title: Rapid nongenomic actions of inhaled corticosteroids on long-acting β(2)-agonist transport in the airway.
abstract: 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 β(2)-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 β(2)-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.
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, University of Miami, Miller School of Medicine, FL, USA. ghorvath.mail@gmail.com
authors.forename: Gabor
authors.initials: G
authors.lastname: Horvath
authors.forename: Eliana S
authors.initials: ES
authors.lastname: Mendes
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schmid
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmid
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Conner
authors.forename: Nevis L
authors.initials: NL
authors.lastname: Fregien
authors.forename: Matthias
authors.initials: M
authors.lastname: Salathe
authors.forename: Adam
authors.initials: A
authors.lastname: Wanner
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D004347:Drug Interactions; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000502:physiology; D000099254:Organic Cation Transporter 3
chemical_list: D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D027701:Organic Cation Transport Proteins; D000099254:Organic Cation Transporter 3