Interaction between phenytoin and valproic acid: Plasma protein binding and metabolic effects

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Abstract
The effect of sodium valproate (400 mg 3 times daily) on the disposition kinetics of i.v. phenytoin (250 mg) was investigated in 7 normal human subjects. After valproate, the free (unbound) fraction of phenytoin in serum rose from 9.6 .+-. 0.9% (SD) to 15.6 .+-. 1.4% on average (P < 0.001). The effect was associated with an increase in systemic clearance and apparent volume of distribution of total drug. There was a strong positive correlation between percent increment in each of these parameters and percent increment in unbound drug in serum. Free phenytoin concentration in serum and phenytoin concentration in saliva increased during valproate administration. As a result, both the clearance and the apparent volume of distribution of free drug were reduced. There was an increase in the renal excretion of unchanged phenytoin during valproate administration, but the effect was too small to have an appreciable influence on the overall clearance of the drug. There were no consistent changes in the excretion of the major metabolite 5,p-hydroxyphenyl,5-phenyl, hydantoin (pHPPH), in the urine. These results suggest that valproic acid may have 2 separate and opposing effects on phenytoin disposition: displacing phenytoin from plasma protein binding sites, enhancing the systemic clearance of total drug, and inhibiting phenytoin metabolism, thereby increasing the concentration of free drug in the serum. Both drugs are commonly used in the treatment of epilepsy.