Interaction of inhaled therapeutics with drug transporters in Calu-3 cell layers

The interaction of inhaled drug molecules with transporter proteins in the airway epithelium is poorly understood, and the clinical significance is largely unknown. This series of experiments aimed to investigate if inhaled drug compounds interacted with transporter-mediated trafficking by the multi-drug resistant transporter, P-glycoprotein/multi-drug resistance protein 1 (P-gp/MDR1). The impact of several marketed inhaled drugs on the transport of the MDR1 substrate 3H-digoxin was assessed as well as their capacity to bind to the MDR1 transporter using a functional MDR1 inhibitory antibody, UIC2. Budesonide and formoterol, but not salbutamol significantly reduced the net secretory transport of 3H-digoxin, whereas only budesonide and salbutamol were found to interact with the MDR1 transporter. To further investigate this contradiction, the transporter(s) involved in 3H-digoxin secretion were more thoroughly assessed using a panel of chemical and immunological inhibitors. As a result, MDR1 was found to have a nominal role in 3H-digoxin transport in Calu-3 cell layers. This work indicates that inhaled drugs are able to modulate the transporter-mediated trafficking of compounds in the bronchial epithelium, and highlights the need for better characterisation of membrane transporters in the airways.