Phenytoin pharmacokinetics in burned rats and plasma protein binding of phenytoin in burned patients.

Unexpectedly low serum phenytoin levels occurred in burned epileptic patients, suggesting the possibility of altered phenytoin disposition. Subsequently, phenytoin log-linear elimination kinetics after a 10 mg/kg i.v. single dose was examined in a burned rat model. Clearance increased from 1.08 +/- 0.28 liters/hr/kg in control rats to 1.50 +/- 0.38 liters/hr/kg in burned rats (P less than .05). The volume of distribution increased from 0.82 +/- 0.058 liters/kg in control rats to 1.01 +/- 0.11 liters/kg in burned rats (P less than .0005). The first order elimination rate constant (KE) did not change significantly (1.31 +/- 0.37) hr-1 in control rats vs. 1.52 +/- 0.48 hr-1 in burned rats; P greater than .05). The increase in clearance and in volume of distribution could be explained on the basis of a decrease in plasma protein binding. The free fraction in plasma increased from 27.1% +/- 1.2 in controls to 33.4% +/- 1.6 in burned rats (P less than .0005). The change in binding was consistent with a decrease in serum albumin from 2.64 +/- 0.33 g/dl in controls to 1.98 +/- 0.16 g/dl in burned rats (P less than .0005). Plasma samples of four burned human subjects revealed low serum albumin and markedly decreased plasma protein binding of phenytoin (2- to 3-fold increase in free fraction in plasma).