title: Characterization of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, and meropenem as substrates of human renal transporters.
abstract: To characterize the renal handling of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, and meropenem in humans, we examined their affinities as substrates to human renal transporters. In vitro studies on the uptake of [14C]CS-023 and [14C]meropenem were conducted using HEK293 cells expressing human organic anion transporters (hOAT) 1, hOAT3, hOAT4, and the human organic cation transporters (hOCT) 1 and hOCT2. CS-023 did not serve as the substrate for any of the transporters tested. On the other hand, meropenem was transported by hOAT1 and hOAT3. The Km value of the hOAT3-mediated transport was 847 microM, and the uptake was inhibited by probenecid, p-aminohippurate and benzylpenicillin with Ki values of 3.76, 712, and 202 microM, respectively. One of the reasons why CS-023 is not a substrate of hOATs, and vice versa for meropenem, would be that a very small proportion of CS-023 exists as the anionic form at the physiological pH, whereas 50% of meropenem exists as the anionic form. These findings indicate that the lack of recognition of CS-023 by renal transporters is one of the reasons for its long plasma half-life in humans compared with meropenem which undergoes renal tubular secretion mediated by hOAT1 and hOAT3.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. sibaya@sankyo.co.jp
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shibayama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sugiyama
authors.forename: Emi
authors.initials: E
authors.lastname: Kamiyama
authors.forename: Taro
authors.initials: T
authors.lastname: Tokui
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirota
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ikeda
mesh_terms: D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001693:Biological Transport, Active; D015780:Carbapenems / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D027202:Cationic Amino Acid Transporter 2 / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D000077731:Meropenem; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000378:metabolism; D013845:Thienamycins / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D002352:Carrier Proteins; D027202:Cationic Amino Acid Transporter 2; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D027702:Organic Cation Transporter 1; D013845:Thienamycins; C114338:organic anion transport protein 3; C492232:tomopenem; D000077731:Meropenem