The Effect of Endotoxin and Dexamethasone on Enrofloxacin Pharmacokinetic Parameters in Swine

Abstract

The impact of Escherichia coli-derived lipopolysaccharide (LPS) on the pharmacokinetic parameters of enrofloxacin in swine was assessed to determine whether this model would substitute for a pleuropneumonia infection model for pharmacokinetic evaluation of drugs. All animals received a single i.v. dose of enrofloxacin (5 mg/kg). Half the animals also received dexamethasone (0.5 mg/kg) to determine the impact of inflammation on any changes in enrofloxacin pharmacokinetics, as most of the effects of LPS are due to elaboration of inflammatory mediators. Administration of LPS alone (2.0 microg/kg) was associated with a decrease in clearance of enrofloxacin. Volume of distribution at steady state was increased in the dexamethasone-treated animals. The terminal elimination half-life of enrofloxacin was significantly increased in the LPS group. Dexamethasone administration, either alone or in combination with LPS challenge, increased the volume of distribution both at steady state and during the elimination phase. Lipopolysaccharide challenge did not affect the volume of distribution. Lipopolysaccharide challenge did not affect urinary excretion of enrofloxacin but did increase the urinary excretion of its principal metabolite, ciprofloxacin. However, the increased excretion did not begin until 24 h after administration of enrofloxacin. Because these pharamcokinetic results are different from those obtained with the pleuropneumonia model using the bacteria Actinobacillus pleuropneumoniae, the results of this study demonstrate that LPS is not a generic substitute for infection for the pharmacokinetic evaluation of drugs.

E. coli Infection Modulates the Pharmacokinetics of Oral Enrofloxacin by Targeting P-Glycoprotein in Small Intestine and CYP450 3A in Liver and Kidney of Broilers

“…Possibly, this is due to the different types of inflammation inducers used (LPS vs. E. coli bacteria); E. coli may induce more cytokines mediating more cell signaling pathways. It has been pointed out that LPS is not a generic substitute for bacterial infection to study its effect on P-gp expression, function and on drug pharmacokinetics [26]. Alternatively, this might be due to different species used (chickens vs. rats).…”

Impact of P-Glycoprotein Inhibition and Lipopolysaccharide Administration on Blood-Brain Barrier Transport of Colistin in Mice

“…However, given that we have demonstrated that the BBB transport of colistin does not appear to be limited by the action of P-gp, any increase in the brain uptake of colistin following LPS administration is likely to be a result of increased paracellular diffusion. Administration of LPS also served another important purpose in this study in that its effects can mirror the infected state in which colistin is normally clinically used (25). The reduced BBB integrity during the infected state may be beneficial as it may lead to increased antibiotic concentrations in the brain.…”

“…Indeed, other investigators have detected colistin in the CSF of infected patients following systemic administration (1,15,21), whereas we have previously observed limited brain uptake in healthy mice although this could also be attributed to species differences and/or differences between BBB and blood-CSF barrier penetration profiles. While the impact of infection on BBB transport may be investigated by inducing bacteremia in mice, bacterial lipopolysaccharide (LPS) is often used to mimic the infective state as it results in the release of proinflammatory cytokines (25,31). Several studies have shown that BBB disruption can be induced by bacterial LPS, leading to increased brain uptake of compounds that normally exhibit limited access into the CNS (3,22).…”

Using In Vitro Dynamic Models To Evaluate Fluoroquinolone Activity against Emergence of Resistant Salmonella enterica Serovar Typhimurium

“…Single daily doses of the three FQs for 3 consecutive days with simulated half-lives (t 1/2 ) consistent with those reported in pigs were used: 12.5 h for DIF (33,34), 10.6 h for ENR (35,36) and 8 h for MAR (37). The doses were selected to include the achievable area under the curve (AUC) and maximum plasma concentration (C max ) over a 24-h dosing interval at the recommended clinical doses (1 to 5 mg/kg of body weight for DIF, 2.5 to 5 mg/kg for ENR, and 2 mg/kg for MAR) in pigs.…”