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.
journal_name
Drug Metab Pharmacokinetjournal_title
Drug metabolism and pharmacokineticsauthors
Shibayama T,Sugiyama D,Kamiyama E,Tokui T,Hirota T,Ikeda Tdoi
10.2133/dmpk.22.41subject
Has Abstractpub_date
2007-02-25 00:00:00pages
41-7issue
1eissn
1347-4367issn
1880-0920pii
JST.JSTAGE/dmpk/22.41journal_volume
22pub_type
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