Endotoxin depresses hepatic cytochrome P450-mediated drug metabolism in women.
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.
Shedlofsky
S I
SI
Department of Medicine-Division of Digestive Diseases, VA Hospital, Lexington, Kentucky 40511, USA.
Israel
B C
BC
Tosheva
R
R
Blouin
R A
RA
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
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