Interactions of valproic acid with phenytoin

The interaction of phenytoin and valproic acid was studied in four adults. We studied serial changes in total phenytoin concentrations, protein binding, urinary hydroxyphenylphenylhydantoin (HPPH) excretion, and half-life. In all four patients valproic acid caused an increase in the free fraction of phenytoin. Total phenytoin plasma concentrations decreased transiently in three patients and remained low throughout the study period in one patient. HPPH excretion increased transiently and then decreased, corresponding to changes in total phenytoin plasma concentrations. Biologic half-life transiently decreased in three patients (not statistically significant) and subsequently increased significantly in all four patients. The data suggest that valproic acid displaced phenytoin from protein-binding sites in all four patients and subsequently inhibited phenytoin metabolism in three patients.