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Development of a Novel Lung Slice Methodology for Profiling of Inhaled Compounds
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden. (Translational PKPD)
AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden.
AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden.; Univ Warwick, Sch Engn, Coventry CV4 7AL, W Midlands, England.
AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden.
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2016 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 2, p. 838-845Article in journal (Refereed) Published
Abstract [en]

The challenge of defining the concentration of unbound drug at the lung target site after inhalation limits the possibility to optimize target exposure by compound design. In this study, a novel rat lung slice methodology has been developed and applied to study drug uptake in lung tissue, and the mechanisms by which this occurs. Freshly prepared lung slices (500 μm) from drug-naive rats were incubated with drugs followed by determination of the unbound drug volume of distribution in lung (Vu,lung), as the total concentration of drug in slices divided by the buffer (unbound) concentration. Vu,lung determined for a set of inhaled drug compounds ranged from 2.21 mL/g for salbutamol to 2970 mL/g for dibasic compound A. Co-incubation with monensin, a modulator of lysosomal pH, resulted in inhibition of tissue uptake of basic propranolol to 13%, indicating extensive lysosomal trapping. Partitioning into cells was particularly high for the cation MPP+ and the dibasic compound A, likely because of the carrier-mediated transport and lysosomal trapping. The results show that different factors are important for tissue uptake and the presented method can be used for profiling of inhaled compounds, leading to a greater understanding of distribution and exposure of drug in the lung.

Place, publisher, year, edition, pages
2016. Vol. 105, no 2, p. 838-845
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-278039DOI: 10.1002/jps.24575ISI: 000381768500050PubMedID: 26178700OAI: oai:DiVA.org:uu-278039DiVA, id: diva2:906071
Funder
EU, FP7, Seventh Framework Programme, 316736AstraZenecaAvailable from: 2016-02-23 Created: 2016-02-23 Last updated: 2018-01-10Bibliographically approved

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Bäckström, EricaHammarlund-Udenaes, MargaretaFridén, Markus

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