To determine whether the slow p-hydroxylation of phenytoin (PHT) is an inherited train, we studied its kinetics in members of a single family in which the trait was observed and in nonfamily control subjects. Each subject was given 5 mg/kg PHT intravenously; plasma and urine samples collected at various intervals after administration were analyzed for PHT or its major metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). Initially. 1 member of the family was observed for 6 mo on oral PHT. The subject became clinically intoxicated on 4.6 mg/kg/day PHT with a plasma level of 52 μg/ml; less than 50% of the dose was excreted as the major metabolite and after 3 mg/kg PHT intravenously, half-life (t 1 2) was 30.6 hr. The results in all subjects were used to determine t 1 2 and volume of distribution (Vd). The mean t 1 2 for the control population was 18.6 ± 3.4 hr and for the family was 24.2 ± 4.2 hr. Individual members of each population were sufficiently far from the mean to suggest a bimodal t 1 2 distribution. Three members of the kinship had t 1 2 for intravenous PHT more than 2 standard deviations longer than the control population mean. HPPH excretion was extremely low in the 3 family, members with long t 1 2 as well as 1 child with a t 1 2 somewhat longer than the mean adult values. Other members of the kinship had normal t'/2s and normal excretion. Vd for all family members was in the normal range. Since hypometabolism was seen in 3 of 4 generations of the kinship and since a bimodal distribution was observed for PHT metabolism, we conclude that it is an inherited trait. The mode of inheritance is not known at this time.
ASJC Scopus subject areas
- Pharmacology (medical)