Summary

Methotrexate and trimethoprim have a significant drug interaction due to their combined antifolate effects, which can lead to increased methotrexate toxicity. This interaction may result in severe bone marrow suppression, mucositis, and other serious adverse effects requiring careful monitoring and potential dose adjustments.

Introduction

Methotrexate is an antimetabolite and antifolate drug primarily used as a chemotherapy agent for various cancers and as an immunosuppressant for autoimmune conditions like rheumatoid arthritis and psoriasis. It belongs to the class of folate antagonists and works by inhibiting dihydrofolate reductase. Trimethoprim is an antibiotic commonly used to treat urinary tract infections and is often combined with sulfamethoxazole (co-trimoxazole). It also acts as a folate antagonist by inhibiting bacterial dihydrofolate reductase, though it has some activity against the human enzyme as well.

Mechanism of Interaction

The interaction between methotrexate and trimethoprim occurs through their shared mechanism as folate antagonists. Both drugs inhibit dihydrofolate reductase, the enzyme responsible for converting dihydrofolate to tetrahydrofolate, which is essential for DNA synthesis and cellular metabolism. When used together, their antifolate effects are additive, leading to enhanced folate depletion. This combined inhibition significantly increases the risk of methotrexate-related toxicity by further reducing the availability of active folate cofactors needed for normal cellular function, particularly in rapidly dividing cells such as those in the bone marrow and gastrointestinal tract.

Risks and Symptoms

The concurrent use of methotrexate and trimethoprim poses several serious clinical risks. The primary concern is increased methotrexate toxicity, which can manifest as severe bone marrow suppression leading to pancytopenia (decreased white blood cells, red blood cells, and platelets). Patients may experience increased susceptibility to infections, bleeding, and anemia. Gastrointestinal toxicity is also heightened, potentially causing severe mucositis, stomatitis, nausea, vomiting, and diarrhea. Hepatotoxicity may be exacerbated, and there is an increased risk of pulmonary toxicity. The interaction is considered clinically significant and may be life-threatening, particularly in elderly patients or those with compromised renal function.

Management and Precautions

Management of the methotrexate-trimethoprim interaction requires careful clinical assessment and monitoring. If possible, alternative antibiotics should be considered to avoid trimethoprim in patients taking methotrexate. When concurrent use is unavoidable, close monitoring is essential, including frequent complete blood counts, liver function tests, and renal function assessment. Leucovorin (folinic acid) rescue may be considered to counteract the enhanced antifolate effects. Patients should be educated about signs and symptoms of toxicity, including fever, sore throat, unusual bleeding or bruising, mouth sores, and persistent nausea or vomiting. Healthcare providers should consider temporary methotrexate dose reduction or discontinuation during trimethoprim therapy. Regular communication between prescribing physicians is crucial to ensure safe medication management.

Methotrexate interactions with food and lifestyle

Alcohol consumption should be avoided or strictly limited while taking methotrexate due to increased risk of liver toxicity and hepatotoxicity. Both methotrexate and alcohol can cause liver damage, and their combination significantly increases this risk. Patients should also maintain adequate hydration and avoid excessive sun exposure, as methotrexate can increase photosensitivity. Folic acid supplementation is commonly recommended to reduce certain side effects, though this should be discussed with a healthcare provider as timing and dosing are important.

Trimethoprim interactions with food and lifestyle

Trimethoprim should be taken with adequate fluid intake to prevent kidney stone formation. Alcohol consumption should be limited as it may increase the risk of side effects and reduce the effectiveness of the antibiotic. Patients should maintain adequate folate intake through diet, as trimethoprim can interfere with folate metabolism, though routine folate supplementation is typically not required for short-term use.