Mephenytoin hydroxylation deficiency: Kinetics after repeated doses

Deficient aromatic hydroxylation of S ‐mephenytoin was observed in an index subject during a kinetic study of stereoselective metabolism of mephenytoin. A genetic basis for this defect was suggested by decreased urinary recovery of 3‐methyl‐5‐(4‐hydroxyphenyl)‐5‐ethylhydantoin (4‐OH‐M) in the 24 hr after oral racemic mephenytoin in two brothers of the propositus. The parents and a third brother had urinary recoveries of 4‐OH‐M of the same order as in a group of 20 normal subjects. The kinetic implications of this defect were studied in the index subject and compared with four normal subjects after a single oral dose of differentially radiolabeled pseudoracemic mephenytoin (5 µCi of 14 C‐S‐mephenytoin, 45 µCi of H 3 ‐R‐mephenytoin, and 11.5 µmol/kg of both S‐ and R‐mephenytoin) followed by single oral doses of 1.4 mmol of unlabeled racemic mephenytoin daily the next 4 days. In normal subjects, there was substrate stereoselective metabolism with the S‐enantiomer rapidly excreted as 4‐OH‐M and the R‐enantiomer slowly excreted as 5‐phenyl‐5‐ethylhydantoin (PEH). Stereoselective metabolism persisted during repeated dosing. In the hydroxylation‐deficient subject, there was no evidence of stereoselective metabolism, recovery of 4‐OH‐M was low, and both enantiomers were slowly excreted, predominantly as PEH. Plasma PEH concentrations and urinary PEH excretion rates were approximately twice that in normal subjects. Thus a genetic deficiency in ability to hydroxylate S‐mephenytoin results in the S‐enantiomer metabolization by the alternate route of demethylation to PEH that cumulates, thereby, in comparison to the normal, effectively doubling the dose of total hydantoin. Clinical Pharmacology and Therapeutics (1984) 35, 33–39; doi: 10.1038/clpt.1984.5