Abstract

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).