Prolonged impairment of the plasma-protein binding of phenytoin in the rat after a single dose of sodium oleate

Abstract

The plasma-protein binding of phenytoin in rats was impaired for more than 14 days after a single injection of sodium oleate compared to that observed in saline-treated controls. A maximum free (unbound) phenytoin fraction value of about 0.30 was found between 30 and 120 min after oleate administration. The free fraction decreased to about 0.20 after 14 days. The free fraction of phenytoin in control rats was essentially constant over this period and averaged about 0.17. The impaired plasma-protein binding of phenytoin was unaffected by prolonged dialysis but was effectively reversed by charcoal treatment of the plasma. Comparison of the in vivo and in vitro effects of sodium oleate on phenytoin binding in plasma indicates that the reduction in binding is unrelated to the in vivo oleate concentration in plasma at the time of the binding determination. For example, 5 min after a bolus injection of oleate, the plasma free fraction of phenytoin was about 0.33. A comparable concentration of oleate in control plasma resulted in a free phenytoin fraction of only 0.21.