title: Endotoxin depresses hepatic cytochrome P450-mediated drug metabolism in women.
abstract: OBJECTIVE
  In men, the inflammatory response to intravenous endotoxin depresses apparent oral clearances of antipyrine, hexobarbitone, and theophylline. The aim of this study was to investigate whether there might be gender differences in the regulation of hepatic cytochromes P450.
  
  
  METHODS
  Experiments were carried out in seven healthy women volunteers (ages 19-51, median 22 years). Each woman received a cocktail of the three drugs on two occasions, once after a saline injection and again after endotoxin.
  
  
  RESULTS
  Endotoxin injections, but not saline, caused the expected physiologic responses of inflammation including fever and increases in circulating tumor necrosis factor-alpha, interleukin-6, and C-reactive protein. When compared with the saline control studies, endotoxin significantly decreased clearances of all probes: antipyrine, 31% (95%CI 21%-41%); hexobarbitone, 20% (95%CI 10-31%); and theophylline, 20% (95%CI 10%-30%). The decreases were comparable with those found in the men previously studied (35%, 27%, and 22%, respectively).
  
  
  CONCLUSIONS
  These data show that endotoxin-induced inflammation decreases hepatic cytochrome P450-mediated metabolism of selected probe drugs in women as it does in men.
authors.affiliation: Department of Medicine-Division of Digestive Diseases, VA Hospital, Lexington, Kentucky 40511, USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Shedlofsky
authors.forename: B C
authors.initials: BC
authors.lastname: Israel
authors.forename: R
authors.initials: R
authors.lastname: Tosheva
authors.forename: R A
authors.initials: RA
authors.lastname: Blouin
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics*; D000983:Antipyrine / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002097:C-Reactive Protein / Q000032:analysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D005334:Fever / Q000139:chemically induced; D006591:Hexobarbital / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics*; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged; D009391:Nephelometry and Turbidimetry; D010726:Phosphodiesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D012044:Regression Analysis; D013806:Theophylline / Q000097:blood / Q000493:pharmacokinetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D006993:Hypnotics and Sedatives; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital; D013806:Theophylline; D000983:Antipyrine