Aims 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 occassions, 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-a, 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.Keywords: antipyrine, cytochrome P450, drug metabolism, endotoxin, gender, hexobarbitone, inflammation, theophylline Gender differences in the metabolism of a number of Introduction drugs have been reported [(18-21)]. Differences for the most part were small, most medications appeared to be TGram-negative bacterial sepsis is still a leading cause of death in the intensive care setting [1, 2] and both men and metabolized similarly in men and women, and a recent report [22] saw no gender differences in amounts of specific women are susceptible to the sequelae of sepsis. A preliminary study [3] of drugs given to these patients P450 proteins in samples of normal liver. However, whether there are important gender differences in the way inflamrevealed that a mean (±s.d.) of 12.1±3.9 systemically active xenobiotic drugs are administered during the period mation affects regulation of P450s has not yet been investigated. To address this question, the current study of sepsis. Animal models of sepsis using endotoxin (lipopolysaccharide or LPS) to elicit the inflammatory response [4][5][6][7][8] administered AP, HB, and TH drug probe cocktails to female volunteers and assessed the effects of two consecutive and administration of inflammatory cytokines such as interleukin-1, tumor necrosis factor, and interleukin-6 [7, LPS injections on expression of the acute phase response and on clearances of the drug probes. 9-14] have demonstrated significant decreases in hepatic cytochrome P450-mediated drug metabolism. Therefore, it is likely that septic patients who have high levels of Methods inflammatory cytokine production have depressed hepatic Nine female volunteers aged 21-51 years participated in P450 activities which could be clinically significant. Our this study. Two were excluded as explained below. The group recently addressed the ...
