Mephenytoin hydroxylation deficiency: kinetics after repeated doses

Area of Science:

• Pharmacogenetics
• Drug Metabolism
• Enzyme Kinetics

Background:

• Mephenytoin is metabolized stereoselectively in humans.
• Aromatic hydroxylation is a key metabolic pathway for S-mephenytoin.
• Genetic variations can influence drug metabolism pathways.

Purpose of the Study:

• To investigate a suspected genetic defect in S-mephenytoin aromatic hydroxylation.
• To elucidate the kinetic implications of this metabolic deficiency.
• To compare drug metabolism in a deficient subject versus normal individuals.

Main Methods:

• Kinetic study using differentially radiolabeled pseudoracemic mephenytoin.
• Administration of single and repeated oral doses of mephenytoin.
• Quantification of urinary metabolites, including 4-hydroxymephenytoin (4-OH-M) and 5-phenyl-5-ethylhydantoin (PEH).

Main Results:

• The index subject exhibited deficient aromatic hydroxylation of S-mephenytoin.
• Normal subjects showed stereoselective metabolism, with rapid S-mephenytoin excretion as 4-OH-M.
• The deficient subject showed low 4-OH-M recovery and slow excretion of both enantiomers, primarily as PEH, with elevated PEH levels.

Conclusions:

• A genetic deficiency in S-mephenytoin hydroxylation was confirmed.
• This defect redirects S-mephenytoin metabolism to demethylation, increasing PEH formation and accumulation.
• The findings highlight the clinical significance of stereoselective metabolism and genetic variability in drug response.