Enantioselective bronchopulmonary pharmacokinetics of salbutamol in horses

Salbutamol (albuterol) is a β2-agonist routinely used for bronchodilation in horses, typically administered as a 50:50 racemic mixture. Studies in horses and other species have suggested that the R- enantiomer is responsible for therapeutic effects, and the S- enantiomer may be responsible for airway hyper-responsiveness. Despite widespread usage, there is comparatively little known about the enantioselective pharmacokinetics for this agent in horses. The current study was undertaken to characterise enantiomers of salbutamol in bronchial epithelial lining fluid (ELF), bronchial epithelium, pulmonary tissue and peripheral blood. Twelve healthy horses were administered 1mg (10 x 100 µg actuations) of racemic (rac-) salbutamol via a pressurised metered dose inhaler with Aerohippus® equine aerosol chamber. Samples of ELF were collected 2, 5, 10 and 15 min following medication. Endoscopic biopsies of bronchial epithelia were collected approximately 20 to 25 min following treatment, and a pulmonary biopsy was taken at 30 min. Peripheral blood samples were collected at each sampling time. Salbutamol enantiomers were analysed by an enantioselective UPLC-MS/MS assay. Concentrations of salbutamol were approximately 400 ng/g ELF for both enantiomers. A reduction of approximately 50% was observed in samples collected over the 2 to 15 min sampling period consistent with mucociliary clearance and tissue absorption, and no stereoselectivity was observed in the lung. Salbutamol was detected in bronchial epithelium and peripheral lung tissue in equal amounts for both R- and S- forms. In contrast to pulmonary findings, plasma concentrations evidenced enantioselectivity, with the S- enantiomer present at approximately 1.5x the concentration observed for R-. Our findings demonstrated local concentrations of salbumatmol in ELF sufficient to exert biological effect, and have established non-enantioselective uptake into bronchial and pulmonary tissues. Differences in enantiomer concentrations in peripheral blood are likely to reflect enantioselective differences in uptake into peripheral tissues.