title: Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.
abstract: In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance 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 expected physiologic responses of inflammation including fever with increases in serum concentrations of TNF alpha, IL-1 beta, IL-6, and acute phase reactants. In the first experiment, only minor decreases in clearances of the probe drugs were observed (7-12%). However in the second 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. The decreases in AP clearance correlated with initial peak values of TNF 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 significantly decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients with much higher exposures to LPS have more profound inhibition of drug metabolism.
authors.affiliation: Department of Medicine, VA Hospital, Lexington, Kentucky 40511.
authors.forename: S I
authors.initials: SI
authors.lastname: Shedlofsky
authors.forename: B C
authors.initials: BC
authors.lastname: Israel
authors.forename: C J
authors.initials: CJ
authors.lastname: McClain
authors.forename: D B
authors.initials: DB
authors.lastname: Hill
authors.forename: R A
authors.initials: RA
authors.lastname: Blouin
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000983:Antipyrine / Q000493:pharmacokinetics; D002097:C-Reactive Protein / Q000032:analysis; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004731:Endotoxins / Q000494:pharmacology*; D006591:Hexobarbital / Q000493:pharmacokinetics; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate; D009961:Orosomucoid / Q000032:analysis; D010599:Pharmacokinetics; D013806:Theophylline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D004731:Endotoxins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009961:Orosomucoid; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital; D013806:Theophylline; D000983:Antipyrine