ß<SUB>2</SUB>-Agonist enantiomers: is there a glitch with the chiral switch?

Abstract

Current guidelines for the treatment of chronic asthma emphasize the use of anti-inflammatory medication and indicate that short-acting b 2 -agonists should only be taken on an as-needed basis [1]. This approach has been adopted because of the inflammatory nature of asthma and because, somewhat controversially, regular use of shortacting b 2 -agonists at best confers no distinct benefit on overall asthma control [2], and at worst may cause a deterioration [3].A number of possible mechanisms have been proposed to explain the adverse effects of chronic short-acting b 2 -agonist therapy [4], but the debate continues. One possible explanation currently under consideration is related to the fact that b 2 -agonists are chiral and are administered as racemic mixtures of a pharmacologically active eutomer (e.g. R-salbutamol) and an inactive distomer (e.g. S-salbutamol). The possibility that the distomers are selectively responsible for the toxic effects occurring during chronic treatment with racemates (e.g. R,S-salbutamol or R,S-fenoterol) has been extensively discussed [5,6], although no firm conclusions have been reached. In animal studies, the administration of racemates and distomers has been shown to enhance bronchial hyperresponsiveness [7,8], but this has not yet been demonstrated in human subjects during chronic dosing.The paper by SCHMEKEL et al. [9] in this issue of the Journal contributes to the debate by providing further data related to the pharmacokinetics of salbutamol enantiomers. The results confirm earlier findings [10±12] that an oral dose of R,S-salbutamol is subject to extensive stereoselective first pass metabolism which leads to a high S:R ratio in the plasma, and to exposure to the more slowly cleared distomer in the absence of the eutomer. In addition, it is shown that salbutamol administered by inhalation is also subject to stereoselective metabolism, and that multiple dosing by inhalation at clinically relevant time intervals leads to an increase in the S:R ratio as steady state is approached. Since there is some evidence that S-salbutamol acts as a functional antagonist to the active enantiomer [12], the potential for exposure to high levels of S-salbutamol provides an attractive alternative to tolerance to explain the reduction in bronchodilator efficacy during chronic dosing with racemic drug.The fact that salbutamol delivered by inhalation undergoes similar enantioselective first pass metabolism to that given orally is not surprising since inhalation of dry powder inevitably involves considerable oral ingestion. It also seems likely that lung metabolism of inhaled salbutamol may be stereoselective, as suggested by in vitro studies [13] and by the results reported by SCHMEKEL et al. [9]. Endotracheal aerosol administration resulted in higher plasma concentration of S-salbutamol but, in the absence of a comparative intravenous study in the same group of patients, it is difficult to quantify pre-systemic metabolism by the lung. In fact, the slow rate of absorption after endotracheal aerosol ...