title: The acute phase response induced by Escherichia coli lipopolysaccharide modifies the pharmacokinetics and metabolism of florfenicol in rabbits.
abstract: The aim of this study was to determine the effect of Escherichia coli lipopolysaccharide (LPS)-induced acute phase response (APR) on the pharmaco-kinetics and biotransformation of florfenicol (FFC) in rabbits. Six rabbits (3.0 ± 0.08 kg body weight (bw)) were distributed through a crossover design with 4 weeks of washout period. Pairs of rabbits similar in bw and sex were assigned to experimental groups: Group 1 (LPS) was treated with three intravenous doses of 1 μg/kg bw of E. coli LPS at intervals of 6 h, and Group 2 (control) was treated with an equivalent volume of saline solution (SS) at the same intervals and frequency of Group 1. At 24 h after the first injection of LPS or SS, an intravenous bolus of 20 mg/kg bw of FFC was administered. Blood samples were collected from the auricular vein before drug administration and at different times between 0.05 and 24.0 h after treatment. FFC and florfenicol-amine (FFC-a) were extracted from the plasma, and their concentrations were determined by high-performance liquid chromatography. A noncompartmental pharmacokinetic model was used for data analysis, and data were compared using the paired Student t-test. The mean values of AUC0-∞ in the endotoxaemic rabbits (26.3 ± 2.7 μg·h/mL) were significantly higher (P < 0.05) than values observed in healthy rabbits (17.2 ± 0.97 μg·h/mL). The total mean plasma clearance (CLT ) decreased from 1228 ± 107.5 mL·h/kg in the control group to 806.4 ± 91.4 mL·h/kg in the LPS-treated rabbits. A significant increase (P < 0.05) in the half-life of elimination was observed in the endotoxaemic rabbits (5.59 ± 1.14 h) compared to the values observed in healthy animals (3.44 ± 0.57 h). In conclusion, the administration of repeated doses of 1 μg/kg E. coli LPS induced an APR in rabbits, producing significant modifications in plasma concentrations of FFC leading to increases in the AUC, terminal half-life and mean residence time (MRT), but a significant decrease in CLT of the drug. As a consequence of the APR induced by LPS, there was a reduction in the metabolic conversion of FFC to their metabolite FFC-a in the liver, suggesting that the mediators released during the APR induced significant inhibitory effects on the hepatic drug-metabolizing enzymes.
authors.affiliation: Laboratorio de Farmacología, Departamento de Ciencias Clínicas, Facultad de Ciencias Veterinarias, Universidad de Concepción, Chillán, Chile.
authors.forename: R
authors.initials: R
authors.lastname: Pérez
authors.affiliation: Laboratorio de Farmacología, Departamento de Ciencias Clínicas, Facultad de Ciencias Veterinarias, Universidad de Concepción, Chillán, Chile.
authors.forename: C
authors.initials: C
authors.lastname: Palma
authors.affiliation: Instituto de Farmacología. Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: R
authors.initials: R
authors.lastname: Burgos
authors.affiliation: Laboratorio de Farmacología, Departamento de Ciencias Clínicas, Facultad de Ciencias Veterinarias, Universidad de Concepción, Chillán, Chile.
authors.forename: J A
authors.initials: JA
authors.lastname: Jeldres
authors.affiliation: Laboratorio de Farmacología, Departamento de Ciencias Clínicas, Facultad de Ciencias Veterinarias, Universidad de Concepción, Chillán, Chile.
authors.forename: A
authors.initials: A
authors.lastname: Espinoza
authors.affiliation: Laboratorio de Farmacología, Departamento de Ciencias Clínicas, Facultad de Ciencias Veterinarias, Universidad de Concepción, Chillán, Chile.
authors.forename: A K
authors.initials: AK
authors.lastname: Peñailillo
mesh_terms: D000210:Acute-Phase Reaction; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004926:Escherichia coli; D005260:Female; D006207:Half-Life; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D011817:Rabbits; D013839:Thiamphenicol / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; C035534:florfenicol; D013839:Thiamphenicol