Rapid nongenomic actions of inhaled corticosteroids on long-acting β 2-agonist transport in the airway

Gabor Horvath, Eliana Mendes, Nathalie Schmid, Andreas Schmid, Gregory E Conner, Nevis L. Fregien, Matthias A Salathe, Adam Wanner

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)654-659
Number of pages6
JournalPulmonary Pharmacology and Therapeutics
Volume24
Issue number6
DOIs
StatePublished - Dec 1 2011

Fingerprint

Adrenal Cortex Hormones
Smooth Muscle Myocytes
Muscle
Cells
Bronchodilator Agents
Tissue
Beclomethasone
Budesonide
Lentivirus
Tissue Distribution
Transcription
Pharmaceutical Preparations
Small Interfering RNA
Cations
Anti-Inflammatory Agents
Epithelial Cells
Formoterol Fumarate

Keywords

  • Asthma
  • Bronchial smooth muscle
  • Formoterol
  • Inhaled corticosteroids
  • Nongenomic
  • Organic cation transporter

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Pharmacology (medical)
  • Biochemistry, medical

Cite this

Rapid nongenomic actions of inhaled corticosteroids on long-acting β 2-agonist transport in the airway. / Horvath, Gabor; Mendes, Eliana; Schmid, Nathalie; Schmid, Andreas; Conner, Gregory E; Fregien, Nevis L.; Salathe, Matthias A; Wanner, Adam.

In: Pulmonary Pharmacology and Therapeutics, Vol. 24, No. 6, 01.12.2011, p. 654-659.

Research output: Contribution to journalArticle

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