High-dose 7-hydromethotrexate: acute toxicity and lethality in a rat model

Area of Science:

• Pharmacology
• Toxicology
• Nephrology

Background:

• Methotrexate (MTX) is a vital chemotherapy agent.
• MTX metabolism produces 7-hydroxymethotrexate (7-OH-MTX), a metabolite implicated in toxicity.
• Mechanisms underlying MTX-induced renal and hepatic toxicity require further elucidation.

Purpose of the Study:

• To investigate the acute toxic effects of 7-OH-MTX in a rat model.
• To characterize the dose-dependent lethality and organ-specific toxicity of 7-OH-MTX.

Main Methods:

• Administration of varying doses of 7-OH-MTX via bolus plus continuous infusion in rats.
• Monitoring of animal survival, serum 7-OH-MTX concentrations, and biochemical markers (creatinine, liver transaminases).
• Histopathological examination of renal and hepatic tissues for morphological changes and evidence of precipitation.

Main Results:

• Acute lethal toxicity observed within hours of 7-OH-MTX administration, with an estimated LD50 of 0.3 g/kg.
• Significant renal and hepatic toxicity, evidenced by morphological damage and elevated serum creatinine and transaminases.
• Microscopic yellow precipitations observed in kidney tubules and hepatic bile ducts, indicating drug crystallization.

Conclusions:

• 7-OH-MTX exhibits acute lethal toxicity and causes significant renal and hepatic damage in rats.
• The formation of 7-OH-MTX during MTX therapy is detrimental.
• Strategies aimed at preventing 7-OH-MTX formation are clinically relevant and warranted.