The elimination of phenytoin in man

ABSTRACT

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 diminished as the dose increased. 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 K_m value for the adults corresponded to a plasma drug concentration of 5·8 μg/ml, and in the children to 5·3 μg/ml. The mean V_max values in the two groups were, respectively 8·1 mg/kg per day and 12·5 mg/kg per day.