Methotrexate and nonsteroidal antiinflammatory drug interactions

Ann Pharmacother. 1992 Feb;26(2):234-7. doi: 10.1177/106002809202600219.


Objective: To determine if the coadministration of methotrexate (MTX) and nonsteroidal antiinflammatory drugs (NSAIDs) results in a clinically significant drug interaction.

Data sources: A case report of hematologic toxicity following the administration of MTX and flurbiprofen at our institution is presented. Six previously published case reports and five pharmacokinetic studies regarding MTX and NSAID interactions are available to assist in the evaluation of this potential interaction.

Data synthesis: Cases of various clinical manifestations during concomitant MTX and NSAID administration, including acute renal failure and pancytopenia, have been reported. The exact mechanism of the interaction has not been fully elucidated. Suggested theories to explain the mechanism of MTX toxicity include reduction in MTX clearance secondary to renal capillary constriction induced by NSAIDs, displacement of MTX or its metabolite from plasma proteins, competition between MTX and NSAIDs for renal tubular excretion, or impairment of hepatic metabolism of MTX by NSAIDs. Studies comparing MTX pharmacokinetics with or without concurrent NSAID therapy have not shown statistical differences in the parameters evaluated. However, one study did demonstrate differences in the pharmacokinetics of 7-hydroxy-methotrexate, the active metabolite of MTX, when MTX was administered with aspirin.

Conclusions: Although a clinically significant interaction does not occur in all patients, numerous case reports are available that demonstrate possible problems following the coadministration of MTX and NSAIDs. To date, the specific circumstances during which the reaction may occur have not been well defined.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Adult
  • Aged
  • Blood Component Transfusion
  • Drug Interactions
  • Female
  • Flurbiprofen / administration & dosage
  • Flurbiprofen / adverse effects*
  • Folic Acid / therapeutic use
  • Hospitalization
  • Humans
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects*
  • Ranitidine / therapeutic use
  • Sucralfate / therapeutic use
  • Vitamin K / therapeutic use


  • Vitamin K
  • Sucralfate
  • Flurbiprofen
  • Ranitidine
  • Folic Acid
  • Methotrexate