methotrexate and probenecid

Probenecid blocks the organic anion transporters OAT1 and OAT3 in the renal proximal tubules, reducing the tubular secretion of methotrexate. This decreases methotrexate clearance, resulting in higher and more prolonged plasma concentrations. Probenecid may also displace methotrexate from plasma protein binding, although the transporter inhibition is the dominant mechanism.

Elevated methotrexate concentrations increase the risk of severe toxicity, including myelosuppression, mucositis, hepatotoxicity, and nephrotoxicity. Fatal outcomes have been reported with high-dose methotrexate regimens when probenecid was co-administered. Even with low-dose methotrexate, toxicity can be unpredictable.

Avoid co-prescription. If treatment with both drugs is essential, do not use high-dose methotrexate. For low-dose methotrexate, consider a substantial dose reduction, or alternative uricosuric or anti-inflammatory agents. Monitor plasma methotrexate concentrations, full blood count, serum creatinine, and liver function tests frequently. Provide supportive care such as hydration and leucovorin rescue as appropriate.

Well established through pharmacokinetic studies and numerous clinical reports. Interaction is consistently listed in major drug interaction databases and prescribing information.