Renal handling of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, in rabbits in comparison with meropenem.
The plasma half-life of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, is longer than that of meropenem in animals and humans. To address this issue, renal clearance studies were conducted in rabbits. A constant rate infusion of CS-023 and meropenem was conducted in male Japanese White rabbits. Concentrations in the plasma, urine and renal cortex were measured to evaluate renal clearance and renal tissue uptake. CS-023 showed a clearance ratio (renal clearance/glomerular filtration rate) of around 1, which was not affected by co-administration of probenecid or p-aminohippurate. On the other hand, meropenem exhibited a clearance ratio of around 3, which was significantly decreased to 1 by co-administration of probenecid. p-Aminohippurate, in contrast, had no effect. The renal cortex/plasma concentration ratio of CS-023 was around 0.6 with or without probenecid co-administration. This ratio of meropenem was around 3, which was decreased significantly by co-administration of probenecid to around 0.6. These data suggest that meropenem is secreted in the renal tubules via organic anion transporters, but CS-023 is not. The present findings in rabbits would indicate that a lack of renal tubular secretion of CS-023 is a reason for the long plasma half-life compared with meropenem.
Shibayama
T
T
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan. sibaya@sankyo.co.jp
Yamamura
N
N
Matsushita
Y
Y
Tokui
T
T
Hirota
T
T
Ikeda
T
T
D000818:Animals; D015780:Carbapenems / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D000077731:Meropenem; D008657:Metabolic Clearance Rate; D008861:Microsomes / Q000378:metabolism; D023421:Models, Animal; D011817:Rabbits; D013845:Thienamycins / Q000493:pharmacokinetics*
D015780:Carbapenems; D013845:Thienamycins; C492232:tomopenem; D000077731:Meropenem