Pharmacokinetics of FK482, a new orally active cephalosporin, in animals.
The pharmacokinetic profile of FK482 was studied in mice, rats, rabbits and dogs after oral dosing and compared with that of cefixime, cefaclor and cephalexin. Considerable differences in oral absorption of FK482 were observed among the animal species. Absolute bioavailabilities of FK482 were 12.6% in mice, 15.3% in rats, 32.3% in rabbits and 72.3% in dogs. In mice and rats, the absorption of FK482 was poor, and was the lowest of the reference antibiotics. FK482 was moderately well absorbed, with higher plasma levels than cefixime in rabbits and, like cefixime, gave higher plasma levels and a longer half-life than cefaclor or cephalexin in dogs. The increase in the area under the serum concentration time curve (AUC) of FK482 was strictly proportional to the increase in dose in the range of 2.5 to 40 mg/kg in rats and dogs, and 2.5 to 20 mg/kg in rabbits and the urinary recovery rates were almost constant. All tissue concentrations of FK482 in rats and rabbits were lower than those of the reference antibiotics and reflected its lower plasma concentrations in these animals. The urinary recovery rates of FK482 were 9.8% for mice, 15.5% for rats, 45.8% for rabbits and 47.1% for dogs. The biliary recovery rate of FK482 was low; 1.4% in rats and less than 0.1% in rabbits and dogs. No active metabolites were detected in the plasma, urine or bile samples from rats, rabbits or dogs. FK482 was mainly absorbed in the jejunum, and was inactivated in the large intestine. The serum-protein binding of FK482 was almost the same as that of cefixime: 60-77% for mouse, rabbit and human serum, and 90-93% for rat and dog serum.
Sakamoto
H
H
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Hirose
T
T
Nakamoto
S
S
Hatano
K
K
Shibayama
F
F
Kikuchi
H
H
Mine
Y
Y
Kuwahara
S
S
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D000077525:Cefdinir; D002511:Cephalosporins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011817:Rabbits; D051381:Rats; D014018:Tissue Distribution
D002511:Cephalosporins; D000077525:Cefdinir