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Methotrexate (MTX) is commonly used for a substantial number of therapeutic cancerous and noncancerous indications. Its immunosuppressive activity allows it to also be used for rheumatoid arthritis, organ transplantation, psoriasis, trophoblastic diseases, and therapeutic abortion.10,29

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Risk factors for MTX toxicity include impaired renal function (primary route of drug elimination); third compartment spacing: ascites and pleural effusions; use of nephrotoxins, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and aminoglycosides37 and certain intravenous radiologic contrast agents16,24; age; folate deficiency; and concurrent infection.60 MTX toxicity depends more on the duration of exposure than the dose itself.

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The therapeutic and toxic effects of methotrexate are based on its ability to limit DNA and RNA synthesis by inhibiting dihydrofolate reductase (DHFR) and thymidylate synthetase (Fig. 53–1). Thymidylate synthesis is inhibited by polyglutamic derivatives of methotrexate. DHFR reduces folic acid to tetrahydrofolate (FH4), which serves as an essential cofactor in the synthesis of purine nucleotides. These reduced folates are also required by thymidylate synthetase to serve as methyl donors in the formation of thymidylate. Thymidylate is then used for DNA synthesis. MTX is a structural analog of folate and competitively inhibits DHFR by binding to this enzyme's site of action. This stops reduced folate production, which is necessary for nucleotide formation and DNA/RNA synthesis.

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Figure 53–1.
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Mechanism of MTX toxicity. Methotrexate inhibits DHFR activity, which is necessary for DNA and RNA synthesis. Leucovorin bypasses blockade to allow for continued synthesis.

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The bioavailability of methotrexate 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 absorption is less than 10% to 20%.8 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 effective drug concentrations. MTX dosing regimens for chemotherapy are variable, but can be generally classified as low (40 mg/m2), moderate, and high doses (1000 mg/m2). Conventional intravenous 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 to 3 g/m2) can be given when MTX is followed by leucovorin in order to prevent life-threatening toxicity. Mortality from high-dose MTX is approximately 6%, and occurs primarily when patients' MTX concentrations are not monitored.60,63

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MTX has a triphasic plasma clearance. The initial plasma distribution half-life is short—0.75 hours. The second half-life is 2 to 3.4 hours and represents renal clearance of the drug. The third phase has a half-life of about 8 to 10.4 hours and ...

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