Effect of OCT/Ns on pulmonary disposition of inhaled drugs

Most inhaled drugs have to cross the pulmonary epithelium to reach their pharmacological effect sites in lung tissue. Several respiratory drugs, however, are cations at physiological pH and thus show only negligible passive transmembrane permeability. Lung epithelial cells abundantly express organic cation transporters, which were shown to interact with inhaled cationic drugs mainly in in vitro studies. In vivo data on the role of organic cation transporters in pulmonary distribution and systemic absorption of inhaled drugs is urgently required for the development of saver inhaled medicines. In the present project, positron emission tomography (PET) imaging will be used to assess the influence of organic cation transporters on the pulmonary disposition of two clinically used inhaled drugs (ipratropium bromide and formoterol). To this end, the drugs will be radiolabeled with carbon-11 and their lung distribution will be assessed with PET after direct administration into the airways of wild-type rats, without and with co-administration of transporter inhibitors, as well as of transgenic transporter knockout rats. To complement the in vivo experiments, a range of in vitro experiments will be performed (transport experiments in a lung epithelial cell line and experiments in lung slices).