Methotrexate Injection and Mercaptopurine: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Methotrexate Injection
Mercaptopurine
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
Mercaptopurine toxicity, increased methotrexate exposure, an increased risk of methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy
Interaction Deep Dive
Coadministration of methotrexate with hepatotoxic agents like mercaptopurine may increase methotrexate exposure, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with mercaptopurine 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. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic products1. Concomitant administration of oral mercaptopurine (75 mg/m(2)) and oral methotrexate (20 mg/m(2)) was reported to result in significant increases in area under the concentration-time curve (AUC) and peak mercaptopurine serum levels (31% and 26%, respectively). This interaction is probably not significant with standard low oral doses of methotrexate 2.
Why it happens (mechanism)
Reduced xanthine oxidase metabolism; additive hepatotoxicity; reduced methotrexate absorption
Literature reports
1 report — tap to read
a) Concomitant administration of oral mercaptopurine (75 mg/m(2)) and oral methotrexate (20 mg/m(2)) was reported to result in significant increases in area under the concentration-time curve (AUC) and peak mercaptopurine serum levels (31% and 26%, respectively). This interaction is probably not significant with standard low oral doses of methotrexate 2.
Common questions
Can I take Methotrexate Injection and Mercaptopurine together?
Mercaptopurine toxicity, increased methotrexate exposure, an increased risk of 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 Methotrexate Injection and Mercaptopurine interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
Questions for your pharmacist
- Does my dose of Methotrexate Injection or Mercaptopurine 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 (2)
Keep reading about Methotrexate Injection
Keep reading about Mercaptopurine
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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