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Methotrexate (MTX) is commonly used in the treatment of cancers and noncancerous conditions. Its immunosuppressive activity allows it to also be used for rheumatoid arthritis, organ transplantation, psoriasis, trophoblastic diseases, and therapeutic abortion.12,33

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) aminoglycosides42) and certain intravenous (IV) radiologic contrast dyes18,26, age, folate deficiency, and concurrent infection.65 MTX toxicity depends on the dose but even more on the duration of exposure.


The therapeutic and toxic effects of MTX are based on its ability to limit DNA and RNA synthesis by inhibiting dihydrofolate reductase (DHFR) and thymidylate synthetase (Fig. 51–1). Thymidylate synthesis is inhibited by polyglutamic derivatives of MTX. DHFR reduces folic acid to tetrahydrofolate (FH4), which serves as an essential cofactor in the synthesis of purine nucleotides. Reduced folate is also required by thymidylate synthetase to serve as a methyl donor in the formation of thymidylate. Thymidylate is then used for DNA synthesis. MTX, a structural analog of folate, competitively inhibits DHFR by binding to the enzymatic site of action. This inhibits reduced folate production, which is necessary for nucleotide formation and DNA/RNA synthesis.

FIGURE 51–1.

Mechanism of methotrexate (MTX) toxicity. MTX and MTX polyglutamates inhibit dihydrofolate reductase (DHFR) and thymidylate synthetase, which are necessary for DNA and RNA synthesis. Leucovorin bypasses DHFR blockade to allow for continued synthesis.

The bioavailability of MTX appears to be limited by a saturable intestinal absorption mechanism. At oral doses less than 30 mg/m2, the absorption is 90%; at doses greater than 80 mg/m2, the total absorption is less than 10% to 20%.9 The weekly adult dose used for the treatment of psoriasis and rheumatoid arthritis is low and can be administered orally. However, the dose used to induce abortion is higher (50 mg/m2) and must be administered parenterally to achieve an effective drug concentration. MTX dosing regimens for chemotherapy are variable but can be generally classified as low (40 mg/m2), moderate range, and high doses (1000 mg/m2). Conventional IV doses of up to 100 mg/m2 can be administered without leucovorin rescue. Doses of 1000 mg/m2 are considered potentially lethal. Much higher doses (2–3 g/m2) can be given when MTX is followed by leucovorin to prevent life-threatening toxicity. The mortality rate from high-dose MTX is approximately 6% and occurs primarily when MTX concentrations are not closely monitored.65,68

Methotrexate has a triphasic plasma clearance. The initial plasma distribution half-life is short at 0.75 hours. The second half-life is 2 to 3.4 ...

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