Genetic polymorphism of S-mephenytoin 4'-hydroxylation

The anticonvulsant drug mephenytoin is available as a racemic mixture of the S and R enantiomers. The S enantiomer is selectively 4'-hydroxylated in the liver by the cytochrome P450 enzyme, CYP2C19. This reaction has a polymorphic distribution in human populations. Racemic mephenytoin has been extensively used as a probe drug to assign metabolic phenotypes for this genetically-determined polymorphism. Specific base substitution mutations in the CYP2C19 gene are responsible for the poor metabolism (PM) phenotype which is inherited as a recessive autosomal trait. The poor metabolizers (PMs) of S-mephenytoin are homozygous for these mutations. In contrast, extensive metabolizers (EMs) are either heterozygous or homozygous for the wild-type allele(s). Poor metabolizers have the inactive enzyme and therefore have reduced ability to metabolize substrates of CYP2C19, many of which are psychotropic drugs. Genotyping an individual before treatment with substrates of CYP2C19 will reduce the risk of side effects and improve compliance in PMs. The prevalence of PMs is relatively low in African-Americans and Caucasians and is as high as 20 percent in Asian populations.