DISTRIBUTION OF FREE AND LIPOSOMAL CEFOXITIN IN PLASMA AND PERITONEAL-FLUID IN A PORCINE INTRAABDOMINAL SEPSIS MODEL

The plasma and peritoneal fluid pharmacokinetic parameters obtained af ter the intravenous administration of free and liposomal cefoxitin wer e studied in a porcine model of intraabdominal sepsis, No prior assump tions were made to predict the number of compartments pertaining to dr ug clearance from the administration of either cefoxitin formulation, The experimental data obtained were applied to fit mathematical models of multiexponential drug clearance and the pharmacokientic data were found to best fit a two-compartment open model, Liposomal encapsulatio n significantly altered the plasma drug distribution pattern resulting in changes in the magnitude of a number of pharmacokinetic parameters examined. The mean post-distributive half-life of liposomal cefoxitin was substantially longer than that of free cefoxitin by at least 3 ti mes, The peritoneal cavity appeared to provide a reservoir for the ini tial distributive phase of rapid drug clearance from the plasma compar tment followed by a less-rapid post-distributive phase. The cumulative drug level, as determined by the area under the concentration curve ( AUC) as a function of time, in the plasma of animals treated with lipo somal cefoxitin was about 3-4 fold as high as that of animals treated with free cefoxitin. The differences in pharmacokinetic parameters app eared to account for the improved therapeutic efficacy of liposomal ce foxitin in this animal model.