Investigation of pulmonary drug permeability and tissue retention by computational analysis of rat ex vivo lung absorption profiles
Johanna Eriksson1, Erik Sjögren1, Helena Thörn2, Katarina Rubin3, Per Bäckman2,4 & Hans Lennernäs1
1Department of Pharmacy, Uppsala University, Uppsala, Sweden
2Pharmaceutical Technology & Development Inhalation, AstraZeneca-Gothenburg, Sweden
3Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development, AstraZeneca-Gothenburg, Sweden
4Current address: Mylan Global Respiratory Group, Mylan Pharma UK Ltd., Kent CT13 9FF, UK
Background To achieve an optimal drug delivery to the lung, it is important to have knowledge not only about residence time and drug release, but also of the rate and mechanisms of pulmonary permeability and tissue retention processes.
Methods Here, the overall pulmonary absorption rate of ten solubilized drug compounds were measured in the single-pass isolated perfused rat lung model. Also included in this study was historical data of re-circulated rat lung ex vivo absorption profiles. The single-pass perfused and re-circulated absorption profiles were computationally analysed with a compartmental in silico model developed to estimate membrane permeability, tissue association and dissociation rate constants.
Results The in silico lung model well described the absorption profiles for all compounds. Tissue retention was found to be an important parameter in describing the absorption profile for most of the compounds. In addition, a good correlation between estimated membrane permeability and obtained intrinsic Caco-2 permeability was established.
Conclusion The use of a computational model to deconvolute absorption profiles obtained from the isolated perfused rat lung model was found to enhance the understanding of pulmonary drug absorption. Further developments of the in silico model could potentially include dissolution of the drug in the epithelial lining fluid of the lung, thus enabling understanding of the absorption of inhaled solids.
