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Pharmacokinetic mechanism involved in the prolonged high retention of laninamivir in mouse respiratory tissues after intranasal administration of its prodrug laninamivir octanoate.
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2013 Jan; Vol. 41 (1), pp. 180-7. Date of Electronic Publication: 2012 Oct 22. - Publication Year :
- 2013
-
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.
- Subjects :
- Administration, Intranasal
Animals
Autoradiography
Cells, Cultured
Enzyme Inhibitors administration & dosage
Enzyme Inhibitors blood
Guanidines
Lung cytology
Mice
Mice, Inbred BALB C
Prodrugs metabolism
Pyrans
Sialic Acids
Trachea cytology
Zanamivir administration & dosage
Zanamivir blood
Zanamivir pharmacokinetics
Enzyme Inhibitors pharmacokinetics
Lung metabolism
Neuraminidase antagonists & inhibitors
Prodrugs pharmacokinetics
Trachea metabolism
Zanamivir analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1521-009X
- Volume :
- 41
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 23091189
- Full Text :
- https://doi.org/10.1124/dmd.112.048280