The genetic defect of mephenytoin hydroxylation.
The antiepileptic drug mephenytoin is a racemate. Mephenytoin hydroxylation is a stereospecific reaction and is confined to the S-enantiomer, which is normally eliminated within hours, allowing the R-enantiomer to accumulate since it can be eliminated only within days or weeks. The inborn deficiency of this hydroxylase prevents the rapid elimination of S-mephenytoin causing it to linger in the body along with R-mephenytoin. Thus, the normal hydantoin levels in blood are doubled with corresponding toxic sequelae. Studies in vitro with liver preparations derived from kidney donors indicate that the hydroxylation depends on a single catalytic site of cytochrome P-450. Sixty-four drugs were screened for their ability to bind to this genetically variable cytochrome, using inhibition studies. The small group of drugs with some ability to bind to mephenytoin hydroxylase included benzodiazepines and inhibitors of mono-amino-oxidase. At this time, there is no clinical evidence that the hydroxylation deficiency of mephenytoin affects any other drug. The sum of data from various authors indicates a frequency of poor metabolizers of 4.8% (1.9-8.0% at a 99.6% confidence range) among 459 persons of European extraction. There were seven poor metabolizers among 31 Canadians of Japanese extraction (23%), and two among 39 Canadian Chinese (5%).
D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D005787:Gene Frequency; D014644:Genetic Variation; D005826:Genetics, Medical; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008617:Mephenytoin / Q000031:analogs & derivatives / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000172:deficiency / Q000235:genetics*; D013329:Structure-Activity Relationship
C014544:ethylphenylhydantoin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008617:Mephenytoin