Methotrexate Interactions

Methotrexate is cleared almost entirely by the kidneys. NSAIDs reduce renal blood flow by blocking prostaglandins and compete with methotrexate at renal tubular transporters, both of which slow methotrexate elimination and raise its blood levels. The danger is greatest with high-dose methotrexate (cancer chemotherapy) or pre-existing kidney impairment, where the buildup can cause bone marrow suppression, mouth and gut ulceration, liver injury, and acute kidney injury. In low-dose weekly methotrexate for autoimmune disease with healthy kidneys, the interaction is usually more modest and often manageable under prescriber supervision.

Methotrexate works by blocking the enzyme that recycles folate into its active form, which depletes folate in normal tissues and drives common side effects such as nausea, mouth sores, and elevated liver enzymes. Folic acid supplementation reduces these side effects without compromising efficacy at the doses used for autoimmune disease, but it should not be taken on the same day as methotrexate, and it should never be added on your own when methotrexate is used for cancer.