Plasma and tissue disposition of florfenicol inEscherichia colilipopolysaccharide-induced endotoxaemic sheep

Abstract

1. The purpose of this study was to understand the effects of the acute inflammatory response (AIR) induced by Escherichia coli lipopolysaccharide (LPS) on florfenicol (FFC) and FFC-amine (FFC-a) plasma and tissue concentrations. 2. Ten Suffolk Down sheep, 60.5 ± 4.7 kg, were distributed into two experimental groups: group 1 (LPS) treated with three intravenous doses of 1 μg/kg bw of LPS at 24, 16, and 0.75 h (45 min) before FFC treatment; group 2 (Control) was treated with saline solution (SS) in parallel to group 1. An IM dose of 20 mg FFC/kg was administered at 0.75 h after the last injection of LPS or SS. Blood and tissue samples were taken after FFC administration. 3. The plasma AUC values of FFC were higher (p = 0.0313) in sheep treated with LPS (21.8 ± 2.0 μg·min/mL) compared with the control group (12.8 ± 2.3 μg·min/mL). Lipopolysaccharide injections increased FFC concentrations in kidneys, spleen, and brain. Low levels of plasma FFC-a were observed in control sheep (C = 0.14 ± 0.01 μg/mL) with a metabolite ratio (MR) of 4.0 ± 0.87%. While in the LPS group, C increased slightly (0.25 ± 0.01 μg/mL), and MR decreased to 2.8 ± 0.17%. 4. The changes observed in the plasma and tissue concentrations of FFC were attributed to the pathophysiological effects of LPS on renal hemodynamics that modified tissue distribution and reduced elimination of the drug.

Pharmacokinetics of ivermectin in sheep following pretreatment with Escherichia coli endotoxin

“…Total leukocyte average count in LPS‐treated animals had a baseline value of 9,280 ± 723 leukocytes/μl, while at 4 hr post‐LPS injection, a decrease in white blood cell count was observed, resulting in a slight leukopenia (5,500 ± 997 leukocytes/μl), this leukopenia, associated with significant decreases in lymphocyte and neutrophil counts, were the most significant hematological changes observed in samples taken after the first administration of E. coli LPS. Our results show that intravenous administration of endotoxin produces an inflammatory response similar to that previously reported by us for this animal species (Pérez et al., ; and Pérez‐Fernández et al., ). Such results have demonstrated that the intravenous administration of LPS produced a mild‐to‐moderate inflammatory response that reproduces the initial state of an infectious disease (Pérez‐Fernández et al., ).…”

“…Our results show that intravenous administration of endotoxin produces an inflammatory response similar to that previously reported by us for this animal species (Pérez et al., ; and Pérez‐Fernández et al., ). Such results have demonstrated that the intravenous administration of LPS produced a mild‐to‐moderate inflammatory response that reproduces the initial state of an infectious disease (Pérez‐Fernández et al., ). Therefore, our model represents a useful tool to evaluate in vivo the effects of the AIR on the pharmacokinetics of drugs (Van Miert, ), either by the inhibitory effect of proteins with enzymatic or transporter function (Morgan et al., ), as well as by blood hemodynamic modifications that are generated by the endotoxin administration (Chvojka et al., ).…”

“…A stock solution of endotoxin was prepared by diluting 2 mg LPS in 10 ml of a sterile and pyrogen‐free saline solution (SS). One milliliter of the stock solution was diluted to obtain a final concentration of 20 μg/ml, necessary to give a dose of 1 ml/20 kg bw (Pérez et al., ; Pérez‐Fernández et al., ). All reagents used for the extraction and chromatographic analysis of plasma samples were of HPLC grade (Merck, Darmstadt, Germany).…”

“…Pairs of five sheep by group, similar in sex, size, and body weight, were assigned to either the experimental group (LPS) or the saline‐treated group (Control) and then monitored in parallel. Group 1 (LPS) was treated with three intravenous doses of 1 μg/kg bw of LPS through the right jugular vein at 24, 16, and 1 hr before the IVM treatment (Pérez et al., ; Pérez‐Fernández et al., ). Group 2 (Control) was treated with an equivalent volume of SS at similar intervals.…”

Extralabel drug use in small ruminants

“…59 Currently, FARAD recommends a 60-day meat and 7-day milk WDI for sheep administered 2 IM doses of florfenicol (20 mg/kg) separated by a 48-hour interval; FARAD also recommends that milk of treated sheep be tested and free of florfenicol residues before it is marketed for human consumption. Given the limited number of published studies 61,[68][69][70] involving IM administration of florfenicol to sheep and the lack of data regarding depletion of tissue drug residues, veterinarians are encouraged to contact FARAD for a WDI recommendation whenever florfenicol is administered by the IM route to sheep. Results of 1 study 15 indicate that the half-life of florfenicol in sheep is 10.3 days in liver, the target tissue for cattle, following SC administration of the drug.…”