OBJECTIVE Exogenous substrates were used to measure hepatic function for the purposes of determining organ dysfunction and to evaluate the effect of experimental hemorrhagic shock with resuscitation on hepatic drug elimination. METHODS Prospective, controlled, non-randomized crossover trial. METHODS Eleven chronically instrumented immature swine were studied using a fixed-volume hemorrhage model (45 mL/kg blood removal over 15 mins) followed by resuscitation with lactated Ringer's solution at three times the volume of shed blood. One week before and immediately after hemorrhage and resuscitation, hepatic function markers (indocyanine green and antipyrine) were simultaneously administered intravenously. METHODS Physiologic data and blood samples were collected over 12 hrs after drug administration. Drug clearances, volumes of distribution, and half-lives were determined. RESULTS For indocyanine green, there was no substantial change in pharmacokinetics from preshock to postshock, suggesting minimal change in hepatic blood flow. For antipyrine, clearance was decreased by 30% after shock and resuscitation (p = .05), suggesting that oxidative metabolism was acutely impaired. CONCLUSIONS The information indicates that hepatic oxidative drug metabolism may be impaired early after hemorrhagic shock and that dosages of drugs in this class should be carefully examined when administered to patients who have sustained injury with hemorrhagic shock.