Nonlinear pharmacokinetics of DQ-2556, a new 3-quaternary ammonium cephalosporin antibiotic, in rats caused by non-Michaelis-Menten type, dose-dependent renal clearance.
The pharmacokinetics and its dose dependency of a new cephalosporin, DQ-2556, were studied in the rat and rabbit. The pharmacokinetics of the compound in the rat was linear up to a dose of 300 mg/kg; however, at a dose of 1200 mg/kg, renal clearance decreased dramatically and the normalized area under the blood concentration-time curve increased remarkably. On the other hand, there were no dose-dependent changes in tissue/serum concentration ratios, serum protein binding, red cell binding, and the distribution of DQ-2556. In the rabbit, the pharmacokinetics of DQ-2556 was linear even up to a dose of 1200 mg/kg and no unusual pharmacokinetic behavior was observed. The renal clearance experiments demonstrated that DQ-2556 is excreted by glomerular filtration. It was also shown that the glomerular filtration rate (GFR) remained constant up to a dose of 1000 mg/kg of DQ-2556 in the rat, whereas the GFR decreased by 95.1% at a dose of 1200 mg/kg. The coincidence of dose relationship and species difference in the disorder of GFR and renal toxicity suggests that the change of pharmacokinetics of DQ-2556 was caused by its renal toxic effects at very high dose.
Matsubayashi
K
K
Exploratory Research Laboratories I, Tokyo Research and Development Center, Daiichi Pharmaceutical Company, Ltd., Japan.
Shintani
S
S
Yoshida
K
K
Yamada
M
M
Tachizawa
H
H
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002511:Cephalosporins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism*; D008297:Male; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D001798:Blood Proteins; D002511:Cephalosporins; C050465:DQ 2556