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Methotrexate


ACCESSION NB: DB00563 (APRD00353)


TYPE: small molecule


GROUP: approved


DESCRIPTION:
An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. [PubChem]

VOLUME OF DISTRIBUTION: 0.4 to 0.8 L/kg

CATEGORIES:
Antineoplastic Agents Antirheumatic Agents Antimetabolites Enzyme Inhibitors Folic Acid Antagonists Dermatologic Agents Immunosuppressive Agents Nucleic Acid Synthesis Inhibitors Abortifacient Agents, Nonsteroidal Abortifacient Agents Antimetabolites, Antineoplastic

ABSORPTION: Generally well absorbed with a mean bioavailability of about 60%.

INDICATION:
For the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. Also for the treatment of severe psoriasis and severe, active, classical or definite rheumatoid arthritis.

PHARMACODYNAMICS:
Methotrexate is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Methotrexate inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid. At two stages in the biosynthesis of purines and at one stage in the synthesis of pyrimidines, one-carbon transfer reactions occur which require specific coenzymes synthesized in the cell from tetrahydrofolic acid. Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Methotrexate selectively affects the most rapidly dividing cells (neoplastic and psoriatic cells). Methotrexate is also indicated in the management of severe, active, classical, or definite rheumatoid arthritis.

MECHANISM OF ACTION:
Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.

PROTEIN BINDING:
50%, primarily to albumin

METABOLISM:
Hepatic.

TOXICITY:
Symptoms of overdose include bone marrow suppression and gastrointestinal toxicity. LD50=43mg/kg(orally in rat).

AFECTED ORGANISMS:
Humans and other mammals