Pterin Mechanism of Action

Pharmacology: Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect 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.
Pharmacodynamics: Tablet: 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: When given in low doses, methotrexate is rapidly absorbed from the gastro-intestinal tract, but higher doses are less well-absorbed. It is also rapidly and completely absorbed following intramuscular administration. Peak serum concentrations are achieved in 1 to 2 hours after an oral dose, and 30 to 60 minutes after an intramuscular one. Methotrexate is distributed to tissues and extracellular fluid with a steady-state volume of distribution of 0.4 to 0.8 liters per kg bodyweight; it penetrates ascitic fluid and effusions which may act as a depot and thus enhance toxicity. Clearance from plasma is reported to be triphasic, with a terminal elimination half-life of between 3 and 10 hours after low oral doses or 8 to 15 hours after high-dose parenteral therapy. It is about 50% bound to plasma protein. Methotrexate enters the cells in part by an active transport mechanism and is bound as polyglutamate conjugates: bound drug may remain in the body for several months, particularly in the liver. It is excreted primarily in the urine, by glomerular filtration and active tubular secretion. Small amounts are excreted in bile and found in faeces; there is some evidence for enterohepatic recirculation.