title: CS-8958, a prodrug of the novel neuraminidase inhibitor R-125489, demonstrates a favorable long-retention profile in the mouse respiratory tract.
abstract: 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 micromol/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 [(14)C]CS-8958, radioactivity was retained in the respiratory tract over long periods. At 24 h postdose, the radioactivity concentrations after administration of [(14)C]CS-8958 were approximately 10-fold higher in both the trachea and the lung than those of [(14)C]R-125489 and [(14)C]zanamivir. The [(14)C]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.
authors.affiliation: Drug Metabolism Research Laboratory, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. koyama.kumiko.hv@daiichisankyo.co.jp
authors.forename: Kumiko
authors.initials: K
authors.lastname: Koyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masataka
authors.initials: M
authors.lastname: Oitate
authors.forename: Naoko
authors.initials: N
authors.lastname: Nakai
authors.forename: Hideo
authors.initials: H
authors.lastname: Takakusa
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Miura
authors.forename: Osamu
authors.initials: O
authors.lastname: Okazaki
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001345:Autoradiography; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D004950:Esterases / Q000037:antagonists & inhibitors; D005260:Female; D006146:Guanidines; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000187:drug effects*; D011355:Prodrugs / Q000493:pharmacokinetics*; D011714:Pyrans; D012794:Sialic Acids; D014132:Trachea / Q000378:metabolism*; D053243:Zanamivir / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000998:Antiviral Agents; C546919:CS 8958; D004791:Enzyme Inhibitors; D006146:Guanidines; D011355:Prodrugs; D011714:Pyrans; D012794:Sialic Acids; C546918:laninamivir; D004950:Esterases; D009439:Neuraminidase; D053243:Zanamivir
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