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Interactions of valproic acid with phenytoin

Neurology Service, Veterans Administration Medical Center and University of Florida College of Medicine (Drs. Bruni and Wilder), University of Florida College of pharmacy (Drs. Gallo and Lee), and the Veterans Administration Research Service, Veterans Administration Medical Center (Mr. Perchalski), Gainesville, FL.

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 deccreased 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.

Address correspondence and reprint requests to Dr. Bruni, Room 318, E. K. Jones Building, Wellesley Hospital, 160 Wellesley Street East, Toronto, Ontario M4Y 1J3, Canada.

Accepted for Publication January 23, 1980.

This work was supported by the Medical Research Service of the Veterans Administration and the Epilepsy Research Foundation of Florida, Inc. Dr. Bruni was sponsored by the Ministry of Health, Ontario, Canada.