Funding tool: Basic research projects
Project-ID: LS17-009
Project start: 07. Jänner 2019
Project end: will follow
Runtime: 36 months / finished
Funding amount: € 292.380,00

Brief summary:

The incidence of lung-related diseases (e.g. asthma, COPD) and the associated morbidity continuously increases. These diseases are commonly treated with orally inhaled medical aerosols (e.g. corticosteroids, ?2-adrenergic agonists and anticholinergic drugs). There is a considerable heterogeneity in response to treatment with inhaled drugs and the sources of this heterogeneity are incompletely understood. Solute carrier (SLC) and adenosine triphosphate-binding cassette (ABC) transporters, localised in the membranes of pulmonary epithelial cells constituting the air-blood barrier, may influence the rate and extent of pulmonary absorption of inhaled drugs, and thereby contribute to heterogeneity in treatment response and occurrence of systemic side effects. Approximately two thirds of all approved low molecular weight drugs for the treatment of pulmonary diseases were shown to interact with drug transporters. However, as opposed to other organs (e.g. liver, intestine, kidney and brain), the exact role of pulmonary drug transporters in the lung disposition of inhaled drugs is poorly understood. In the present project, we will use positron emission tomography (PET) combined with magnetic resonance (MR) imaging to assess the influence of major pulmonary ABC transporters (i.e. MRP1, P-gp and BCRP) on pulmonary disposition of radiolabelled model transporter substrates, which will be directly administered as aerosols into the airways of wild-type and relevant transgenic transporter knockout rats. In addition, we will perform in vitro transport experiments in isolated pulmonary epithelial cells in primary culture and precision-cut lung slices to further characterise the interaction of the tested model substrates with pulmonary transporters. Moreover, immunohistochemical analysis of the exact spatial localisation of ABC transporters in rat and human lung tissues will be performed. Our project aims at developing validated PET/MR imaging protocols, which allow for non-invasive measurement of the function of major ABC transporters in the lungs. These PET/MR imaging protocols allow for a plethora of clinical applications, such as the assessment of the influence of disease or genetic polymorphisms on pulmonary transporter function or the assessment of transporter-mediated drug-drug interactions in the lungs. Following the timely concept of precision medicine, our project aims at providing an improved understanding of a possible link between pharmacokinetic variability caused by transporters and variability in response and occurrence of side effects in the treatment of pulmonary diseases with inhaled drugs.

Keywords:
pharmacology