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Rapid nongenomic actions of inhaled corticosteroids on long-acting ?(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 ?(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 ?(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.

SUBMITTER: Horvath G

PROVIDER: S-EPMC3220932 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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

Horvath Gabor G Mendes Eliana S ES Schmid Nathalie N Schmid Andreas A Conner Gregory E GE Fregien Nevis L NL Salathe Matthias M Wanner Adam A

Pulmonary pharmacology & therapeutics 20110908 6

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. Cortic ...[more]

PMID: 21914487

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Project description:BACKGROUND:We previously showed that the long-acting beta agonist (LABA) salmeterol as inhalation powder or metered-dose inhaler improves lung-function parameters assessed by impulse oscillometry (IOS) in 2- to 5-year-old children with reversible-airway disease within 15 minutes. OBJECTIVE:We studied 12- to 45-year-olds with mild persistent asthma in order to compare the onset and extent of peripheral airway effects following the first dose and after 4 weeks dosing with two inhaled corticosteroid (ICS)/LABA combinations: fluticasone propionate/salmeterol 115/21 and budesonide/formoterol 160/4.5. METHODS:Thirty subjects with mild persistent asthma using only an as-needed short-acting beta-agonist (albuterol) who had at least a 40% change in integrated low-frequency reactance postalbuterol were selected and randomized to receive either fluticasone propionate/salmeterol or budesonide/formoterol (15 subjects each). We collected three to six IOS replicates at baseline, at 5, 20, 40, 60, 120, and 240 minutes postdose at randomization, and after 4 weeks of twice-daily dosing. Blinded investigators calculated IOS frequency-dependent resistance and reactance (R5-R20 and AX), indicative of small-airway dysfunction, and also estimated the peripheral airway resistance (Rp ) and peripheral airway compliance (Cp ), using a respiratory-impedance model. RESULTS:At randomization visits, onset of action was detected as early as 5 minutes (t-test, P < 0.05) after fluticasone propionate/salmeterol by Cp , and within 5 minutes after budesonide/formoterol by R5-R20, AX, Rp , and Cp . However, after 4 weeks of dosing, only Rp was significantly different (from 60 to 120 minutes) after fluticasone propionate/salmeterol, while R5-R20, AX, Rp , and Cp were not significantly different within 240 minutes after budesonide/formoterol. CONCLUSION:These two ICS/LABA combinations initially improved the peripheral airway function of 12- to 45-year-old asthmatics significantly in about 5 minutes or less, as measured by R5-R20, AX, Rp , and/or Cp . After regular dosing for 4 weeks, pre- to postdose differences in these parameters had diminished significantly due to improved predose status of peripheral airways. Single dosing with ICS/LABA combinations in mild persistent asthma improves small-airway function, and the effect is maintained over a 12-hour interval by regular use for 4 weeks.