Absolute bioavailability of cefprozil after oral administration in beagles

Abstract

The absolute bioavailability of cefprozil, a new oral cephalosporin, in four beagles was evaluated. In this two-way crossover study, each dog received a 125-mg dose of cefprozil either as an oral aqueous solution or as a 15-min intravenous infusion. A high-performance liquid chromatographic assay with UV detection was employed for the determination of cefprozil concentrations in plasma and urine. Key pharmacokinetic parameters were calculated by noncompartmental methods. Cefprozil was well absorbed after oral administration, and peak concentrations of 17.6 to 26.6 ,ug/ml were attained at 60 min after drug administration. The apparent elimination half-life of cefprozil was about 70 min. The renal clearance was about 60% of total body clearance and is suggestive of significant nonrenal clearance. The absolute bioavailability of cefprozil ranged from 67.1 to 79.1% in the dogs.Cefprozil is a new oral cephalosporin with an antibacterial spectrum that includes important gram-positive and gramnegative organisms (4, 6). It is structurally similar to other cephalosporins in that it has a phenylglycine side chain. Cephalosporins with phenylglycine side chains, such as cephalexin and cefadroxil, are almost completely absorbed and undergo minimal metabolism after oral administration (7, 12). As a result, urinary excretion of these cephalosporins accounts for more than 80% of the administered dose (7, 12). Cefprozil, like other oral cephalosporins, is also well absorbed after oral administration (1-3) in humans. However, urinary recovery accounts for about 60% of the administered dose of cefprozil (1-3). It appears that cefprozil is incompletely absorbed, is metabolized, and/or is eliminated via biliary excretion in humans. The extent of oral absorption of cefprozil in humans is not known at this time. The present two-way crossover study was designed to evaluate absolute bioavailability of orally administered cefprozil in dogs.In a two-way crossover study, four beagles weighing 8 to 12 kg each were administered a 125-mg dose of cefprozil either as an oral aqueous solution or as a 15-min intravenous infusion. There was a 1-week washout period between treatments. The dosing solution was freshly prepared by dissolving 1,000 mg of cefprozil in 200 ml of sterile water. A solution containing 5 mg of cefprozil per ml was filtered through a 0.22-,um-pore-size filter and administered within 2 h of preparation. Food was withheld for about 12 to 14 h prior to dosing and for 4 h after dosing. For intravenous administration of cefprozil, 25 ml of the dosing solution (5 mg/ml) was infused over a 15-min period with a Harvard infusion pump. For oral administration of cefprozil, 25 ml of the dosing solution was administered by gavage through a stomach tube and was followed by 25 ml of tap water to rinse the tube. Blood samples were obtained by saphenous venipuncture just prior to dosing (predose) and at 3, 9, 15 (end of intravenous infusion), 18, 24, 30, and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 h after intravenous administration and p...