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Antimicrobial Agents and Chemotherapy, January 2007, p. 257-263, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00459-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics and Disposition of CS-023 (RO4908463), a Novel Parenteral Carbapenem, in Animals{triangledown}

Takahiro Shibayama,1* Yoko Matsushita,1 Kenji Kawai,1 Takashi Hirota,1 Toshihiko Ikeda,1 and Shogo Kuwahara2

Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., Shinagawa-ku,1 Toho University School of Medicine, Ohta-ku, Tokyo, Japan2

Received 13 April 2006/ Returned for modification 23 July 2006/ Accepted 18 October 2006

The distribution, metabolism, and excretion of CS-023 (RO4908463), a new carbapenem, were investigated in rats and monkeys after a single intravenous administration of [14C]CS-023. In addition, the drug's pharmacokinetics were examined in rats, dogs, and monkeys. Whole-body autoradioluminograms of rats indicated that the radioactivity is distributed throughout the body immediately after administration except for the central nervous system and testes. The highest radioactivity was found in the kidneys, which are responsible for the excretion of CS-023. R-131624 with an open ß-lactam ring, the pharmacologically inactive form, was detected in the plasma and urine as the major metabolite. In rat plasma, the R-131624 levels became higher than CS-023 levels at 30 min postdose and thereafter, while in monkey plasma, CS-023 accounted for most of the radioactivity, with low levels of R-131624. More than 80% of the radioactivity administered was recovered in the urine, and CS-023 and R-131624 accounted for 29.6% and 31.4%, respectively, of the dose in rats and 51.2% and 18.5%, respectively, of the dose in monkeys. The faster metabolism to R-131624 in rats than in monkeys was likely due to the metabolism by dehydropeptidase I in rat lungs. The plasma elimination half-life of CS-023 was 0.16 h in rats, 0.75 h in dogs, and 1.4 h in monkeys. There were no appreciable interspecies differences among the animals tested in either volume of distribution (172 to 259 ml/kg) or serum protein binding (5.0 to 15.6%). The total clearance in monkeys (1.62 ml/min/kg) was lower than that in rats (15.1 ml/min/kg) or dogs (4.19 ml/min/kg).

* Corresponding author. Mailing address: Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., 2-58 Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. Phone: 81-3-3492-3131. Fax: 81-3-5436-8567. E-mail: sibaya{at}sankyo.co.jp.

{triangledown} Published ahead of print on 30 October 2006.

Antimicrobial Agents and Chemotherapy, January 2007, p. 257-263, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00459-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Morinaga, Y., Yanagihara, K., Nakamura, S., Yamamoto, K., Izumikawa, K., Seki, M., Kakeya, H., Yamamoto, Y., Yamada, Y., Kohno, S., Kamihira, S. (2008). In vivo efficacy and pharmacokinetics of tomopenem (CS-023), a novel carbapenem, against Pseudomonas aeruginosa in a murine chronic respiratory tract infection model. J Antimicrob Chemother 62: 1326-1331 [Abstract] [Full Text]  


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