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Pulmonary absorption - estimation of effective pulmonary permeability and tissue retention of ten drugs using an ex vivo rat model and computational analysis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0003-4318-6039
AstraZeneca, Phannaceut Technol & Dev Inhalat, Pepparedsleden 1, S-43183 Molndal, Sweden..
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2018 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 124, p. 1-12Article in journal (Refereed) Published
Abstract [en]

Permeation of inhaled drugs across the pulmonary epithelium can regulate the rate and extent of local drug absorption and hence the pulmonary tissue concentration. Therefore, understanding pulmonary epithelial transport could be important for successful design of novel inhaled medicines. To enhance understanding of pulmonary epithelial transport, drug transport data were generated for a set of inhaled compounds (n = 10) in the single-pass, isolated perfused rat lung model. A compartmental in silica model was used to estimate pulmonary permeability and tissue retention. The theoretical model was also used to re-analyze previously obtained historical drug transport data from the isolated perfused lung (n = 10) with re-circulating buffer. This was performed to evaluate the re-circulating model for assessing tissue retention measurements and to increase the number of data points. The tissue retention was an important parameter to estimate to be able to describe the drug transport profiles accurately of most of the investigated compounds. A relationship between the pulmonary permeability and the intrinsic (carrier-mediated transport inhibited) permeability of Caco-2 cell monolayers (n = 1-6) was also established. This correlation (R-2 = 0.76, p < .0001) suggests that intrinsic Caco-2 permeability measurements could offer early predictions of the passive transcellular permeability of lung epithelium to candidate drugs. Although, for some compounds a deviation from the correlation suggests that other transport mechanisms may coexist. The compartmental in silica model was successful in describing the pulmonary drug transport profiles of the investigated compounds and has potential for further development to investigate the effects of formulations with different features on the pulmonary overall absorption rate.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2018. Vol. 124, p. 1-12
Keyword [en]
Inhalation, Lung permeability, Isolated perfused lung model, Pulmonary drug delivery, Pulmonary drug absorption
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-350060DOI: 10.1016/j.ejpb.2017.11.013ISI: 000425839500001PubMedID: 29191716OAI: oai:DiVA.org:uu-350060DiVA, id: diva2:1203908
Funder
AstraZeneca
Available from: 2018-05-04 Created: 2018-05-04 Last updated: 2018-05-04Bibliographically approved

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Eriksson, JohannaSjögren, ErikLennernäs, Hans

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