Comparative pharmacokinetics of SCE-2787 and related antibiotics in experimental animals

Abstract

The pharmacokinetic properties of SCE-2787 administered intravenously at a dose of 20 mg/kg of body weight were studied with mice, rats, rabbits, dogs, and monkeys and were compared with those of ceftazidime, cefpirome, and cefclidin in mice and dogs. The area under the concentration-time curve for plasma after intravenous administration was the largest in monkeys, followed by those in dogs, rabbits, rats, and mice, in that order. The elimination half-life ranged from 0.2 to 0.3 h in mice and rats to 0.7 to 1.3 h in rabbits, dogs, and monkeys. In young dogs, the concentrations of SCE-2787 in plasma were somewhat lower than those in the mature dogs. SCE-2787 was distributed well to the tissues, and the highest concentration was found in the kidneys in all species tested; the distribution to the lungs, liver, and spleen was also good, but the concentrations in these tissues were lower than those in the plasma. The pharmacokinetic parameters and urinary excretion of SCE-2787 in mice and dogs were similar to those of ceftazidime, cefpirome, and cefcidin. The maximum concentrations in the cerebrospinal fluid of rats and rabbits were 0.8 and 1.3 igIml, and the relative percentages of the area under the concentration-time curve of SCE-2787 in the cerebrospinal fluid to that in the plasma were 4.6 and 6.4%, respectively. SCE-2787 was excreted mainly in the urine; the recovery rate ranged from 74% (rats) to 90%o (dogs) of the dose. The biliary excretion of SCE-2787, however, was low, amounting to about 1.4% for mice and rats and less than 0.5% for rabbits and dogs. In rats, there was no accumulation in the tissues and no delay in urinary excretion upon multiple intravenous administration of 20 mg of SCE-2787 per kg once daily for 7 days. No active metabolites were found in the plasma or urine of animals given SCE-2787. The binding of SCE-2787 to serum protein in mice, rats, rabbits, dogs, monkeys, and humans was less than 11% and similar to that of cefclidin. SCE-2787 (Fig. 1) is a new injectable cephalosporin that has potent and well-balanced antibacterial activity against a wide range of aerobic gram-positive and gram-negative bacteria, such as Staphylococcus aureus, members of the family Enterobacteriaceae, and Pseudomonas aeruginosa (3, 6). Its activity is similar to that of structurally related antibiotics, such as ceftazidime, cefpirome, and cefclidin, but SCE-2787 is more potent than ceftazidime against gram-positive cocci and members of the Enterobacteriaceae and comparable to ceftazidime and more potent than cefpirome against P. aeruginosa.In the present study, the pharmacokinetic properties of SCE-2787 in experimental animals were compared with those of ceftazidime, cefpirome, and cefclidin.( 2.9 kg were used. All animals were fasted for 16 to 18 h before the antibiotic was administered; water was given ad libitum.Antibiotic administration. Just before use, each antibiotic was dissolved in sterile saline. A single dose of 20 mg of the antibiotic per kg of body weight was administered intravenously to mice (2 mg...

Pharmacokinetics and Penetration of Ceftazidime and Avibactam into Epithelial Lining Fluid in Thigh- and Lung-Infected Mice

“…The half-life values in plasma for both drugs were relatively short, as would be expected in mice, and within the same range. The half-life of ceftazidime as determined in this study was comparable to that found in other studies (32)(33)(34) and in our own laboratory in earlier experiments (35), although the half-life found by Fantin et al (32) was slightly longer. However, the pharmacokinetic analysis in the study reported here was far more extensive than in the previous analyses, and the concentration-time curves are reproducible and clearly dose proportional.…”

Therapeutic effect of cefozopran (SCE-2787), a new parenteral cephalosporin, against experimental infections in mice

“…Against the infection, cefpiramide was less effective than we had expected by the MIC than other antibiotics. The plasma half-life of cefpiramide after intravenous administration in mice is reported to be 11 min, which is comparable to those of other antibiotics, including cefozopran (12,15). However, the binding of cefpiramide to serum protein in mice is 44%, which is higher than that of cefozopran (7.1%) (12,15 3 after infection (8).…”

“…DISCUSSION Cefozopran, a new semisynthetic cephalosporin, showed a potent therapeutic effect against all infections used in this study. The pharmacokinetic profile of cefozopran is known to be similar to those of reference antibiotics used in this study, except for the protein-binding rate of cefpiramide in mouse serum (10,12,15).…”

In Vitro and In Vivo Antifungal Activities of TAK-456, a Novel Oral Triazole with a Broad Antifungal Spectrum

“…To obtain blood, mice were sacrificed by bleeding from the axillary arteries and veins under ether anesthesia and plasma was obtained by centrifugation (3,000 ϫ g) of the blood sample. on May 10, 2018 by guest http://aac.asm.org/ modifications of the method described previously (14). There was no major detectable bioactive metabolite of TAK-456 in the mouse plasma.…”