A patient on methotrexate for rheumatoid arthritis develops toxicity after starting trimethoprim. Which mechanism of drug interaction best explains this adverse effect?

Explanation

## Methotrexate–Trimethoprim Interaction **Key Point:** Trimethoprim inhibits the renal tubular secretion of methotrexate, leading to reduced renal clearance and increased systemic exposure, resulting in methotrexate toxicity. ### Mechanism of Interaction Methotrexate is eliminated primarily through: 1. **Glomerular filtration** (passive) 2. **Active renal tubular secretion** (via organic anion transporters, OAT) Trimethoprim is a competitive inhibitor of renal tubular secretion pathways. When both drugs are present, trimethoprim competes for the same renal transporters, reducing methotrexate clearance and increasing its plasma concentration. ### Consequences ```mermaid flowchart TD A[Methotrexate + Trimethoprim]:::outcome --> B[Trimethoprim inhibits renal tubular secretion]:::action B --> C[↓ Renal clearance of MTX]:::outcome C --> D[↑ MTX plasma concentration]:::outcome D --> E[Toxicity: bone marrow suppression, mucositis, hepatotoxicity]:::urgent ``` **High-Yield:** Other drugs that inhibit renal tubular secretion of methotrexate include: - NSAIDs (especially indomethacin) - Probenecid - Penicillins - Cephalosporins - Sulfonamides **Clinical Pearl:** Patients on methotrexate should avoid or use with caution any drug known to inhibit renal tubular secretion. Adequate hydration and urine alkalinization can help maintain methotrexate clearance. ### Why Other Mechanisms Are Incorrect - **CYP3A4 induction:** Methotrexate is not significantly metabolized by hepatic enzymes; it is eliminated renally - **Protein binding displacement:** While possible with some drugs, this is not the primary mechanism for trimethoprim–methotrexate interaction - **Increased GI absorption:** Both drugs are already well absorbed; this mechanism would not explain acute toxicity