Comparative Pharmacokinetics of Ceforanide (BL-S786R) and Cefazolin in Laboratory Animals and Humans

Abstract

Ceforanide (BL-S786R) is a new, broad-spectrum, parenteral cephalosporin. Pharmacokinetic properties weredetermined in rats (100 mg/kg), rabbits (30 mg/ kg), dogs (25 mg/kg), and humans (2 g or 30 mg/kg) and compared with equivalent single doses of cefazolin. Plasma half-lives for ceforanide and cefazolin were 1.1 and 0.5 h in the rat, 5 and 0.3 h in the rabbit, 1 and 0.8 h in the dog, and 2.6 and 2 h in humans, respectively. The slower elimination of ceforanide, as reflected by longer plasma half-life, larger area under the curve, and peak plasma concentrations, was due to slower body and renal clearances. The apparent volumes of distribution of ceforanide and cefazolin were comparable. Rats, dogs, and humans excreted 80 to 100% of the ceforanide dose in the 0-to 24-h urine; rabbits excreted only 50%. Tubular secretion constituted 50% of ceforanide renal excretion in rabbits, dogs, and humans and 90% in rats; the remainder was excreted by glomerular filtration. There was no apparent correlation between the extent of tubular secretion and degree of plasma protein binding in different species. There was no ignificant pharmacokinetic interaction between ceforanide and amikacin in the rat. The slower elimination kinetics of ceforanide are indicative of the potential for a longer dosing interval and more effective antibiotic therapy as compared with available cephalosporins.Ceforanide is a new, parenteral cephalosporin with a broad spectrum of antibiotic activity (7 metabolized before elimination, and renal excretion is the major elimination route. The usual adult dose is 0.5 to 1.0 g administred twice daily. Since combination cephalosporin-aminoglycoside therapy is employed clinically, the potential for pharmacokinetic interaction of ceforanide and amikacin was also evaluated in rats. This paper reports the renal-plasma pharmacokinetics of ceforanide and cefazolin in laboratory animals (rats, rabbits, and dogs) and humans. MATERIALS AND METHODSCephalosporins. Ceforanide (BL-S786R), the Llysine salt of 7-(2-amino-methylphenylacetamido)-3-(1-carboxymethyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid, was synthesized at and supplied by Bristol Laboratories. Cefazolin, the sodium salt of 3-

Penetration of cefazolin into normal and osteomyelitic canine cortical bone

“…Cefazolin binds to serum proteins to a different extent in dogs and humans. In humans, cefazolin is highly protein bound, with reports ranging from 73 to 92% (9,10,12,13,22,24,30,31), whereas in dogs reports have varied from 32.5% (20) to 47% (13) to 80% (37). The results of this study indicate that serum protein binding of cefazolin in dogs is relatively low, 35.8% by isotope assay and 38.8% by bioassay.…”

“…Studies have also shown that cefazolin does not bind to the membrane filtration cones (13,31 (15) Cefazolin concentration in the ultrafiltrate and unfiltered serum was analyzed by isotope and bioassay methods. Standards for the bioassay were prepared with phosphate buffer for the ultrafiltrate samples and with pooled dog serum for the serum samples.…”

Pharmacokinetics of the cephalosporin SM-1652 in mice, rats, rabbits, dogs, and rhesus monkeys

“…According to Actor and co-workers (1), the plasma half-lives of SK&F 75073 (cefonicid) were 124 min in mice, 38 min in dogs, and 97 min in squirrel monkeys. Lee and co-workers (7) reported that the plasma half-lives of ceforanide were 1.1 h in rats, 5.0 h in rabbits, and 1.0 h in dogs. The tl/2(0) values of YM09330, presented by Komiya and colleagues (5), were 13.0 min in mice, 15.9 min in rats, 30.5 min in rabbits, 55.5 min in dogs, and 75.6 min in rhesus monkeys.…”

Pharmacokinetics of intramuscular ceforanide in infants, children, and adolescents

“…The half-life (tQ12) of the drug (2.6 to 2.98 h) in adults is substantially longer than those of most other cephalosporins (4,6). Also, the peak serum concentrations are generally higher, and the areas under the curve (AUCs) are generally larger than the values for other cephalosporins.…”

“…Initially, only patients older than 1 year were enrolled, but when the safety and efficacy of the drug were established, infants were also included. The age range of the 46 patients (36 males and 10 females) was 1 month to 17 years (mean 5.8 years, median 4 years), and the weight range was 5.2 to 100 kg. All patients had normal blood urea nitrogen and serum creatinine levels.…”