The effect of endotoxin and dexamethasone on enrofloxacin pharmacokinetic parameters in swine.
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.
Post
Lynn O
LO
Food and Drug Administration, Center for Veterinary Medicine, Office of Surveillance and Compliance, Division of Surveillance, Rockville, Maryland 20708, USA.
Farrell
Dorothy E
DE
Cope
Carol V
CV
Baker
John D
JD
Myers
Michael J
MJ
D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D003404:Creatinine / Q000652:urine; D003907:Dexamethasone / Q000494:pharmacology*; D004731:Endotoxins / Q000494:pharmacology*; D000077422:Enrofloxacin; D004927:Escherichia coli Infections / Q000139:chemically induced / Q000378:metabolism / Q000652:urine; D024841:Fluoroquinolones; D008297:Male; D015363:Quinolones / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013552:Swine
D000890:Anti-Infective Agents; D004731:Endotoxins; D024841:Fluoroquinolones; D015363:Quinolones; D000077422:Enrofloxacin; D003907:Dexamethasone; D003404:Creatinine