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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
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 | ||||||||||
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| 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: |
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| 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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