The acute phase response induced by Escherichia coli lipopolysaccharide modifies the pharmacokinetics and metabolism of florfenicol in rabbits |
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| Authors: | R Pérez C Palma R Burgos J A Jeldres A Espinoza A K Peñailillo |
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| Affiliation: | 1. Laboratorio de Farmacología, Departamento de Ciencias Clínicas, Facultad de Ciencias Veterinarias, Universidad de Concepción, Chillán, Chile;2. Instituto de Farmacología. Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile |
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| 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. |
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