title: Pharmacokinetic mechanism involved in the prolonged high retention of laninamivir in mouse respiratory tissues after intranasal administration of its prodrug laninamivir octanoate.
abstract: Laninamivir octanoate (LO) (Inavir; Daiichi Sankyo, Japan) is an ester prodrug of the neuraminidase inhibitor laninamivir. We previously reported that a prolonged high retention of laninamivir in mouse respiratory tissues was achieved by intranasal administration of LO. In this study, we evaluated intrapulmonary pharmacokinetics both in vivo and in vitro to investigate the potential mechanism involved in such a preferable retention. After intranasal administration of LO to mice (0.5 μmol/kg), the drug was distributed from the airway space into the lungs, and laninamivir remained in the lung at 24 hours postdose (2680 pmol/g), with a higher concentration than that in the epithelial lining fluid. The laninamivir was localized mainly on the epithelial cells of airway tracts, determined by microautoradiography using (14)C-labeled LO. In mouse airway epithelial cells, the cellular uptake and hydrolysis of LO were observed over incubation time without any apparent saturation at the highest concentration tested (1000 μM). Furthermore, after additional incubation in drug-free medium, the intracellular laninamivir was released very slowly into the medium with an estimate rate constant of 0.0707 h(-1), which was regarded as a rate-limiting step in the cellular retention. These results demonstrated that the prolonged high retention of laninamivir in the respiratory tissues was attributed to a consecutive series of three steps: uptake of LO into the airway epithelial cells, hydrolysis of LO into laninamivir by intracellular esterase(s), and limited efflux of the generated laninamivir due to its poor membrane permeability. This prodrug approach could be useful for lung-targeting drug delivery.
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, 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: Daisuke
authors.initials: D
authors.lastname: Nakai
authors.forename: Makoto
authors.initials: M
authors.lastname: Takahashi
authors.forename: Naoko
authors.initials: N
authors.lastname: Nakai
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Teruko
authors.initials: T
authors.lastname: Imai
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001345:Autoradiography; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006146:Guanidines; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics*; D011714:Pyrans; D012794:Sialic Acids; D014132:Trachea / Q000166:cytology / Q000378:metabolism*; D053243:Zanamivir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D011355:Prodrugs; D011714:Pyrans; D012794:Sialic Acids; C546918:laninamivir; D009439:Neuraminidase; D053243:Zanamivir