Pharmacokinetics of florfenicol and florfenicol‐amine after intravenous administration in sheep

Abstract

Florfenicol (FFC) is a broad spectrum antibacterial agent that is structurally related to chloramphenicol but differs from it by the presence of a para-methyl sulphonyl group instead of the p-nitro group and the presence of a fluorine atom instead of the hydroxyl group in the terminal primary alcohol function (EMEA, 2002). Their potency and broad spectrum of activity make FFC a good antibiotic for replacing chloramphenicol, which has been banned from use in food animals (Adams et al., 1987). Reports have shown that after administration FFC is partially transformed into FFC-amine (FFC-a), FF oxamic acid, monochloroFFC, and FFC alcohol in the bodies of animals. Although their ratios are different in different species, FFC-a is the largest of all of the metabolites, mostly in food animals (Li et al., 2006). Owing to that it is the longest-lived major metabolite in the liver of cattle, FFC-a is used as a marker residue for withdrawal calculations (EMEA, 1999). Thus, biotransformation is able to influence not only the safety and effectiveness of drugs, but also the pattern and the amount of residues that animal products intended for human consumption may eventually accumulate (Nebbia et al., 2003). The pharmacokinetics of FFC have been studied in different ruminant species such as cattle (Varma et al., 1986; Adams et al., 1987; Soback et al.,1995), sheep (Ali et al., 2003; Jianzhong et al., 2004; Lane et al., 2004), and goats (Atef et al., 2001). However, reports about the pharmacokinetics of its major metabolite FFC-a in animals are scarce, and at present, there are only limited references that describe its plasma disposition in rabbits (Park et al., 2007), chickens (Anadon et al., 2008), and dogs (Park et al., 2008). The therapeutic use of FFC in animals must be assessed not only in terms of its clinical efficacy but also considering the risk of presence of residues in edible tissues (Anadon et al., 2008). Actually, it seems that there is no available information about the metabolism of FFC and the plasmatic disposition of its main metabolite FFC-a, in sheep. Thus, in the current study, we quantified the plasma disposition of FFC-a, to estimate the level of metabolism of FFC in this animal species. For this purpose, we injected an intravenous bolus of FFC to adult clinically health sheep. This route of administration was selected to avoid any interference that could have the absorption phase on metabolism and disposition of FFC when the drug is administered by an extra-vascular route. The aim of this study was to evaluate the plasma disposition of FFC and its major metabolite FFC-a after a single intravenous administration in adult sheep. A group of six adult clinically healthy Suffolk Down sheep, 2.5 years old and 49.4 ± 6.4 kg in body weight (bw) were selected for this study. The sheep were housed in collective pens on a dry bed, fulfilling the individual requirements of space, ventilation, and free access to fresh water. The sheep were fed daily with alfalfa hay and supplemented with grain (400 g of barley per ewe) and water was provided ad libitum. The sheep had no previous exposure to any antibiotic and no drugs were given to the animals during acclimation or the study period. All procedures were performed with the authorization of the Ethical Committee for Animal Experimentation of the Faculty of Veterinary Sciences, Universidad de Concepcion, Chile. FFC 30% injectable solution (Nuflor ; Schering Plough, Kenilworth, NJ, USA) was administered as a single intravenous bolus at a dosage level of 20 mg ⁄kg bw to each animal. Blood samples (5 mL) were collected from the jugular vein before drug administration and at 0.05, 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0, and 48.0 h after treatment. Samples were collected in heparinized tubes and then centrifuged at 1000 g to obtain the plasma, which was stored at )18 C. Animals were subjected to a visual inspection for any adverse effect for a period of 1 h after drug administration and then during each sampling time for a 48 h period. Florfenicol and FFC-a were extracted from the plasma by the method described by Li et al. (2006) and their concentrations were determined by reverse-phase high-performance liquid chromatography (HPLC). The analytical standard FFC (99.4% J. vet. Pharmacol. Therap. 35, 508–511. doi: 10.1111/j.1365-2885.2011.01357.x. SHORT COMMUNICATION