Effects of bacterial endotoxin on drug pharmacokinetics.

Abstract

Bacterial endotoxin (lipopolysaccharide) has a variety of biological and immunological activities. Endotoxin-induced physiological changes in several organs might modify the pharmacokinetic behavior, including the biliary and urinary excretions and hepatic metabolism, of various drugs. We have conducted a series of studies as part of a program for the development of guidelines for the safe use of various drugs in patients with Gram-negative bacterial infections. We have found that endotoxin isolated from Klebsiella pneumoniae dramatically reduces renal and biliary excretion of organic anionic drugs actively secreted into the urine and bile, respectively. More recently, we found that K. pneumoniae endotoxin decreases the activity of cytochrome P450-mediated drug-metabolizing enzymes in a time-dependent manner. This article reviews recent progress in the description of pharmacokinetic properties of drugs during conditions of endotoxemia, focusing especially upon the effects of K. pneumoniae endotoxin on the hepatic metabolism and biliary excretion of drugs, and the relationship between pharmacokinetic changes and various endotoxin-induced mediators.