Estudio farmacocinético de formulaciones poliméricas de liberación controlada y excreción en leche de ceftiofur en caprino

Abstract

OBJECTIVES: The pharmacokinetics of ceftiofur was studied following intravenous and subcutaneous (SC1) administration of single doses of 2 mg/kg to healthy goats, and as a long-acting poloxamer 407 gel formulation and poloxamer 407 + carboxymethylcellulose (SC2) of 6 mg/kg. METHODS: Plasma concentrations were determined by HPLC assay with ultraviolet detection. Data were fitted to compartmental and non compartimental pharmacokinetic methods. The ceftiofur plasma concentration versus time data after intravenous and extravascular administrations could best be described by a two compartment open model. RESULTS AND CONCLUSIONS: The ceftiofur terminal half-life (t½z) was 4,21 h after intravenous administration, with a mean residence time (MRT) of 4,27 h. The apparent volumes of distribution calculated at steady-state (Vss) and by the area method (Vz) were 0,18 and 0,31 L/kg, respectively, indicating a wide body distribution. Total body clearance was 0,007 L/kg/h. After extravascular administrations, terminal half-lives were 5,10 and 41,12 h for ceftiofur administration subcutaneously for conventional formulation and for long-acting poloxamer 407 + carboxymethylcellulose, respectively. MRT values obtained were 6,29 and 25,11 h respectively. Absolute bioavailability was 85,16% after ceftiofur subcutaneous administration of conventional formulation. Similar value was obtained, 84,43 %, after ceftiofur administration subcutaneously with long-acting poloxamer 407 + carboxymethylcellulose. The in vivo ceftiofur absorption rate from conventional and poloxamer formulation was estimated by non-compartmental method and numeric deconvolution. In the case of numeric deconvolution, the calculated absorption rates and the cumulative absorption in terms of fraction input SC1 and SC2 formulations were 56,64 ± 24,27 mg/h at 0,64 ± 0,26 h and 29,30 ± 5,10 mg/h at 1,92 ± 0,32 h, respectively. From non-compartmental approach, only the MAT values for SC2 (20,84 h) was higher than MRTIV (4,27 h). These results show that the differences on elimination rate constants and mean residence times between conventional SC1 and long-acting SC2 formulations must be due to differences on the absorption process. Minimal inhibitory concentrations (MIC) assays of ceftiofur against different strains of Mannheimia haemolytica were performed in order to compute pharmacodynamic surrogate markers. In vitro and ex vivo analysis were performed over the same strains. From these data, it is concluded that in a multiple dose regimen of ceftiofur for the SC2 formulation, efficacy would prolonge longer than 72 h. This conclusion has been inforced by the in vitro and ex vivo analysis showing the time-dependent profile of ceftiofur, and also showing a growth decay of bacteria until at least 72 h.