Probenecid and Methotrexate Injection: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Probenecid
No brand names on recordMethotrexate Injection
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Increased methotrexate exposure, an increased risk of methotrexate toxicity or methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy
Interaction Deep Dive
Concomitant use of methotrexate and probenecid has resulted in greatly increased serum methotrexate levels2341. which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with probenecid may also subsequently reduce active metabolite formation, which may reduce the clinical effectiveness of methotrexate. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions 1.
Why it happens (mechanism)
Reduced methotrexate absorption/clearance
Literature reports
3 reports — tap to read
a) Concomitant probenecid and methotrexate therapy is reported to result in reduction of the renal clearance of methotrexate by interfering with tubular secretion in the proximal tubule 5.
b) Recent studies have showed that probenecid failed to prolong methotrexate half-life in the cerebrospinal fluid (CSF) despite increasing CSF methotrexate concentrations two- to four- fold. Low levels of methotrexate in CSF would be desirable in some instances and associated with less neurotoxicity 3.
c) Administration of oral probenecid (500 mg every six hours) for five doses beginning 12 hours before the administration of methotrexate (50 mg/m2 intravenous bolus with 100 mg/m2 oral every three hours) for eight doses in 10 patients resulted in a doubling of the serum methotrexate level with a significant increase in the area under the concentration-time curve 6.
Common questions
Can I take Probenecid and Methotrexate Injection together?
Increased methotrexate exposure, an increased risk of methotrexate toxicity or methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy Always confirm with your pharmacist or prescriber before making any change.
How serious is the Probenecid and Methotrexate Injection interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "rapid". Effects can appear quickly, often within about 24 hours of combining the drugs.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Probenecid or Methotrexate Injection need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (6)
- Product Information: JYLAMVO oral solution, methotrexate oral solution. Shorla Oncology Inc (per FDA), Cambridge, MA, 2024. DailyMed
- Aherne GW, Piall E, Marks V, et al: Prolongation and enhancement of serum methotrexate concentrations by probenecid. Br Med J 1978; 1:1097-1099. PubMed
- Howell SB, Olshen RA, & Rice JA: Effect of probenecid on cerebrospinal fluid methotrexate kinetics. Clin Pharmacol Ther 1979; 26:641-646. DOI
- Basin KS, Escalante A, & Beardmore TD: Severe pancytopenia in a patient taking low dose methotrexate and probenecid. J Rheumatol 1991; 18:609-610.
- Liegler DG, Henderson ES, Hahn MA, et al: The effect of organic acids on renal clearance of methotrexate in man. Clin Pharmacol Ther 1969; 10:849-857. PubMed
- Lilly MB & Omura GA: Clinical pharmacology of oral intermediate-dose methotrexate with or without probenecid. Cancer Chemother Pharmacol 1985; 15:220-222. DOI
Keep reading about Probenecid
Keep reading about Methotrexate Injection
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