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.

Optimal treatment schedule of meropenem for adult patients with febrile neutropenia based on pharmacokinetic–pharmacodynamic analysis

“…Body weight and LBM in males are generally greater than in females, as the ratio of body fat to body weight in males is lower than that in females. The logarithm of the partition coefficient (1 -octanol/ water) in meropenem is reported as -3.28 [22], and therefore meropenem seems to be distributed to watersoluble compartments. Considering the physicochemical characteristics of meropenem, LBM in patient might be related to V c and body weight may have an indirect relationship to Vc.…”

In vivo efficacy and pharmacokinetics of tomopenem (CS-023), a novel carbapenem, against Pseudomonas aeruginosa in a murine chronic respiratory tract infection model

“…6 Shibayama et al reported that the lack of recognition of tomopenem by renal transporters involved in uptake across the basolateral membrane is one of the reasons for its long plasma half-life in humans compared with meropenem, since no tomopenem molecules exist as an anionic form at physiological pH. 20 The MICs of tomopenem for clinical isolates of P. aeruginosa showed more activity than meropenem. 3 Considering the longer half-life of tomopenem, the %T.MIC for tomopenem is much higher than that for meropenem for humans.…”

Effect of Impaired Renal Function on the Pharmacokinetics of Tomopenem (RO4908463/CS-023), a Novel Carbapenem

“…Recent in vivo work has shown that tubular secretion in rabbits is not involved in the clearance of tomopenem, in contrast to meropenem (16). In vitro work using cells expressing human organic transporters also supported the idea by showing that tomopenem was not a substrate of these transporters, again in contrast to meropenem (17). The CL R of metabolite in healthy subjects was greater than the glomerular filtration rate.…”