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Methotrexate and the fluoropyrimidines (5-fluorouracil and capecitabine) belong to the chemotherapeutic class of antimetabolites. Patients affected by these chemotherapeutics present with significant clinical toxicities that are potentially fatal. Clinicians must recognize these patients early and be prepared to provide immediate interventions that include specific antidotal therapies. The oral formulations of methotrexate and capecitabine present a risk for intentional or unintentional chemotherapeutics ingestion in the home.



Methotrexate (MTX) is commonly used for a many malignant conditions. Its immunosuppressive activity also allows it to be used for rheumatoid arthritis, organ transplantation, psoriasis, trophoblastic diseases, and termination of pregnancy.20,47

Risk factors for MTX toxicity include impaired kidney function ­(primary route of drug elimination); third compartment spacing: ascites and pleural effusions; concurrent use of nephrotoxins, such as nonsteroidal antiinflammatory drugs (NSAIDs) and aminoglycosides55 and certain intravenous radiologic contrast agents;30,40 age; folate deficiency; and concurrent ­infection.95 Methotrexate toxicity depends on the dose, but even more on the duration of exposure.


The therapeutic and toxic effects of methotrexate are based on its ability to limit DNA and RNA syntheses by inhibiting dihydrofolate reductase (DHFR) and thymidylate synthetase (Fig. 51–1). Dihydrofolate reductase reduces folic acid first to dihydrofolate and then to tetrahydrofolate (FH4), which serves as an essential cofactor in the synthesis of purine nucleotides that are used in the synthesis of DNA and RNA. Methotrexate, a structural analog of folate, competitively inhibits DHFR by binding to the enzymatic site of action. Methotrexate polyglutamates are formed intracellularly by folylpolyglutamate synthetase and they also inhibit DHFR. The inhibition of DHFR diminishes reduced folate production, which is necessary for the formation of purine nucleotides. Reduced folates are also required by thymidyl synthetase to serve as methyl donors in the formation of thymidyl. Thymidyl is then used for DNA synthesis. In addition, thymidyl production is impaired by the direct inhibition of thymidylate synthetase by polyglutamated derivatives of methotrexate.

FIGURE 51–1.

Mechanism of MTX toxicity. Methotrexate inhibits dihydrofolate reductase activity, which is necessary for DNA and RNA synthesis. Leucovorin bypasses blockade to allow for continued synthesis. MTX = methotrexate.

The antiinflammatory effect of MTX likely involves the following mechanisms: (1) inhibition of trans-methylation (by depletion of intracellular folate stores) which causes the death of T cells and inhibits the formation of polyamines (spermine and spermidine) that are involved in the inflammatory cascade, (2) reduction in intracellular concentration of glutathione, and (3) inhibition of intracellular 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, which leads to increased extracellular concentration of adenosine through a series of steps (see below). Adenosine binds to the A2a receptor located on the surface of leukocytes, and it affects selected functions, where it inhibits the syntheses of cytokines (TNF α) ...

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