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A lipopolysaccharide-induced acute phase response in the pig is associated with a decrease in hepatic cytochrome
M Monshouwer1, R F Witkamp, S M Nijmeijer
1Department of Veterinary Basic Sciences, Utrecht University, The Netherlands.
Journal of Veterinary Pharmacology and Therapeutics
|October 1, 1996
Summary
Infection and inflammation significantly alter drug metabolism. An Escherichia coli lipopolysaccharide (LPS) model in pigs revealed reduced drug clearance and cytochrome P450 activity during the acute phase response.
Area of Science:
- Pharmacology
- Toxicology
- Veterinary Medicine
Background:
- Infection and inflammation trigger the acute phase response, impacting drug disposition.
- Understanding these effects is crucial for optimizing drug therapy during illness.
Purpose of the Study:
- To investigate the impact of an acute phase response on drug metabolism in pigs.
- To compare findings from an Escherichia coli lipopolysaccharide (LPS)-induced model with a bacterial infection model.
Main Methods:
- Developed an LPS-induced acute phase response model in pigs.
- Administered LPS intravenously to induce inflammation and measured physiological changes.
- Assessed drug disposition (antipyrine clearance) and hepatic drug metabolism (cytochrome P450 content and activity) in vivo and in vitro.
Main Results:
- LPS administration induced a mild acute phase response, characterized by fever, anorexia, and elevated cytokines.
- Antipyrine plasma clearance significantly decreased in LPS-treated pigs.
- Total cytochrome P450 content and related enzyme activities were reduced, with losses in P4501A and P4503A apoproteins.
- Microsomal glucuronidation of 1-naphthol remained unaffected.
Conclusions:
- The LPS-induced acute phase response model effectively mimics the alterations in drug metabolism observed during infection.
- Acute phase response significantly impairs hepatic drug metabolism, primarily affecting cytochrome P450-dependent pathways.
- Findings highlight the importance of considering inflammatory states when predicting drug efficacy and safety.