Effect of acute phase response on phenytoin metabolism in neurotrauma patients

The purpose of this prospective study was to correlate measures of the acute phase response, associated therapeutic interventions, and other clinical variables with the process of altered drug metabolism previously observed in patients with severe neurotrauma. Nine patients with severe head injury (Glasgow Coma Scale < or = 8) requiring intravenous phenytoin were included in the study. A loading dose of phenytoin was followed by daily maintenance doses. Serial blood samples were taken after the loading dose and every even-numbered study day for 10 to 14 days for measurement of total and unbound concentrations of phenytoin, interleukin-1 beta, interleukin-6 (IL-6), tumor necrosis factor alpha, alpha 1-acid-glycoprotein, C-reactive protein, and albumin. Time-invariant and time-variant Michaelis-Menten models were fit to the phenytoin concentration-time data. Protein intake was closely monitored. The mean (+/- SEM) unbound fraction of phenytoin increased from 0.17 +/- 0.02 on day 1 to 0.24 +/- 0.04 on day 10 (P < 0.05). The time-variant model was superior in describing the concentration-time data of unbound phenytoin in eight of nine patients. Mean (+/- SEM) pharmacokinetic parameter estimates for unbound phenytoin were: Vmax delta = 605 +/- 92 mg/day, VmaxB = 149 +/- 26.3 mg/day, K(ind) = 0.013 +/- 0.004 hr-1. Interleukin-6 was the only cytokine with significant concentration changes over time; it was inversely correlated with Vmax,t. Peak concentrations of interleukin-6 also proved to be inversely correlated with VmaxB. The daily amount of protein administered was significantly correlated with Vmax,t. Significant alterations in the metabolism of phenytoin occur after severe neurotrauma. The etiology of these changes is probably multifaceted. These results suggest that low initial phenytoin Vmax may be explained by the presence of interleukin-6. An increase in oxidative metabolism that correlated with nutritional protein administration was observed later in these patients.