The pharmacokinetics of levosalbutamol - What are the clinical implications?

Salbutamol (albuterol) is a beta (2)-adrenoceptor agonist used as a broncho dilator for the treatment of asthma and as a uterine relaxant for the suspe nsion of premature labour. Salbutamol has been marketed as a racemic mixtur e, although beta (2)-agonist activity resides almost exclusively in the (R) -enantiomer. The enantioselective disposition of salbutamol and the possibi lity that (S)-salbutamol has adverse effects have led to the development of an enantiomerically pure (R)-salbutamol formulation known as levosalbutamo l (levalbuterol). Salbutamol is metabolised almost exclusively by sulphotransferase (SULT) 1A 3 to an inactive metabolite. (R)-Salbutamol is metabolised up to 12 times f aster than (S)-salbutamol. This leads to relatively higher plasma concentra tions of (S)-salbutamol following all routes of administration, but particu larly following oral administration because of extensive metabolism by the intestine. Enantiomer concentrations are similar for the first hour followi ng an inhaled dose, reflecting the fact that salbutamol in the lung probabl y undergoes little metabolism. Subsequently, (S)-salbutamol predominates du e to absorption and metabolism of the swallowed portion of the inhaled dose . Following oral or inhaled; administration of enantiomerically pure salbut amol, 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 bin ding is relatively low. Both enantiomers are actively excreted into the uri ne. Compared with healthy individuals, patients with asthma do not have sub stantially different pharmacokinetics of the salbutamol enantiomers, but th ey do appear to have less drug delivered to the lung following inhaled admi nistration because of their narrowed airways. Levosalbutamol elicits an equal or slightly larger response than an equival ent dose of the racemic mixture. This is probably due to competitive inhibi tion between the enantiomers at beta -adrenoceptors. Pharmacokinetic-pharma codynamic relationships for levosalbutamol show relatively large interindiv idual variations. Functionally significant genetic polymorphisms have been identified for beta (2)-adrenoceptors, SULT1A3 and organic action transport ers, all of which affect the disposition or action of levosalbutamol. Animal, in vitro and some clinical studies have reported deleterious effect s of (S)-salbutamol on smooth muscle contractility or lung function. Howeve r, well-designed clinical studies in patients with asthma have failed to fi nd evidence of significant toxicity associated with (S)-salbutamol. The cli nical consequences of relatively higher plasma concentrations of (S)-salbut amol following administration of racemate remain unclear, but in the absenc e of clear evidence of toxicity the clinical superiority of levosalbutamol over racemic salbutamol appears to be small.