Bronchopulmonary pharmacokinetics of (R)‐salbutamol and (S)‐salbutamol enantiomers in pulmonary epithelial lining fluid and lung tissue of horses

摘要

Aims Salbutamol is usually administered as a racemic mixture but little is known about the enantioselectivity of salbutamol pharmacokinetics in the lung. This study was designed to investigate enantiomer concentrations in lung tissue after inhaled dosing. Methods Horses ( n =?12) received racemic salbutamol 1000 μg via inhalation. Enantioselective ultra performance liquid chromatography–tandem mass spectrometry was used to determine salbutamol concentrations in pulmonary epithelial lining fluid (PELF) sampled 2, 5, 10 and 15?min after administration, in central lung (endoscopic bronchial biopsy) and peripheral lung (percutaneous pulmonary biopsy) tissues (at 20 and 25?min respectively), and in plasma samples. Results Mean?±?95% confidence interval (CI) yield of PELF was 57?±?10?mg. Initial mean?±?95%CI (R)‐ and (S)‐salbutamol PELF concentrations were 389?±?189?ng?g–1 and 378?±?177?ng?g–1 respectively, and both reduced approximately 50% by 15?min. Mean?±?95%CI central lung levels of drug were higher than peripheral lung tissue for both (R)‐salbutamol (875?±?945 vs. 49.5?±?12?ng?g–1) and (S)‐salbutamol (877?±?955 vs. 50.9?±?12?ng?g–1) respectively. There was no evidence of enantioselectivity in PELF or central lung but minor (~2%) enantioselectivity was observed in the peripheral lung. Enantioselectivity was clearly evident in plasma with (S):(R) ratio of 1.25 and 1.14 for both area under the concentration–time curve (0–25?min) and C_max respectively. Conclusions PELF sampling in horses offers sufficient yield allowing direct detection of drug and, combined with tissue sampling, is a valuable model to investigate bronchopulmonary pharmacokinetics. Salbutamol did not demonstrate enantioselectivity in PELF or central lung tissue uptake following acute dosing, however, enantioselective plasma concentrations were demonstrated, with minor enantioselectivity in the peripheral lung.