, Volume 1, Issue 5, pp 305-311
Date: 20 Aug 2012

β2-Agonist Eutomers

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Abstract

β2-adrenoceptor agonists (β2-agonists) such as albuterol (salbutamol) and terbutaline and their long-acting analogs salmeterol and formoterol are widely used as bronchodilators in the treatment of asthma. They are chiral drugs historically marketed as racemic mixtures of an active (eutomer) and essentially inactive (distomer) stereoisomer. Despite their obvious therapeutic value and widespread use, β2-agonists have been implicated, somewhat controversially, in causing an increase in asthma mortality and a deterioration of asthma control by a mechanism that remains elusive. Inherent toxicity of the distomers has been widely touted as an explanation and has given rise to pressure for the replacement of the racemates with pure eutomer formulations (the so-called chiral or racemic switch). This has culminated in the recent introduction into clinical practice of the single active stereoisomer of albuterol (levalbuterol) and the promise of other pure β2-agonist eutomer formulations to follow. This article examines the evidence on which these chiral switches are based.

Clinical studies designed to reveal negative effects of β2-agonists have searched for reductions in lung function, increases in airway responsiveness to bronchoconstrictor mediators and worsening of asthma control. Crossover studies administering the pure stereoisomers and racemate of albuterol have not shown a clear superiority of the pure eutomer formulation over the racemate in terms of either bronchial hyperresponsiveness, tachyphylaxis to bronchoprotective effects or improvements in lung function. Clinical toxicity of β2-agonist distomers on any aspect of asthmatic lung function has also not been demonstrated in the relatively short-term inhalational studies (single dose or repeated dose studies <1 week) that have been carried out.

In animal studies, the administration of β2-agonist racemates and distomers has been shown to enhance bronchial hyperresponsiveness but only in ovalbumin-sensitized animals where the relevance to humans is questionable.

The pharmacokinetics and metabolism of β2-agonist stereoisomers appear to be essentially similar whether administered as single stereoisomers or as racemates. Levalbuterol may be slightly more potent than an equivalent dose given as racemate, but there is some evidence that it forms a small amount of the distomer in vivo which detracts somewhat from its purported benefits over use of the racemate.

Whilst there remains a clear need for studies of longer duration with sensitive clinical endpoints to evaluate the benefits of β2-agonist eutomers and to investigate distomer toxicity, the chiral switch for β2-agonists in general, and for albuterol in particular, does not appear to be justified on the basis of the evidence available to date.