EFFECT OF NEUROTRAUMA ON HEPATIC DRUG CLEARANCE

Lorazepam, antipyrine, and indocyanine green were administered to 10 patients with severe head injuries as marker substrates of hepatic glucuronidation, oxidation, and hepatic blood flow, respectively. Pharmacokinetic parameter estimates were determined at baseline (20 to 80 hours after injury) and up to three additional times thereafter (study days 4, 7, and 14). Antipyrine clearance was increased significantly from baseline (0.50 +/- 0.31 ml/min/kg) on study days 4, 7, and 14 (p < 0.0001). Increases in antipyrine clearance from baseline to the last study day were observed in all study patients ranging from 14% to 207%. A significant increase was also observed in lorazepam clearance on study day 14 relative to baseline (1.39 +/- 0.56 ml/min/kg) (p < 0.005). Increases in lorazepam clearance occurred in seven of nine patients over time ranging from 9% to 13O%. The unbound fraction of lorazepam did not change significantly over the study period. Likewise, no significant change was observed in the clearance of indocyanine green over time. Antipyrine clearance and alpha-1-acid glycoprotein (r = 0.41), and lorazepam clearance and C-reactive protein (r = -0.38) were significantly correlated (p < 0.05). Similarly, antipyrine and lorazepam clearances were significantly correlated with injury severity based on the Acute Physiologic and Chronic Health Evaluation (APACHE II) score (r = -0.43 and r = -O.37, respectively). These findings suggest that hepatic oxidative and conjugative metabolism increase significantly over time in patients after acute head injury. An awareness of the potential for pharmacokinetic alterations in similarly metabolized drugs used for patients with severe head injuries is recommended.