Trexan Mechanism of Action

Pharmacotherapeutic group: Immunosuppressive agents. ATC code: L04AX03.
PHARMACOLOGY: Pharmacodynamics: Mechanism of action: Methotrexate is a folic acid antagonist and its major site of action is the enzyme dihydrofolate reductase. Its main effect is inhibition of DNA synthesis but it also acts directly both on RNA and protein synthesis. Methotrexate is a phase specific substance, the main effect being directed during the S-phase of cell division.
The inhibition of dihydrofolate reductase can be circumvented by the use of leucovorin (folinic acid; citrovorum factor) and protection of normal tissues can be carried out by properly timed administration of leucovorin calcium.
Pharmacokinetics: Absorption: Orally administered, the absorption of methotrexate seems to be dose-dependent. Peak serum levels are reached within 1 to 2 hours. Generally, at doses of 30 mg/m² or less, methotrexate is absorbed rapidly and completely. The bioavailability of orally administered methotrexate is high (80-100%) at doses of 30 mg/m² or less. Saturation of the absorption starts at doses above 30 mg/m² and absorption of doses exceeding 80 mg/m² is incomplete. After parenteral injection, peak serum levels are seen in about one half this period. After intramuscular injection, peak serum concentrations occur in 30 to 60 minutes.
About one half of absorbed methotrexate is reversibly bound to serum protein but is readily distributed in tissues. Excretion takes place mainly via the kidneys. Approximately 41% of the dose is excreted unchanged in the urine within the first six hours, 90% within 24 hours. A minor part of the dose is excreted in the bile of which there is pronounced enterohepatic circulation.
The half-life is approximately 3-10 hours following low dose treatment and 8-15 hours following high dose treatment. If the renal function is impaired, the concentration of methotrexate in serum and in tissues may increase rapidly.
Methotrexate does not enter the cerebrospinal fluid at oral or parenteral therapeutic doses. However, cytotoxic concentrations (>10^-7 M) can be achieved in the CSF with high doses (>500 mg/m²). When high drug concentrations are indicated, direct intrathecal administration should be used.
Toxicology: Preclinical safety data: Chronic toxicity studies in mice, rats and dogs showed toxic effects in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity. Animal studies show that methotrexate impairs fertility and is embryo- and foetotoxic. Teratogenic effects have been identified in four species (rats, mice, rabbits, cats). In rhesus monkeys no malformations occurred. Methotrexate is mutagenic in vivo and in vitro. There is evidence that methotrexate causes chromosomal aberrations in animal cells and in human bone marrow cells, but the clinical significance of these findings has not been established. Rodent carcinogenicity studies do not indicate an increased incidence of tumours.