Rapid nongenomic actions of inhaled corticosteroids on long-acting β2-agonist transport in the airway

Corticosteroids inhibit organic cation transporters (OCTs) that play an important role in drug absorption, tissue distribution and elimination. Corticosteroid sensitivity of bronchodilator trafficking in the airway tissue, however, is poorly understood. To assess the effects of inhaled corticosteroids on airway absorption and disposal mechanisms of long-acting β2-agonists, human airway epithelial and smooth muscle cell uptake of tritiated formoterol and salmeterol was measured in vitro. Corticosteroids caused a rapid, concentration-dependent inhibition of uptake of the cationic formoterol by airway smooth muscle cells, but not airway epithelial cells. Uptake of the non-charged lipophilic salmeterol was corticosteroid-insensitive in both cell types. In smooth muscle cells, inhaled corticosteroids inhibited formoterol uptake with a novel potency rank order: des-ciclesonide > budesonide > beclomethasone 17-monopropionate > beclomethasone dipropionate > ciclesonide > fluticasone. The inhibitory action was rapidly reversible, and was not enhanced by prolonged corticosteroid exposure or sensitive to a transcription inhibitor. Suppression of OCT3 expression using lentivirus-mediated production of shRNA reduced corticosteroid sensitivity of formoterol uptake by smooth muscle cells. Our data support a corticosteroid insensitive absorption and a corticosteroid-sensitive disposition mechanism for cationic long-acting β2-agonist bronchodilators in the airway. Potency rank order and other ‘classical’ features of anti-inflammatory effects do not apply to inhaled corticosteroids’ rapid drug transport actions.

► We examine corticosteroid actions on long-acting β2-agonist uptake by airway cells. ► We find an acute inhibition of smooth muscle uptake of the cationic formoterol. ► The rapid effect does not require the ‘classical’ pathway of steroid action. ► We also show a novel hierarchy for corticosteroids to limit formoterol uptake. ► These rapid interactions may have a role in the superior effect of drug combinations.