American Journal of Respiratory Medicine

, Volume 1, Issue 5, pp 305–311

β2-Agonist Eutomers

A Rational Option for the Treatment of Asthma?
Current Opinion


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.


  1. 1.
    Brittain RT, Farmer JB, Marshall RJ. Some observations on the β-adrenoceptor agonist properties of the isomers of salbutamol. Br J Pharmacol 1973; 48: 144–7PubMedCrossRefGoogle Scholar
  2. 2.
    Patil PN, Militer DD, Trendelenberg U. Molecular geometry and adrenergic drug activity. Pharmacol Rev 1975; 26: 323–92Google Scholar
  3. 3.
    Ariëns EJ. Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur J Clin Pharmacol 1984; 26: 663–8PubMedCrossRefGoogle Scholar
  4. 4.
    Cotzias GC, Papavasiliow PS, Gellene R. Modification of Parkinsonism: chronic treatment with L-dopa. N Engl J Med 1969; 280: 337–45PubMedCrossRefGoogle Scholar
  5. 5.
    Owen MD, Dean LS. Ropivacaine. Expert Opin Pharmacother 2000; 1: 325–36PubMedCrossRefGoogle Scholar
  6. 6.
    Scott AK. Stereoisomers and drug toxicity. Drug Saf 1993; 8: 149–59PubMedCrossRefGoogle Scholar
  7. 7.
    Conolly ME, Davies DS, Dollery CT, et al. Resistance to β-adrenoceptor stimulants (a possible explanation for the rise in asthma deaths). Br J Pharmacol 1971; 43: 389–402PubMedGoogle Scholar
  8. 8.
    Speizer FE, Doll R, Heaf P, et al. Investigation into use of drugs preceding death from asthma. BMJ 1968; 1: 339–43PubMedCrossRefGoogle Scholar
  9. 9.
    Stolley P, Schinnar R. Association between asthma mortality and isoproterenol aerosols: a review. Prev Med 1978; 7: 519–38PubMedCrossRefGoogle Scholar
  10. 10.
    Crane J, Flatt A, Jackson R, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981–1983: case-control study. Lancet 1989; 8644: 917–22CrossRefGoogle Scholar
  11. 11.
    Pearce N, Granger J, Atkinson M, et al. Case control study of prescribed fenoterol and death from asthma in New Zealand, 1977–81. Thorax 1990; 45: 170–5PubMedCrossRefGoogle Scholar
  12. 12.
    Spitzer WO, Suissa S, Ernst P, et al. The use of beta-agonists and the risk of death or near death from asthma. N Engl J Med 1992; 326: 501–6PubMedCrossRefGoogle Scholar
  13. 13.
    Suissa S, Ernst P, Boivin JF, et al. A cohort analysis of excess mortality in asthma and the use of inhaled beta-agonists. Am J Respir Crit Care Med 1994; 149: 604–10PubMedGoogle Scholar
  14. 14.
    Barrett TE, Strom BL. Inhaled beta-adrenergic receptor agonists in asthma: more harm than good? Am J Respir Crit Care Med 1995; 151: 574–7PubMedGoogle Scholar
  15. 15.
    McFadden ER. Perspectives in β2-agonist therapy: Vox clamantis in deserto vel lux in tenebris? J Allergy Clin Immunol 1995; 9: 641–51CrossRefGoogle Scholar
  16. 16.
    Sears MR, Taylor DR. Regular beta-agonist therapy: the quality of the evidence [letter]. Eur Respir J 1992; 5: 896–7PubMedGoogle Scholar
  17. 17.
    Pearlman DS, Chervinsky P, LaForce C, et al. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med 1992; 327: 1420–5PubMedCrossRefGoogle Scholar
  18. 18.
    Taylor DR, Town GI, Herbison GP, et al. Asthma control during long-term treatment with regular inhaled salbutamol and salmeterol. Thorax 1998; 53: 744–52PubMedCrossRefGoogle Scholar
  19. 19.
    Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997; 337: 1405–11PubMedCrossRefGoogle Scholar
  20. 20.
    Perrin-Fayolle M. Salbutamol in the treatment of asthma [letter]. Lancet 1995; 346: 1101PubMedCrossRefGoogle Scholar
  21. 21.
    Perrin-Fayolle M, Blum PS, Morley J, et al. Differential responses of asthmatic airways to enantiomers of albuterol: implications for clinical treatment of asthma. Clin Rev Allergy Immunol 1996; 14: 139–47PubMedCrossRefGoogle Scholar
  22. 22.
    Cockcroft DW, Swystun VA. Effect of single doses of S-salbutamol, R-salbutamol, racemic salbutamol, and placebo on the airway response to methacholine. Thorax 1997; 52: 845–8PubMedCrossRefGoogle Scholar
  23. 23.
    Lötvall J, Palmqvist M, Arvidsson P, et al. The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients. J Allergy Clin Immunol 2001; 108: 726–31PubMedCrossRefGoogle Scholar
  24. 24.
    Ramsay CM, Cowan J, Flannery E, et al. Bronchoprotective and bronchodilator effects of single doses of (S)-salbutamol, (R)-salbutamol and racemic salbutamol in patients with bronchial asthma. Eur J Clin Pharmacol 1999; 55: 353–9PubMedCrossRefGoogle Scholar
  25. 25.
    Cockcroft DW, Davis BE, Swystun VA, et al. Tolerance to the bronchoprotective effect of beta2-agonists: comparison of the enantiomers of salbutamol with racemic salbutamol and placebo. J Allergy Clin Immunol 1999; 103: 1049–53PubMedCrossRefGoogle Scholar
  26. 26.
    Sanjar S, Kristersson A, Mazzoni L, et al. Increased airway reactivity in the guinea-pig follows exposure to intravenous isoprenaline. J Physiol 1990; 425: 43–54PubMedGoogle Scholar
  27. 27.
    Morley J, Chapman ID, Foster A, et al. Effects of (+) and racemic salbutamol on airway responses in the guinea-pig. Br J Pharmacol 1991; 104: 295PGoogle Scholar
  28. 28.
    Chapman I, Mazzoni L, Morley J. An anomalous effect of salbutamol in sensitised guinea-pigs [abstract]. Br J Pharmacol 1990; 99: 66PGoogle Scholar
  29. 29.
    Galland BC, Blackman JG. Enhancement of airway reactivity to histamine by isoprenaline and related β-adrenoceptor agonists in the guinea-pig. Br J Pharmacol 1993; 108: 1016–23PubMedCrossRefGoogle Scholar
  30. 30.
    Costello RW, Jacoby DB, Fryer AD. Pulmonary neuronal M2 muscarinic receptor function in asthma and animal models of hyperreactivity. Thorax 1998; 53: 613–6PubMedCrossRefGoogle Scholar
  31. 31.
    Trofast J, Osterberg K, Kallstrom BL, et al. Steric aspects of agonism and antagonism at beta-adrenoceptors: synthesis of and pharmacological experiments with the enantiomers of formoterol and their diastereomers. Chirality 1991; 3: 443–50PubMedCrossRefGoogle Scholar
  32. 32.
    Schmidt D, Kallstrom BL, Waldeck B, et al. The effect of the enantiomers of formoterol on inherent and induced tone in guinea-pig trachea and human bronchus. Naunyn Schmiedebergs Arch Pharmacol 2000; 361: 405–9PubMedCrossRefGoogle Scholar
  33. 33.
    Johansson F, Rydberg I, Aberg G, et al. Effects of albuterol enantiomers on in vitro bronchial reactivity. Clin Rev Allergy Immunol 1996; 14: 57–64PubMedCrossRefGoogle Scholar
  34. 34.
    Templeton AG, Chapman ID, Chilvers ER, et al. Effects of S-salbutamol on human isolated bronchus. Pulm Pharmacol Ther 1998; 11: 1–6PubMedCrossRefGoogle Scholar
  35. 35.
    Kallstrom BL, Sjoberg J, Waldeck B. Steric aspects of formoterol and terbutaline: is there an adverse effect of the distomer on airway smooth muscle function? Chirality 1996; 8: 567–73PubMedCrossRefGoogle Scholar
  36. 36.
    Mitra S, Ugur M, Ugur O, et al. (S)-Albuterol increases intracellular free calcium by muscarinic receptor activation and a phospholipase C-dependent mechanism in airway smooth muscle. Mol Pharmacol 1998; 53: 347–54PubMedGoogle Scholar
  37. 37.
    Cho SH, Hartleroad JY, Oh CK. (S)-Albuterol increases the production of histamine and IL-4 in mast cells. Int Arch Allergy Immunol 2001; 124: 478–84PubMedCrossRefGoogle Scholar
  38. 38.
    Lipworth BJ, Struthers AD, McDevitt DG. Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics. Am Rev Respir Dis 1989; 140: 586–92PubMedGoogle Scholar
  39. 39.
    Hancox RJ, Aldridge RE, Cowan JO, et al. Tolerance to beta-agonists during acute bronchoconstriction. Eur Respir J 1999; 14: 283–7PubMedCrossRefGoogle Scholar
  40. 40.
    Hawkins CJ, Klease GT. Relative potency of (−)- and (±)-salbutamol on guinea pig tracheal tissue. J Med Chem 1973; 16: 856–7PubMedCrossRefGoogle Scholar
  41. 41.
    Hartley D, Middlemiss D. Absolute configuration of the optical isomers of salbutamol. J Med Chem 1971; 14: 995–6PubMedCrossRefGoogle Scholar
  42. 42.
    Gumbhir-Shah K, Kellerman DJ, DeGraw S, et al. Pharmacokinetics and pharmacodynamics of cumulative single doses of inhaled salbutamol enantiomers in asthmatic subjects. Pulm Pharmacol Ther 1999; 12: 353–62PubMedCrossRefGoogle Scholar
  43. 43.
    Nelson HS, Bensch G, Pleskow WW, et al. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol 1998; 102: 943–52PubMedCrossRefGoogle Scholar
  44. 44.
    Gawchik SM, Saccar CL, Noonan M, et al. The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allergy Clin Immunol 1999; 103: 615–21PubMedCrossRefGoogle Scholar
  45. 45.
    Handley DA, Tinkelman D, Noonan M, et al. Dose-response evaluation of levalbuterol versus racemic albuterol in patients with asthma. J Asthma 2000; 37: 319–27PubMedCrossRefGoogle Scholar
  46. 46.
    Black P. Levosalbutamol. Biodrugs 1999; 11: 439–40PubMedCrossRefGoogle Scholar
  47. 47.
    Ahrens R, Weinberger M. Levalbuterol and racemic albuterol: are there therapeutic differences? J Allergy Clin Immunol 2001; 108: 681–4PubMedCrossRefGoogle Scholar
  48. 48.
    Busse WW, Greos L, Vaickus L. Lower doses of Xenoprex are as effective as racemic albuterol in the prevention of exercise-induced asthma (EIB) [abstract]. J Allergy Clin Immunol 1999; 103: S136CrossRefGoogle Scholar
  49. 49.
    Israel E, Hong C, Claus R, et al. Levalbuterol is effective in the prevention of cold air induced bronchospasm and does not induce tachyphylaxis in the degree of bronchoprotection [abstract]. J Allergy Clin Immunol 2000; 105: S22CrossRefGoogle Scholar
  50. 50.
    Boulton DW, Fawcett JP. Pharmacokinetics and pharmacodynamics of single oral doses of albuterol and its enantiomers in humans. Clin Pharmacol Ther 1997; 62: 138–44PubMedGoogle Scholar
  51. 51.
    Borgström L, Nyberg L, Jonsson S, et al. Pharmacokinetic evaluation in man of terbutaline given as separate enantiomers and as the racemate. Br J Clin Pharmacol 1989; 27: 49–56PubMedCrossRefGoogle Scholar
  52. 52.
    Borgström L, Kennedy BM, Nilsson B, et al. Relative duodenal absorption of the two enantiomers of terbutaline after duodenal administration. Eur J Clin Pharmacol 1990; 38: 621–3PubMedCrossRefGoogle Scholar
  53. 53.
    Boulton DW, Fawcett JP. Enantioselective disposition of albuterol in humans. Clin Rev Allergy Immunol 1996; 14: 115–38PubMedCrossRefGoogle Scholar
  54. 54.
    Fawcett JP, Boulton DW. Enantioselective disposition of β2-agonists in humans. In: Costello JF, editor. Sympathomimetic enantiomers in the treatment of asthma. Carnforth: The Parthenon Publishing Group Inc, 1997: 101–122Google Scholar
  55. 55.
    Gumbhir-Shah K, Kellerman DJ, DeGraw S, et al. Pharmacokinetics and pharmacodynamic characteristics and safety of inhaled albuterol enantiomers in healthy volunteers. J Clin Pharmacol 1998; 38: 1096–106PubMedGoogle Scholar
  56. 56.
    Lecaillon JB, Kaiser G, Palmisano M, et al. Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of Foradil dry powder inhalation via aerolizer. Eur J Clin Pharmacol 1999; 55: 131–8PubMedCrossRefGoogle Scholar
  57. 57.
    Boulton DW, Fawcett JP. The pharmacokinetics of levosalbutamol: what are the clinical implications? Clin Pharmacokinet 2001; 40: 23–40PubMedCrossRefGoogle Scholar
  58. 58.
    Ward JK, Dow J, Dallow N, et al. Enantiomeric disposition of inhaled, intravenous and oral racemic-salbutamol in man: no evidence of enantioselective lung metabolism. Br J Clin Pharmacol 2000; 49: 15–22PubMedCrossRefGoogle Scholar
  59. 59.
    Walle T, Walle UK. Stereoselective sulphate conjugation of racemic terbutaline by human liver cytosol. Br J Clin Pharmacol 1990; 30: 127–33PubMedCrossRefGoogle Scholar
  60. 60.
    Walle T, Walle UK. Stereoselective sulphate conjugation of 4-hydroxypropranolol and terbutaline by the human liver phenolsulfotransferases. Drug Metab Dispos 1992; 20: 333–6PubMedGoogle Scholar
  61. 61.
    Zhang M, Fawcett JP, Kennedy JM, et al. Stereoselective glucuronidation of formoterol by human liver microsomes. Br J Clin Pharmacol 2000; 49: 152–7PubMedCrossRefGoogle Scholar
  62. 62.
    Butter JJ, van den Berg BTJ, Portier EJG, et al. Determination by HPLC with electrochemical detection of formoterol RR and SS enantiomers in urine. J Liquid Chromatogr Rel Tech 1996; 19: 993–1005CrossRefGoogle Scholar
  63. 63.
    Zhang M, Fawcett JP, Shaw JP. Rapid chiral high-performance liquid Chromatographic assay for salmeterol and alpha-hydroxysalmeterol: application to in vitro metabolism studies. J Chromatogr B Biomed Sci Appl 1999; 729: 225–30PubMedCrossRefGoogle Scholar
  64. 64.
    Boulton DW, Fawcett JP. Determination of salbutamol enantiomers in human plasma and urine by chiral high-performance liquid chromatography. J Chromatogr B Biomed Appl 1995; 672: 103–9PubMedCrossRefGoogle Scholar
  65. 65.
    Boulton DW, Fawcett JP. Enantioselective disposition of salbutamol in man following oral and intravenous administration. Br J Clin Pharmacol 1996; 41: 35–40PubMedCrossRefGoogle Scholar
  66. 66.
    Zhang M, Fawcett JP, Shaw JP. Stereoselective urinary excretion of formoterol and its glucuronide conjugate in human. Br J Clin Pharmacol. In pressGoogle Scholar
  67. 67.
    Landoni MF, Soraci A. Pharmacology of chiral compounds: 2-arylpropionic acid derivatives. Curr Drug Metab 2001; 2: 37–51PubMedCrossRefGoogle Scholar
  68. 68.
    Solomons TWG. Organic chemistry. 5th ed. New York: John Wiley and Sons Inc., 1992: 231–2Google Scholar
  69. 69.
    Fawcett JP, Taylor DR. Beta2-agonist enantiomers: is there a glitch with the chiral switch? Eur Respir J 1999; 13: 1223–4PubMedGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Clinical DiscoveryBristol-Myers Squibb Pharmaceutical Research InstitutePrincetonUSA
  2. 2.School of PharmacyUniversity of OtagoDunedinNew Zealand

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