0.8L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound.
Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration.
Methotrexate is reversibly bound in pleural exudates and ascites, for which reason the elimination from the body may be considerably delayed (see also Precautions).
Methotrexate is metabolised predominantly to three forms: 7-hydroxy-methotrexate is produced by hepatic aldehyde oxidase, especially after high-dose infusions, although it has a 200 fold lower affinity to dihydrofolate reductase it may play a role in the cellular uptake of methotrexate, polyglutamylation and inhibition of DNA-synthesis. 2,4-diamino-N-methylpteroic acid (DAMPA) is produced by an enteral bacterial carboxypeptidase. Following intravenous administration of methotrexate, DAMPA represented only 6% of the metabolites recovered from the urine.
Methotrexate polyglutymation results in intracellular accumulation of drug which is not at steady state with extracellular methotrexate concentration. As methotrexate and natural folates compete for the enzyme polyglutamyl synthetase, a high level of intracellular methotrexate will result in increased methotrexate polyglutymate synthesis, augmenting the cytotoxic effect of the drug.
The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis or rheumatoid arthritis or low-dose anti-neoplastic therapy (less than 30mg/m²). For patients receiving high doses of methotrexate, the terminal half-life is 8 to 15 hours. Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.
Toxicology: Preclinical safety data: Methotrexate acts mainly on proliferating tissues. This effect is common in all mammalian species studied including humans.
Reproductive toxicity: Methotrexate is capable of inducing teratogenic and embryolethal effects in several species at dose levels non-toxic to the mother.
Animal carcinogenicity studies have demonstrated methotrexate to be free of carcinogenic potential. Although methotrexate has been reported to cause chromosomal damage to animal somatic cells and bone marrow cells in humans, these effects are transient and reversible. In patients treated with methotrexate, evidence is insufficient to permit conclusive evaluation of any increased risk of neoplasia.
Mutagenicity: methotrexate is genotoxic in a number of in vitro and in vivo mammalian test systems.