A pharmacokinetic study of amoxycillin in febrile beagle dogs following repeated administrations of endotoxin

The pharmacokinetics of amoxycillin was studied in nine male beagle dogs under healthy and febrile conditions. In Period 1, dogs received 20 mg/kg of an oral suspension of amoxycillin. Intravenous doses of saline, 2 and 20 mug/kg of endotoxin (LPS from Escherichia coli serotype) were administered to dogs (three per group) prior to administration of 20 mg/kg of amoxycillin in Period 2. Rectal temperature and behavioral changes were recorded and blood samples were collected over 12 h for pharmacokinetic analysis. Amoxycillin was assessed in plasma using liquid chromatography coupled with mass spectrometry. Plasma concentrations were analysed using a one-compartment model with lag-time for absorption using an iterative two-stage method. As compared with control groups, amoxycillin clearance decreased significantly with preliminary treatments of 2 mug/kg endotoxin (0.209 vs. 0.140 L/h kg, P<0.05) and 20 <mu>g/kg endotoxin (0.214 vs. 0.075 L/h kg, P<0.05). As a result of this, the area under curve for the 2 and 20 <mu>g/kg endotoxin groups increased significantly 100.4 vs. 149.4 mug h/mL (P<0.05) and 99.2 vs. 277.7 <mu>g h/mL (P<0.05), respectively. Other drugs currently used for the treatment of fever and septic shock should be re-evaluated using a febrile animal model to avoid improper dose administration.