ENDOTOXIN ADMINISTRATION TO HUMANS INHIBITS HEPATIC CYTOCHROME P450-MEDIATED DRUG-METABOLISM

In experimental animals, injection of gram-negative endotoxin (LPS) de creases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was admi nistered on two consecutive days to healthy male volunteers during whi ch time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg) , and theophylline (TH-150 mg) was ingested and the apparent oral clea rance of each drug determined. Each subject had a control drug clearan ce study with saline injections. In the first experiment, six subjects received the drug cocktail 0.5 h after the first dose of LPS. In the second experiment, another six subjects received the drug cocktail 0.5 h after the second dose of LPS. In both experiments, LPS caused the e xpected physiologic responses of inflammation including fever with inc reases in serum concentrations of TNF alpha, IL-1 beta, IL-6, and acut e phase reactants. In the first experiment, only minor decreases in cl earances of the probe drugs were observed (7-12%). However in the seco nd experiment, marked decreases in the clearances of AP (35, 95% CI 18 -48%), HB (27, 95% CI 14-34%), and TH (22, 95% CI 12-32%) were seen. T he decreases in AP clearance correlated with initial peak values of TN F alpha (r = 0.82) and IL-6 (r = 0.86). These data show that in humans the inflammatory response to even a very low dose of LPS significantl y decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients w ith much higher exposures to LPS have more profound inhibition of drug metabolism.