Inheritance of phenytoin hypometabolism: A kinetic study of one family

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 (t½) was 30.6 hr. The results in all subjects were used to determine t½ and volume of distribution (Vd). The mean t½ 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 t½ distribution. Three members of the kinship had t½ 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 t½ as well as 1 child with a t½ somewhat longer than the mean adult values. Other members of the kinship had normal t½s 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. Clinical Pharmacology and Therapeutics (1980) 27, 96–103; doi: 10.1038/clpt.1980.15