Phenytoin metabolism in mice.

Area of Science:

• Pharmacology
• Drug Metabolism
• Toxicology

Background:

• Phenytoin (5,5-diphenylhydantoin, DPH) is a widely used anticonvulsant medication.
• Understanding the dose-dependent metabolism of DPH is crucial for optimizing its therapeutic use and managing potential toxicity.

Purpose of the Study:

• To investigate the effect of varying doses of phenytoin on its metabolic pathways in adult male mice.
• To identify and quantify major urinary metabolites of DPH and determine their excretion patterns in relation to administered dose.

Main Methods:

• Adult male mice received a single intraperitoneal injection of 14C-labeled DPH at doses of 1, 20, or 100 mg/kg.
• Urine and feces were collected over 72 hours post-injection.
• Urinary metabolites including DPH, p-HPPH, DHD, OMCAT, and DPHA were separated and quantified using HPLC after appropriate sample preparation.

Main Results:

• Excretion of unchanged DPH and diphenylhydantoic acid (DPHA) increased with higher doses.
• The metabolite 5-(3-methoxy-4-hydroxyphenyl)-5-phenylhydantoin (OMCAT) decreased at higher doses.
• Excretion of 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) and 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin (DHD) remained constant across all doses, suggesting a common precursor.
• A small fraction of p-HPPH or DHD was converted to OMCAT, indicating dual pathways for OMCAT formation.

Conclusions:

• Phenytoin metabolism exhibits dose-dependent characteristics in mice.
• The formation of the catechol metabolite (DHD) appears to be independent of dose, while other metabolites show significant dose-related changes.
• These findings highlight the complexity of DPH metabolism and the potential for altered metabolic profiles at different therapeutic concentrations.