Phenotypic differences in mephenytoin pharmacokinetics in normal subjects.

Area of Science:

• Pharmacology
• Drug Metabolism
• Clinical Pharmacokinetics

Background:

• Mephenytoin exhibits stereoselective metabolism, with significant differences observed between its enantiomers.
• Polymorphic oxidation affects approximately 2-5% of Caucasians, impairing mephenytoin's 4-hydroxylation.
• Understanding these metabolic differences is crucial for predicting drug efficacy and toxicity.

Purpose of the Study:

• To investigate the plasma concentration-time profiles of mephenytoin enantiomers and their metabolite, phenylethylhydantoin (PEH).
• To compare these profiles in individuals with different mephenytoin metabolizing abilities: extensive metabolizers (EMs) and poor metabolizers (PMs).

Main Methods:

• Administration of a single oral dose of racemic mephenytoin to human subjects.
• Categorization of subjects into EM and PM phenotypes based on their mephenytoin metabolizing ability.
• Analysis of plasma concentrations of mephenytoin enantiomers and PEH over time.

Main Results:

• In EMs, S-mephenytoin clearance was 100-200 times higher than R-mephenytoin, with shorter half-lives.
• R-PEH accumulated significantly in EMs, with a very long elimination half-life (approx. 200 hr), while S-PEH levels were negligible.
• In PMs, stereoselective elimination of mephenytoin was reduced, with similar disposition for both enantiomers and comparable S- and R-PEH plasma levels.

Conclusions:

• Mephenytoin's metabolism is highly stereoselective, with significant differences between EMs and PMs.
• Impaired mephenytoin oxidation in PMs leads to altered drug and metabolite pharmacokinetics.
• These findings highlight the clinical relevance of pharmacogenetic variations in drug metabolism.