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 affec ted by infection, inflammation and other conditions that invoke the ac ute phase response. In the present study, an Escherichia coli lipopoly saccharide (LPS)induced acute phase response model was developed in pi gs. This model was used to study the effects of the acute phase respon se on drug disposition and hepatic drug metabolism in vivo and in micr osomal preparations. The results obtained were compared with those fro m Actinobacillus pleuropneumoniae-infected pigs. Intermittent intraven ous administration of LPS induced a mild acute phase response as evide nced by increased rectal body temperatures, anorexia and increased cyt okine (TNF-alpha and IL-6) serum levels within 1-2 h after the first L PS 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 de creased after 24 h. The decrease in cytochrome P450 activities was acc ompanied by losses of cytochrome P4501A and P4503A apoproteins. The mi crosomal glucuronidation rate of 1-naphthol was nor affected in LPS-tr eated pigs. Comparing the LPS model with our previous findings in the Actinobacillus pleuropneumoniae model showed a remarkable similarity w ith regard to the effects on hepatic drug metabolism.