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Biochemical and pharmacological consequences of the interaction between methotrexate and ketoprofen in the rabbit

A Perrin1, G Milano, A Thyss

  • 1Centre Antoine Lacassagne, Nice, France.

British Journal of Cancer
|November 1, 1990
PubMed

Insights

Combining methotrexate (MTX) with ketoprofen (KP) can cause kidney damage, especially at higher MTX doses. This interaction affects MTX clearance and excretion, highlighting the renal origin of toxicity.

Area of Science:

  • Pharmacology
  • Toxicology
  • Nephrology

Background:

  • Methotrexate (MTX) toxicity is a known risk when co-administered with non-steroidal anti-inflammatory drugs (NSAIDs).
  • Understanding the specific interaction between MTX and ketoprofen (KP) is crucial for patient safety.

Purpose of the Study:

  • To investigate the pharmacokinetic and toxicodynamic interaction between MTX and KP in a rabbit model.
  • To determine the effect of KP pretreatment on MTX-induced renal dysfunction and MTX elimination.

Main Methods:

  • Rabbits were administered MTX (50 or 100 mg kg-1) with or without prior 8-day pretreatment of KP (3 mg kg-1 day-1).
  • Renal function was assessed by monitoring blood urea and creatinine levels.
  • MTX pharmacokinetics, including clearance and urinary excretion, were analyzed.
  • Urinary prostaglandin 6-keto-PGF1 alpha levels were measured.

Main Results:

  • Co-administration of MTX and KP led to a reversible increase in blood urea and creatinine, dose-dependent on MTX.
  • KP pretreatment significantly reduced urinary 6-keto-PGF1 alpha excretion by 70%.
  • At higher MTX doses, KP reduced MTX total body and renal clearance, and the fraction eliminated in urine.
  • A reduction in MTX plasma binding was observed in vivo with KP co-administration.

Conclusions:

  • Ketoprofen interacts with methotrexate, primarily causing renal toxicity.
  • The interaction involves altered MTX pharmacokinetics, reduced renal clearance, and decreased urinary excretion.
  • This study confirms the renal origin of MTX-KP drug interaction toxicity.

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