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Chapter: Clinical Pharmacology: Antineoplastic drugs

Folic acid analogues

Although researchers have developed many folic acid analogues, the early compound methotrexate remains the most commonly used.

Folic acid analogues


Although researchers have developed many folic acid analogues, the early compound methotrexate remains the most commonly used.



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.

Metabolism and excretion


Although methotrexate is metabolized partially, it’s excreted pri-marily unchanged in urine.


A disappearing act


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 subarachnoid space)


·                 choriocarcinoma (cancer that develops from the chorionic por-tions of the products of conception)


·                 osteogenic sarcoma (bone cancer)


·                 malignant lymphomas


·                 cancers of the head, neck, bladder, testis, and breast.


Unconventional treatment


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.

Drug interactions


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 toxicity.


·                 Cholestyramine reduces absorption of methotrexate from the GI tract.


·                 Concurrent use of alcohol and methotrexate increases the risk of liver toxicity.


·                 Taking co-trimoxazole with methotrexate may produce blood cell abnormalities.


·                 Penicillin decreases renal tubular secretion of methotrexate, in-creasing the risk of methotrexate toxicity. (See Adverse reactionsto methotrexate.)



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