Rapid corticosteroid effect on long-acting β2-agonist disposal by smooth muscle cells in the airway: A new paradigm of inhaled combination therapy

Gabor Horvath, Eliana S. Mendes, Nathalie Schmid, Andreas Schmid, Gregory E. Conner, Matthias Salathe, Adam Wanner

Research output: Contribution to journalArticle

Abstract

Organic cation transporters (OCTs) have an important role in tissue distribution and elimination of cationic drugs. To assess airway disposal of cationic bronchodilators, human airway cells and tissues obtained from organ donors were evaluated for drug transporter expression by quantitative RT-PCR and immunofluorescence. For in vitro functional studies, [3H]-formoterol (FORM) and [3H]-salmeterol (SALM) uptake by bronchial and vascular smooth muscle cells (SMC) was measured. RT-PCR analysis indicated high mRNA levels for the corticosteroid-sensitive OCT3 in bronchial and vascular SMC. Immunofluorescence staining of airway sections confirmed OCT3 expression in these cells. In bronchial SMC, uptake of the cationic FORM was inhibited with OCT inhibitors. Corticosteroids also inhibited FORM uptake through a rapid (within 15 min) nongenomic action, with the following rank order for inhibitory potency: corticosterone >budesonide >fluticasone (IC50: 0.48 ± 0.09, 1.88 ± 0.24, 4.48 ± 0.31 μmol·l-1, respectively). The corticosteroid-induced inhibition was significantly higher in vascular than bronchial SMC (40.5¡1.3% vs. 27.4¡3.1%, respectively; p,0.05). In comparison to FORM, uptake of the noncharged lipophilic SALM was about 10-fold higher (28.4 ± 1.7 vs. 327.5 ± 13.7 pmol·mg-1 protein/15 min; p<0.05), and insensitive to all OCT inhibitors and corticosteroids. Our findings suggest that corticosteroids, through OCT3 inhibition, rapidly interfere with the disposal of cationic bronchodilators in the airway. This novel immediate interaction supports the use of such combinations in the pharmacotherapy of asthma. Copyright

Original languageEnglish (US)
Pages (from-to)41-42
Number of pages2
JournalEuropean Respiratory Review
Volume17
Issue number107
DOIs
StatePublished - Apr 1 2008

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Fingerprint Dive into the research topics of 'Rapid corticosteroid effect on long-acting β<sub>2</sub>-agonist disposal by smooth muscle cells in the airway: A new paradigm of inhaled combination therapy'. Together they form a unique fingerprint.

  • Cite this