Plasma protein binding of phenytoin in health and disease: relevance to therapeutic drug monitoring.

It is generally accepted that only the unbound drug in plasma is in equilibrium with drug in the biophase. Under these circumstances, routine measurement of total drug levels in plasma can be justified only if the interpatient variability in protein binding is small. In the case of phenytoin, this is not always true. Important alterations in the plasma protein binding of phenytoin may occur in the perinatal period, in late pregnancy, in hepatic disease, in renal failure, in the nephrotic syndrome and other conditions associated with hypoalbuminemia, and in the presence of displacing agents such as valproic acid, phenylbutazone, and salicylic acid. Changes in protein binding may alter substantially the relationship between the plasma concentration of total drug and the magnitude of pharmacological effect. This possibility needs to be taken into account when interpreting serum phenytoin levels in clinical practice.