The elimination of phenytoin in man

1. Plasma phenytoin (diphenylhydantoin) levels after different drug doses were correlated with urinary 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) excretions in four subjects. 2. In three of four subjects the proportion of the phenytoin dose that was excreted as p-HPPH. In the fourth, p-HPPH output remained proportionate to dose of phenytoin until elimination of the drug fell below its input. 3. Plasma p-HPPH levels were measured in two subjects; the data suggested that the renal excretion of p-HPPH was not rate-limited. 4. In three of four subjects, there was the possibility that alternative pathways for eliminating phenytoin may have developed as drug doses increased and the capacity for forming p-HPPH became saturated. 5. Overall phenytoin elimination appeared to approach saturation at concentrations of the drug encountered therapeutically. When Michaelis-Menten kinetics were applied to data for phenytoin elimination in twenty-one adults and fifteen children, the mean apparent Km value for the adults corresponded to a plasma drug concentration of 5-8 mug/ml, and in the children to 5-3 mug/ml. The mean Vmax values in the two groups were, respectively 8-1 mg/kg per day and 12-5 mg/kg per day.