Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism

J Clin Invest. 1994 Dec;94(6):2209-14. doi: 10.1172/JCI117582.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Adult
  • Antipyrine / pharmacokinetics
  • C-Reactive Protein / analysis
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Endotoxins / pharmacology*
  • Hexobarbital / pharmacokinetics
  • Humans
  • Interleukin-6 / blood
  • Lipopolysaccharides / pharmacology*
  • Liver / enzymology
  • Male
  • Metabolic Clearance Rate
  • Orosomucoid / analysis
  • Pharmacokinetics*
  • Theophylline / pharmacology
  • Tumor Necrosis Factor-alpha / analysis

Substances

  • Endotoxins
  • Interleukin-6
  • Lipopolysaccharides
  • Orosomucoid
  • Tumor Necrosis Factor-alpha
  • C-Reactive Protein
  • Cytochrome P-450 Enzyme System
  • Hexobarbital
  • Theophylline
  • Antipyrine