Methotrexate Interactions

NSAIDs reduce renal blood flow through prostaglandin inhibition and compete with methotrexate at renal tubular transporters, decreasing methotrexate clearance and raising serum levels. The risk is greatest with high-dose methotrexate or pre-existing renal impairment, where the combination can precipitate myelosuppression, mucositis, hepatotoxicity, and acute kidney injury.

Methotrexate works by inhibiting dihydrofolate reductase, depleting active folate and causing GI, mucosal, and hepatic side effects. Folic acid supplementation reduces those side effects by 26-77% without compromising efficacy, but must be timed correctly to avoid blunting the drug's action.