title: Pharmacokinetics of florfenicol after intravenous administration in Escherichia coli lipopolysaccharide-induced endotoxaemic sheep.
abstract: Experiments in different animal species have shown that febrile conditions, induced by Escherichia coli lipopolysaccharide (LPS), may alter the pharmacokinetic properties of drugs. The objective was to study the effects of a LPS-induced acute-phase response (APR) model on plasma pharmacokinetics of florfenicol (FFC) after its intravenous administration in sheep. Six adult clinically healthy Suffolk Down sheep, 8 months old and 35.5 ± 2.2 kg in body weight (bw), were distributed through a crossover factorial 2 × 2 design, with 4 weeks of washout. Pairs of sheep similar in body weight were assigned to experimental groups: Group 1 (LPS) was treated with three intravenous doses of 1 μg/kg bw of E. coli LPS before FFC treatment. Group 2 (control) was treated with an equivalent volume of saline solution (SS) at similar intervals as LPS. 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 (5 mL) were collected before drug administration and at different times between 0.05 and 48.0 h after treatment. FFC plasma concentrations were determined by liquid chromatography. A noncompartmental pharmacokinetic model was used for data analysis, and data were compared using a Mann-Whitney U-test. The mean values of AUC0-∞ in the endotoxaemic sheep (105.9 ± 14.3 μg·h/mL) were significantly higher (P < 0.05) than values observed in healthy sheep (78.4 ± 5.2 μg·h/mL). The total mean plasma clearance (CLT ) decreased from 257.7 ± 16.9 mL·h/kg in the control group to 198.2 ± 24.1 mL·h/kg in LPS-treated sheep. A significant increase (P < 0.05) in the terminal half-life was observed in the endotoxaemic sheep (16.9 ± 3.8 h) compared to the values observed in healthy sheep (10.4 ± 3.2 h). In conclusion, the APR induced by the intravenous administration of E. coli LPS in sheep produces higher plasma concentrations of FFC due to a decrease in the total body clearance of the drug.
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.forename: C
authors.initials: C
authors.lastname: Palma
authors.forename: C
authors.initials: C
authors.lastname: Drápela
authors.forename: M
authors.initials: M
authors.lastname: Sepulveda
authors.forename: A
authors.initials: A
authors.lastname: Espinoza
authors.forename: A K
authors.initials: AK
authors.lastname: Peñailillo
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D019446:Endotoxemia / Q000139:chemically induced / Q000662:veterinary*; D004926:Escherichia coli / Q000378:metabolism*; D005260:Female; D008070:Lipopolysaccharides / Q000378:metabolism / Q000633:toxicity*; D012756:Sheep; D012757:Sheep Diseases / Q000139:chemically induced*; D013839:Thiamphenicol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; C035534:florfenicol; D013839:Thiamphenicol