Distribution of free and liposomal cefoxitin in plasma and peritoneal fluid in a porcine intra-abdominal sepsis model.
The plasma and peritoneal fluid pharmacokinetic parameters obtained after the intravenous administration of free and liposomal cefoxitin were studied in a porcine model of intraabdominal sepsis. No prior assumptions were made to predict the number of compartments pertaining to drug clearance from the administration of either cefoxitin formulation. The experimental data obtained were applied to fit mathematical models of multiexponential drug clearance and the pharmacokinetic data were found to best fit a two-compartment open model. Liposomal encapsulation 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 times. The peritoneal cavity appeared to provide a reservoir for the initial distributive phase of rapid drug clearance from the plasma compartment 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 liposomal cefoxitin was about 3-4 fold as high as that of animals treated with free cefoxitin. The differences in pharmacokinetic parameters appeared to account for the improved therapeutic efficacy of liposomal cefoxitin in this animal model.
Defence and Civil Institute of Environmental Medicine, North York, Ontario, Canada.
P N
PN
Shek
P
P
Tikuisis
J
J
Zamecnik
S
S
Soltes
R A
RA
Mustard
M W
MW
Mittelman
D000005:Abdomen; D000818:Animals; D019540:Area Under Curve; D001202:Ascitic Fluid / Q000378:metabolism*; D002440:Cefoxitin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002513:Cephamycins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004337:Drug Carriers; D006207:Half-Life; D007275:Injections, Intravenous; D008081:Liposomes; D008297:Male; D018805:Sepsis / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D013552:Swine
D002513:Cephamycins; D004337:Drug Carriers; D008081:Liposomes; D002440:Cefoxitin