Methotrexate (MTX) has been used to treat pediatric malignancies since the late second half of the twentieth century. Its mechanism of action as an inhibitor of DNA replication has been used in a variety of disease states, including psoriasis and rheumatoid arthritis, and as part of chemotherapy regimens for leukemia, lymphoma, and sarcoma. High-dose methotrexate (HD-MTX) is usually defined by doses of greater than 100 to 500mg/m2, and its use in chemotherapy must be closely monitored due to its narrow therapeutic index. Side effects increase with dose escalation and frequency of administration and can include nausea, vomiting, headache, mucositis, dizziness, convulsions, nephrotoxicity, thrombocytopenia, and hepatitis.

In patients receiving HD-MTX, therapeutic drug monitoring is required for drug clearance. The use of leucovorin, and now levoleucovorin rescue, is recommended in patients receiving greater than 100mg/m2 of MTX to provide folate to normal cells and bypass the metabolic block produced by HD-MTX. MTX doses over 1g are usually given with hydration, urinary alkalinization, and leucovorin rescue to increase clearance and decrease nephrotoxicity.

One of the major issues with HD-MTX is the potential for MTX toxicity, which can cause acute renal failure, prolonged MTX exposure, decreased renal elimination, and myelosuppression. More severe side effects may also result, including seizures, chronic kidney disease, coma, and even death. MTX toxicity also leads to prolonged patient stay, increased patient monitoring, and the potential need for numerous interventions to reduce MTX levels, all of which are costly to both the institution and the patient. 

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Several drug interactions have been described throughout the literature focusing on MTX toxicity. Recently, the FDA issued a warning to healthcare professionals that administering a proton pump inhibitor (PPI) in conjunction with IV MTX could lead to elevated MTX serum levels, potentially resulting in MTX toxicity. The warning cited numerous case reports, case series, and pharmacokinetic studies. Other drug therapies that have been shown to cause delayed MTX elimination when administered concomitantly include: nonsteroidal anti-inflammatory drugs (NSAIDs); antibiotics including beta-lactam-based agents (penicillin and cephalosporins), trimethoprim-sulfamethoxazole, ciprofloxacin, doxycycline, and vancomycin; dantrolene; and cyclosporine.  

These drug interactions that can occur with MTX are caused by numerous mechanisms including absorption, distribution, protein binding, elimination, and cellular transport of MTX. In some cases, the cause is purely related to the nephrotoxicity of these agents, subsequently decreasing MTX renal clearance. In other cases, the cause can be on the renal tubular secretion of MTX, as in the case of increased oral intake of bicarbonate beverages that leads to decreased urine pH and retention of MTX. The potential for genetic mutations may also contribute to the increased risk of MTX toxicity, as recently reported with methylenetetrahydrofolate reductase gene mutations and delayed MTX toxicity.

However, the clinical significance of many of these drug interactions is not known or has not been substantiated by extensive clinical observations. Careful evaluation of drug interactions and the patient’s lab values and characteristics should always be evaluated before initiating HD-MTX to reduce the risk of  toxicity.