Characterization of CS-023 (RO4908463), a Novel Parenteral Carbapenem Antibiotic, and Meropenem as Substrates of Human Renal Transporters

• Published in: DRUG METABOLISM AND PHARMACOKINETICS Vol. 22; no. 1; pp. 41 - 47
• Main Authors: Shibayama, Takahiro, Sugiyama, Daisuke, Kamiyama, Emi, Tokui, Taro, Hirota, Takashi, Ikeda, Toshihiko
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 2007; Japanese Society for the Study of Xenobiotics
• Subjects: Algorithms; Anti-Bacterial Agents - metabolism; Biological Transport, Active; carbapenem antibiotics; Carbapenems - metabolism; Carrier Proteins - metabolism; Cationic Amino Acid Transporter 2 - metabolism; Cell Line; CS-023 (RO4908463); Humans; Kidney - metabolism; Kinetics; meropenem; Organic Anion Transport Protein 1 - metabolism; organic anion transporters; Organic Anion Transporters, Sodium-Independent - metabolism; Organic Cation Transporter 1 - metabolism; renal tubular secretion; Thienamycins - metabolism; meropenem; carbapenem antibiotics; CS-023 (RO4908463); organic anion transporters; renal tubular secretion
• ISSN: 1347-4367; 1880-0920
• DOI: 10.2133/dmpk.22.41

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 μM, and the uptake was inhibited by probenecid, p-aminohippurate and benzylpenicillin with Ki values of 3.76, 712, and 202 μM, 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.