A lipopolysaccharide-induced acute phase response in the pig is associated with a decrease in hepatic cytochrome P450-mediated drug metabolism.
Drug disposition, including hepatic drug metabolism, is markedly affected by infection, inflammation and other conditions that invoke the acute phase response. In the present study, an Escherichia coli lipopolysaccharide (LPS)-induced acute phase response model was developed in pigs. This model was used to study the effects of the acute phase response on drug disposition and hepatic drug metabolism in vivo and in microsomal preparations. The results obtained were compared with those from Actinobacillus pleuropneumoniae-infected pigs. Intermittent intravenous administration of LPS induced a mild acute phase response as evidenced by increased rectal body temperatures, anorexia and increased cytokine (TNF-alpha and IL-6) serum levels within 1-2 h after the first LPS injection. The acute phase response is associated with a pronounced decrease of antipyrine plasma clearance (control 8.5 +/- 0.8 vs. LPS 2.2 +/- 0.7 mL/min.kg). Furthermore, total cytochrome P450 content and microsomal cytochrome P450-dependent activities were significantly decreased after 24 h. The decrease in cytochrome P450 activities was accompanied by losses of cytochrome P4501A and P4503A apoproteins. The microsomal glucuronidation rate of 1-naphthol was not affected in LPS-treated pigs. Comparing the LPS model with our previous findings in the Actinobacillus pleuropneumoniae model showed a remarkable similarity with regard to the effects on hepatic drug metabolism.
Department of Veterinary Basic Sciences, Utrecht University, The Netherlands.
M
M
Monshouwer
R F
RF
Witkamp
S M
SM
Nijmeijer
L A
LA
Van Leengoed
H C
HC
Vernooy
J H
JH
Verheijden
A S
AS
Van Miert
D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D001798:Blood Proteins / Q000378:metabolism; D015153:Blotting, Western; D001831:Body Temperature / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous / Q000662:veterinary; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D013552:Swine; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001798:Blood Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A