Folic acid analogues
Although researchers have developed many folic acid analogues, the early compound
methotrexate remains the most
Methotrexate is well absorbed and distributed
throughout the body. It can accumulate in any fluid collection, such as ascites
or pleural or pericardial effusion, possibly resulting in prolonged elimination
and higher than expected toxicity, especially myelo-suppression. At usual
dosages, it doesn’t enter the CNS readily.
Although methotrexate is metabolized partially,
it’s excreted pri-marily unchanged in urine.
Methotrexate exhibits a three-part disappearance
from plasma; the rapid distributive phase is followed by a second phase, which
reflects kidney clearance. The last phase, the terminal half-life, is 3 to 10
hours for a low dose and 8 to 15 hours for a high dose.
Methotrexate reversibly inhibits the action of the
enzyme dihydro-folate reductase, thereby blocking normal folic acid processing
and thus inhibiting DNA and RNA synthesis. The result is cell death. Folinic
acid is used in high-dose methotrexate therapy to help prevent cell death.
Methotrexate is especially useful in treating:
acute lymphoblastic leukemia (abnormal growth of lympho-cyte precursors,
the lymphoblasts), the most common leukemia in children
acute lymphocytic leukemia (abnormal growth of lymphocytes);
methotrexate may be given as treatment or prophylaxis for meningeal leukemia
CNS diseases (given intrathecally, or through the spinal cord into the
choriocarcinoma (cancer that develops from the chorionic por-tions of
the products of conception)
osteogenic sarcoma (bone cancer)
cancers of the head, neck, bladder, testis, and breast.
The drug is also prescribed in low doses to
treat such disorders as severe psoriasis, graft versus host disease, and
rheumatoid arthri-tis that don’t respond to conventional therapy.
Methotrexate interacts with several other drugs:
Probenecid decreases methotrexate excretion, increasing therisk of
methotrexate toxicity, including fatigue, bone marrow sup-pression, and
stomatitis (mouth inflammation).
Salicylates and nonsteroidal anti-inflammatory drugs, especially
diclofenac, ketoprofen, indomethacin, and naproxen, also in-crease methotrexate
Cholestyramine reduces absorption of methotrexate from the GI tract.
Concurrent use of alcohol and methotrexate increases the risk of liver
Taking co-trimoxazole with methotrexate may produce blood cell
Penicillin decreases renal tubular secretion of methotrexate,
in-creasing the risk of methotrexate toxicity. (See Adverse reactionsto methotrexate.)