A patient on methotrexate is prescribed trimethoprim. Which type of drug interaction is most likely to occur, and what is the mechanism?

## Methotrexate–Trimethoprim Interaction **Key Point:** This is a pharmacokinetic interaction involving competition for renal tubular secretion. Both drugs are substrates for organic anion transporters (OAT) in the proximal tubule, and trimethoprim reduces methotrexate elimination, increasing MTX toxicity. ### Mechanism of Renal Interaction 1. **Methotrexate elimination:** ~90% renal excretion; undergoes glomerular filtration and active tubular secretion via OAT1 and OAT3 2. **Trimethoprim:** Also secreted via the same transporters 3. **Competition:** Trimethoprim inhibits the tubular secretion of methotrexate 4. **Result:** Reduced MTX clearance → increased plasma concentration → increased toxicity **High-Yield:** This interaction is clinically significant because methotrexate has a narrow therapeutic window. Even modest increases in plasma concentration can cause severe toxicity (bone marrow suppression, hepatotoxicity, nephrotoxicity). ### Clinical Consequences | Effect | Manifestation | |--------|---------------| | Increased MTX levels | Bone marrow suppression (anemia, thrombocytopenia, leukopenia) | | Delayed clearance | Mucositis, GI toxicity | | Renal accumulation | Acute kidney injury (especially if volume depleted) | **Clinical Pearl:** NSAIDs, probenecid, and sulfonamides (including trimethoprim-sulfamethoxazole, TMP-SMX) also compete for renal tubular secretion and should be avoided or used with caution in MTX-treated patients. **Warning:** TMP-SMX is commonly prescribed for Pneumocystis prophylaxis in immunocompromised patients. If the patient is also on MTX (e.g., for rheumatoid arthritis or malignancy), this combination carries high risk and requires dose adjustment or alternative prophylaxis. ### Management - Avoid trimethoprim in MTX-treated patients if possible - If unavoidable, reduce MTX dose or increase dosing interval - Monitor renal function and MTX levels - Ensure adequate hydration - Consider alternative antibiotics (e.g., fluoroquinolones, which do not compete for tubular secretion)