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Biochemical and pharmacological consequences of the interaction between methotrexate and ketoprofen in the rabbit
Abstract:
Severe methotrexate (MTX) toxicity is a proven complication of associations of MTX and non-steroidal anti-inflammatory drugs (NSAIDs). This study investigated the interaction between MTX (50 or 100 mg kg-1) and ketoprofen (KP) (3 mg kg-1 day-1, pretreatment for 8 days) in the rabbit. The drug association induced a reversible increase in blood urea and creatinine. The severity degree of renal dysfunction was significantly related to the MTX dose; it was not modified by prolonged exposure to KP after MTX administration. The biological markers of haematopoietic and hepatic functions were unchanged. Pretreatment by KP induced a marked reduction (70%) in the urinary excretion of the prostaglandin 6-keto-PGF1 alpha. MTX dose-related alterations in MTX pharmacokinetics were also observed with the drug association: at a MTX dose of 100 mg kg-1, the presence of KP significantly reduced the total body clearance, the renal clearance and the fraction of MTX eliminated in urine as compared to controls. An appreciable reduction in the plasma binding of MTX was also noted in vivo when KP was associated. This experimental study confirms the existence of an interaction between MTX and KP and demonstrates its renal origin.
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.