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Antimicrobial Agents and Chemotherapy, November 2009, p. 4845-4851, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00731-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

CS-8958, a Prodrug of the Novel Neuraminidase Inhibitor R-125489, Demonstrates a Favorable Long-Retention Profile in the Mouse Respiratory Tract{triangledown}

Kumiko Koyama,1* Makoto Takahashi,1 Masataka Oitate,1 Naoko Nakai,1 Hideo Takakusa,1 Shin-ichi Miura,2 and Osamu Okazaki1

Drug Metabolism and Pharmacokinetics Research Laboratories,1 Translational Medicine and Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan2

Received 1 June 2009/ Returned for modification 21 July 2009/ Accepted 6 August 2009

CS-8958 is a prodrug of the pharmacologically active form R-125489, a selective neuraminidase inhibitor, and has long-acting anti-influenza virus activity in vivo. In this study, the tissue distribution profiles after a single intranasal administration of CS-8958 (0.5 µmol/kg of body weight) to mice were investigated, focusing especially on the retention of CS-8958 in the respiratory tract by comparing it with R-125489 and a marketed drug, zanamivir. After administration of [14C]CS-8958, radioactivity was retained in the respiratory tract over long periods. At 24 h postdose, the radioactivity concentrations after administration of [14C]CS-8958 were approximately 10-fold higher in both the trachea and the lung than those of [14C]R-125489 and [14C]zanamivir. The [14C]CS-8958-derived radioactivity present in these two tissues consisted both of unchanged CS-8958 and of R-125489 at 1 h postdose, while only R-125489, and no other metabolites, was detected at 24 h postdose. After administration of unlabeled CS-8958, CS-8958 was rapidly eliminated from the lungs, whereas the lung R-125489 concentration reached a maximum at 3 h postdose and gradually declined, with an elimination half-life of 41.4 h. The conversion of CS-8958 to R-125489 was observed in mouse trachea and lung S9 fractions and was inhibited by esterase inhibitors, such as diisopropylfluorophosphate and bis-p-nitrophenylphosphate. These results demonstrated that CS-8958 administered intranasally to mice was efficiently converted to R-125489 by a hydrolase(s) such as carboxylesterase, and then R-125489 was slowly eliminated from the respiratory tract. These data support the finding that CS-8958 has potential as a long-acting neuraminidase inhibitor, leading to significant efficacy as an anti-influenza drug by a single treatment.

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

{triangledown} Published ahead of print on 17 August 2009.

Antimicrobial Agents and Chemotherapy, November 2009, p. 4845-4851, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00731-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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