Jacobson Glenn A, Raidal Sharanne, Robson Kate, Narkowicz Christian K, Nichols David S, Haydn Walters E
School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.
School of Animal and Veterinary Sciences, Charles Sturt University, Wagga Wagga, New South Wales, Australia.
Br J Clin Pharmacol. 2017 Jul;83(7):1436-1445. doi: 10.1111/bcp.13228. Epub 2017 Feb 8.
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.
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.
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 and 378 ± 177 ng g 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 ) and (S)-salbutamol (877 ± 955 vs. 50.9 ± 12 ng g ) 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 respectively.
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.
沙丁胺醇通常以消旋混合物形式给药，但关于其在肺部药代动力学的对映体选择性知之甚少。本研究旨在调查吸入给药后肺组织中的对映体浓度。
12匹马通过吸入接受1000μg消旋沙丁胺醇。采用对映体选择性超高效液相色谱-串联质谱法测定给药后2、5、10和15分钟采集的肺上皮衬液（PELF）、中央肺组织（内镜下支气管活检）和外周肺组织（经皮肺活检）（分别在20和25分钟时）以及血浆样本中的沙丁胺醇浓度。
PELF的平均±95%置信区间（CI）产量为57±10mg。初始平均±95%CI（R）-和（S）-沙丁胺醇PELF浓度分别为389±189ng/g和378±177ng/g，两者在15分钟时均降低约50%。（R）-沙丁胺醇（875±945对49.5±12ng/g）和（S）-沙丁胺醇（877±955对50.9±12ng/g）在中央肺组织中的平均±95%CI药物水平均高于外周肺组织。在PELF或中央肺中没有对映体选择性的证据，但在外周肺中观察到轻微（约2%）的对映体选择性。在血浆中对映体选择性明显，浓度-时间曲线下面积（0-25分钟）和C的（S）:（R）比值分别为1.25和1.14。
在马中采集PELF可提供足够的产量，允许直接检测药物，并且与组织采样相结合，是研究支气管肺药代动力学的有价值模型。急性给药后，沙丁胺醇在PELF或中央肺组织摄取中未表现出对映体选择性，然而，显示出对映体选择性血浆浓度，在外周肺中有轻微的对映体选择性。
