Summary

Probenecid significantly increases methotrexate blood levels by blocking its kidney elimination, leading to potentially dangerous methotrexate toxicity. This interaction requires careful monitoring and possible dose adjustments when both medications are used together.

Introduction

Methotrexate is an antifolate medication commonly used to treat rheumatoid arthritis, psoriasis, and certain cancers by inhibiting cell division and immune system activity. Probenecid is a uricosuric agent primarily prescribed for gout management and as an adjunct to increase antibiotic levels by blocking their renal elimination. Both drugs are processed through the kidneys, which creates the potential for significant pharmacokinetic interactions.

Mechanism of Interaction

Probenecid inhibits the organic anion transporters (OAT1 and OAT3) in the proximal tubules of the kidneys, which are responsible for actively secreting methotrexate from the blood into the urine. When probenecid blocks these transporters, methotrexate clearance is significantly reduced, leading to elevated and prolonged blood levels of methotrexate. This mechanism can increase methotrexate concentrations by 2-3 fold, substantially raising the risk of dose-dependent toxicities.

Risks and Symptoms

The primary risk of this interaction is methotrexate toxicity, which can manifest as severe bone marrow suppression (leading to dangerous drops in white blood cells, red blood cells, and platelets), liver toxicity with elevated enzymes, kidney damage, and gastrointestinal toxicity including severe mucositis and diarrhea. These effects can be life-threatening, particularly in elderly patients or those with pre-existing kidney or liver dysfunction. The interaction is considered clinically significant and requires immediate attention when both drugs are prescribed together.

Management and Precautions

When this combination cannot be avoided, methotrexate doses should be reduced by 25-50% and patients require intensive monitoring including weekly complete blood counts, liver function tests, and kidney function assessments. Leucovorin (folinic acid) rescue may be necessary to counteract methotrexate toxicity. Healthcare providers should consider alternative medications when possible, such as using different gout treatments instead of probenecid. Patients must be educated about early signs of methotrexate toxicity including unusual fatigue, easy bruising, mouth sores, and persistent nausea, with instructions to seek immediate medical attention if these occur.

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.

Probenecid interactions with food and lifestyle

Probenecid should be taken with food or milk to reduce gastrointestinal irritation and improve tolerance. Adequate fluid intake (at least 2-3 liters per day) is recommended to prevent kidney stone formation, as probenecid can increase uric acid excretion in urine. Alcohol consumption should be limited or avoided, as alcohol can increase uric acid levels and counteract the uric acid-lowering effects of probenecid, potentially reducing its effectiveness in treating gout.