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Acute hepatotoxicity after high-dose methotrexate administration to rats
R M Bremnes1, E Smeland, N E Huseby
1Department of Pharmacology, University of Tromsø, Norway.
Pharmacology & Toxicology
|August 1, 1991
Summary
High doses of methotrexate (MTX) can cause acute liver damage in rats. The metabolite 7-hydroxy-methotrexate (7-OH-MTX) may precipitate in bile, leading to cholestasis and severe hepatotoxicity.
Area of Science:
- Toxicology
- Pharmacology
- Hepatology
Background:
- Methotrexate (MTX) is a chemotherapy agent with known hepatotoxicity.
- Understanding the mechanisms of MTX-induced liver injury is crucial for patient safety.
- Dose-limiting toxicities of MTX can impact treatment efficacy.
Purpose of the Study:
- To investigate the mechanisms of acute MTX-induced hepatotoxicity in rats.
- To evaluate the role of 7-hydroxy-methotrexate (7-OH-MTX) in MTX liver injury.
- To assess the impact of MTX dosage on liver function and bile composition.
Main Methods:
- Administered varying doses of MTX (10-1000 mg/kg) to rats.
- Monitored serum transaminases (ASAT, ALAT) and liver morphology.
- Analyzed disposition kinetics of MTX and 7-OH-MTX in serum and bile.
- Utilized bile duct cannulation in a subset of rats.
Main Results:
- High-dose MTX (1000 mg/kg) induced significant hepatotoxicity, evidenced by elevated transaminases and cellular damage.
- Bile-drained rats treated with high-dose MTX developed cholestasis.
- Biliary 7-OH-MTX levels in cholestatic rats reached precipitation thresholds, with 7-OH-MTX comprising 95% of precipitated material.
Conclusions:
- 7-hydroxy-methotrexate (7-OH-MTX) precipitation in bile is implicated in acute MTX hepatotoxicity.
- This mechanism may contribute to dose-limiting toxicity.
- Leukovorin rescue may not prevent MTX-induced liver injury mediated by 7-OH-MTX precipitation.