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Lung Retention by Lysosomal Trapping of Inhaled Drugs Can Be Predicted In Vitro With Lung Slices
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. AstraZeneca R&D Gothenburg, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden..
AstraZeneca R&D Gothenburg, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden.;Univ Warwick, Sch Engn, Coventry CV4 7AL, W Midlands, England..
AstraZeneca R&D Gothenburg, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2016 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 11, 3432-3439 p.Article in journal (Refereed) Published
Abstract [en]

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 beta-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 beta-adrenergic bronchodilators are prolonged.

Place, publisher, year, edition, pages
2016. Vol. 105, no 11, 3432-3439 p.
Keyword [en]
pharmacokinetics, pulmonary drug delivery, tissue partition, distribution, pulmonary
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-311212DOI: 10.1016/j.xphs.2016.08.014ISI: 000388268200023PubMedID: 27671235OAI: oai:DiVA.org:uu-311212DiVA: diva2:1059009
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2016-12-22Bibliographically approved

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Bäckström, EricaHammarlund-Udenaes, MargaretaFridén, Markus
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