Phenytoin: pharmacogenetic polymorphism of 4'-hydroxylation

The metabolism of phenytoin via 4'-hydroxylation is subject to large inter-individual variability. The ratio of drug/metabolite (DPH/HPPH) in plasma and the reverse ratio for urine, metabolite/drug (HPPH/DPH), have been adopted to characterize the variability. Early recognition of the genetic/familial control of para(4'-)hydroxylation of phenytoin by Kutt and associates in the early 1960s was substantiated some 20 years later by Vasko et al. (1980) and Vermeij et al. (1988). The mode of inheritance has not been established. The frequency of 'insufficient' or slow hydroxylators is low, in the order of 1 in 500. The finding by Sloan et al. (1981) of an association between phenytoin 4'-hydroxylation and the well known debrisoquine/sparteine polymorphism was not confirmed later by several other groups. Formation of the R-enantiomer of HPPH was clearly deficient in some Caucasian subjects and was linked to the mephenytoin polymorphism as shown by Fritz and associates (1987).