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Lung retention by lysosomal trapping of inhaled drugs can be predicted in vitro with lung slices

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Bäckström, Erica, Boger, Elin, Lundqvist, Anders, Hammarlund-Udenaes, Margareta and Fridén, Markus (2016) Lung retention by lysosomal trapping of inhaled drugs can be predicted in vitro with lung slices. Journal of Pharmaceutical Sciences, 105 (11). pp. 3432-3439. doi:10.1016/j.xphs.2016.08.014

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Official URL: http://dx.doi.org/10.1016/j.xphs.2016.08.014

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Abstract

Modulating and optimizing the local pharmacokinetics of inhaled drugs by chemical design or formulation is challenged by the lack of predictive in vitro systems and in vivo techniques providing a detailed description of drug location in the lung. The present study investigated whether a new experimental setup of freshly prepared agarose-filled lung slices can be used to estimate lung retention in vitro, by comparing with in vivo lung retention after intratracheal instillation. Slices preloaded with inhaled β-adrenergic compounds (salbutamol, formoterol, salmeterol, indacaterol or AZD3199) were incubated in a large volume of buffer (w/wo monensin to assess the role of lysosomal trapping), and the amount remaining in slices at different time points was determined with liquid chromatography-tandem mass spectrometry. The in vitro lung retention closely matched the in vivo lung retention (half-lives within 3-fold for 4/5 compounds), and monensin shortened the half-lives for all compounds. The results suggest that freshly prepared rat lungs slices can be used to predict lung retention and that slow kinetics of lysosomal trapping is a key mechanism by which retention in the lung and the effect duration of inhaled β-adrenergic bronchodilators are prolonged.

Item Type: Journal Article
Divisions: Faculty of Science > Engineering
Journal or Publication Title: Journal of Pharmaceutical Sciences
Publisher: John Wiley & Sons, Inc.
ISSN: 0022-3549
Official Date: November 2016
Dates:
DateEvent
November 2016Published
23 September 2016Available
19 August 2016Accepted
9 July 2016Submitted
Volume: 105
Number: 11
Page Range: pp. 3432-3439
DOI: 10.1016/j.xphs.2016.08.014
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access

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