methotrexate and trimethoprim

Both methotrexate and trimethoprim inhibit dihydrofolate reductase, the enzyme that converts dihydrofolate to tetrahydrofolate, causing additive depletion of active folate. Trimethoprim may also reduce renal clearance of methotrexate by inhibiting tubular secretion, raising plasma methotrexate concentrations.

This interaction increases the risk of severe haematological toxicity, including bone marrow suppression, megaloblastic anaemia, leucopenia, thrombocytopenia and mucositis. Patients with renal impairment or those receiving high-dose methotrexate are particularly vulnerable, as elevated methotrexate levels can cause life-threatening toxicity.

Avoid co-prescription where possible, especially with high-dose methotrexate. If combined use is essential, closely monitor full blood counts, renal function and serum methotrexate levels. Consider prophylactic folic acid, ensure adequate hydration, and adjust doses accordingly. Consult specialist advice for each individual case.

This interaction is well documented in case reports and clinical studies, and is recognised in standard drug interaction references. The additive folate antagonism is pharmacologically predictable, and the pharmacokinetic component has been shown in small studies.