Boulton D W, Fawcett J P
Laboratory of Drug Disposition and Pharmacogenetics, Institute of Psychiatry, Medical University of South Carolina, Charleston 29425, USA.
Clin Pharmacokinet. 2001 Jan;40(1):23-40. doi: 10.2165/00003088-200140010-00003.
Salbutamol (albuterol) is a beta2-adrenoceptor agonist used as a bronchodilator for the treatment of asthma and as a uterine relaxant for the suspension of premature labour. Salbutamol has been marketed as a racemic mixture, although beta2-agonist activity resides almost exclusively in the (R)-enantiomer. The enantioselective disposition of salbutamol and the possibility that (S)-salbutamol has adverse effects have led to the development of an enantiomerically pure (R)-salbutamol formulation known as levosalbutamol (levalbuterol). Salbutamol is metabolised almost exclusively by sulphotransferase (SULT) 1A3 to an inactive metabolite. (R)-Salbutamol is metabolised up to 12 times faster than (S)-salbutamol. This leads to relatively higher plasma concentrations of (S)- salbutamol following all routes of administration, but particularly following oral administration because of extensive metabolism by the intestine. Enantiomer concentrations are similar for the first hour following an inhaled dose, reflecting the fact that salbutamol in the lung probably undergoes little metabolism. Subsequently, (S)-salbutamol predominates due to absorption and metabolism of the swallowed portion of the inhaled dose. Following oral or inhaled administration of enantiomerically pure salbutamol, a small amount (6%) is converted to the other enantiomer, probably by acid-catalysed racemisation in the stomach. Tissue binding of salbutamol is not enantioselective and plasma protein binding is relatively low. Both enantiomers are actively excreted into the urine. Compared with healthy individuals, patients with asthma do not have substantially different pharmacokinetics of the salbutamol enantiomers, but they do appear to have less drug delivered to the lung following inhaled administration because of their narrowed airways. Levosalbutamol elicits an equal or slightly larger response than an equivalent dose of the racemic mixture. This is probably due to competitive inhibition between the enantiomers at beta-adrenoceptors. Pharmacokinetic-pharmacodynamic relationships for levosalbutamol show relatively large interindividual variations. Functionally significant genetic polymorphisms have been identified for beta2-adrenoceptors, SULT1A3 and organic action transporters, all of which affect the disposition or action of levosalbutamol. Animal, in vitro and some clinical studies have reported deleterious effects of (S)-salbutamol on smooth muscle contractility or lung function. However, well-designed clinical studies in patients with asthma have failed to find evidence of significant toxicity associated with (S)-salbutamol. The clinical consequences of relatively higher plasma concentrations of (S)-salbutamol following administration of racemate remain unclear, but in the absence of clear evidence of toxicity the clinical superiority of levosalbutamol over racemic salbutamol appears to be small.
沙丁胺醇（舒喘宁）是一种β2肾上腺素能受体激动剂，用作支气管扩张剂治疗哮喘，也用作子宫松弛剂以延缓早产。沙丁胺醇一直以消旋混合物形式上市销售，尽管β2激动剂活性几乎完全存在于（R）-对映体中。沙丁胺醇的对映体选择性处置以及（S）-沙丁胺醇可能产生不良反应，促使了一种对映体纯的（R）-沙丁胺醇制剂的开发，即左沙丁胺醇（左旋沙丁胺醇）。沙丁胺醇几乎完全由磺基转移酶（SULT）1A3代谢为无活性代谢物。（R）-沙丁胺醇的代谢速度比（S）-沙丁胺醇快达12倍。这导致在所有给药途径后，尤其是口服给药后，（S）-沙丁胺醇的血浆浓度相对较高，因为肠道会进行广泛代谢。吸入剂量后第一小时内对映体浓度相似，这反映出肺中的沙丁胺醇可能很少发生代谢。随后，由于吸入剂量中吞咽部分的吸收和代谢，（S）-沙丁胺醇占主导。口服或吸入对映体纯的沙丁胺醇后，少量（6%）会转化为另一种对映体，可能是通过胃中的酸催化外消旋化。沙丁胺醇的组织结合没有对映体选择性，血浆蛋白结合率相对较低。两种对映体都能被主动排泄到尿液中。与健康个体相比，哮喘患者的沙丁胺醇对映体药代动力学没有实质性差异，但由于气道变窄，他们吸入给药后到达肺部的药物似乎较少。左沙丁胺醇比等量的消旋混合物产生的反应相同或略大。这可能是由于对映体在β肾上腺素能受体处的竞争性抑制。左沙丁胺醇的药代动力学-药效学关系显示个体间差异相对较大。已确定β2肾上腺素能受体、SULT1A3和有机转运体存在具有功能意义的基因多态性，所有这些都会影响左沙丁胺醇的处置或作用。动物、体外和一些临床研究报告了（S）-沙丁胺醇对平滑肌收缩力或肺功能的有害影响。然而，针对哮喘患者的精心设计的临床研究未能找到与（S）-沙丁胺醇相关的明显毒性证据。消旋体给药后（S）-沙丁胺醇血浆浓度相对较高的临床后果仍不清楚，但在没有明确毒性证据的情况下，左沙丁胺醇相对于消旋沙丁胺醇的临床优势似乎很小。
