Development of bambuterol; a long acting, orally active beta-agonist prodrug

  • Leif-Ake Svensson
Conference paper


Bambuterol, Bambec®, is a novel, orally active, long-acting bronchodilator with 24 hours duration of action and a lower incidence of adverse advents as compared with other oral bronchodilators [1]. Bambuterol, dimethylcarbamic acid 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-1,3-phenylene ester, is a prodrug to the β2-adrenoceptor agonist terbutaline. It was developed by Astra Draco AB, and is currently approved for the treatment of bronchial asthma, chronic bronchitis and other lung diseases, where bronchospasm is a complicating factor.

This paper reviews how bambuterol was developed from terbutaline by use of the prodrug technique.


Hydrolytic Stability Plasma Cholinesterase Lung Uptake Ester Prodrug Pivalic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bauer CA, Svenson L-Å (1992) Bambuterol (Bambec®): A new long-acting oral bronchodilator. Drugs of Today 28: 547–557Google Scholar
  2. 2.
    Kristoffersson J, Svensson L-Å, Tegnér K (1974) Drug latentiation of terbutaline. In vitro serum esterase catalyzed hydrolysis of a series of acylsubstituded mono-and diesters of terbutaline. Acta Pharm Suec 11: 427–438PubMedGoogle Scholar
  3. 3.
    Hörnblad Y, Ripe E, Magnusson PO, Tegnér K (1976) The metabolic and clinical activity of terbutaline and its ester prodrug ibuterol. Eur J Clin Pharmacol 10: 9–18CrossRefGoogle Scholar
  4. 4.
    Ryrfeldt Å, Nilsson E (1978) Uptake and biotransformation of ibuterol and terbutaline in isolated perfused rat and guinea pig lungs. Biochem Pharmacol 27: 301–305PubMedCrossRefGoogle Scholar
  5. 5.
    Svensson L-Å (1987) Development of β2-adrenoceptor agonist bronchodilator prodrugs. In: Hollinger MA (ed) Current topics in pulmonary pharmacology and toxicology, Vol. 3. Elsevier, New York, 1–26Google Scholar
  6. 6.
    Olsson OAT, Svensson L-Å (1984) New lipophilic terbutaline ester prodrugs with long effect duration. Pharm Res 1: 19–23CrossRefGoogle Scholar
  7. 7.
    Svensson L-Å (1991) A prodrug approach to a long-acting β2-agonist. DN&P 4: 544–549Google Scholar
  8. 8.
    Tunek A, Svensson L-Å (1988) Bambuterol, a carbamate ester prodrug of terbutaline, as inhibitor of cholinesterases in human blood. Drug Metab Dispos 16: 759–764PubMedGoogle Scholar
  9. 9.
    Sharma M, Svensson L-Å (1991) Bambuterol, a selective inhibitor of plasma butyryl cholinesterase. In: Massoulié J et al (eds) Cholinesterases. Structure, function, mechanism, genetics, and cell biology. ACS Books, Washington, DCGoogle Scholar
  10. 10.
    Wetterlin K (1972) Resolution of terbutaline, a new β-sympathomimetic amine. J Med Chem 15: 1182–1183PubMedCrossRefGoogle Scholar
  11. 11.
    Jeppsson A-B, Johansson U, Waldeck B (1984) Steric aspects of agonism and antagonism at 3-adrenoceptors: Experiments with the enantiomers of terbutaline and pindolol. Acta Pharmacol et toxicol 54: 285–291CrossRefGoogle Scholar
  12. 12.
    Tunek A, Kennedy B-M, Svensson L-Å (1991) Stereoselective interactions of bambuterol with human plasma cholinesterase. Symposium on recent progress in extrahepatic metabolism (May 15–17, Ronneby) Abst 19Google Scholar
  13. 13.
    Lindberg C, Roos C, Tunek A, Svensson L-Å (1989) Metabolism of bambuterol in rat liver microsomes: Identification of hydroxylated and demethylated products by liquid chromatography mass spectrometry. Drug Metab Disp 17: 311–322Google Scholar
  14. 14.
    Svensson L-Å, Tunek A (1988) The design and bioactivation of presystemically stable prodrugs. Drug Metab Rev 19: 165–194PubMedCrossRefGoogle Scholar
  15. 15.
    Svensson L-Å (1987) BambuteroL-Å prodrug-prodrug with built-in hydrolysis brake. Acta Pharm Suec 24: 333–341PubMedGoogle Scholar
  16. 16.
    Tunek A, Borgström L, Nyberg L (1986) Metabolism in man of 3H-bambuterol: A carbamate ester prodrug of terbutaline. Acta Pharmacol Toxicol 59 [Suppl 5]: 214Google Scholar
  17. 17.
    Viby Mogensen J, Bang U, Nyberg L, Weibull E, Nilsson M (Manuscript in preparation)Google Scholar
  18. 18.
    Tunek A, Hjertberg E, Viby Mogensen J (1991) Interactions of bambuterol with human serum cholinesterase of the genotypes EuEu (normal), EaEa (atypical) and EuEa. Biochem Pharmacol 41: 345–348PubMedCrossRefGoogle Scholar
  19. 19.
    Yata N, Toyoda T, Murakami T, Nishiura A, Higashi Y (1990) Phosphatidylserine as a determinant for the tissue distribution of weakly basic drugs in rats. Pharm Res 7: 1019–1025PubMedCrossRefGoogle Scholar
  20. 20.
    Nishiura A, Murakami T, Higashi Y, Yata N (1988) Role of phasphatidylserine in the cellular and subcellular lung distribution of quinidine in rats. Pharm Res 5: 209–213PubMedCrossRefGoogle Scholar
  21. 21.
    Yoshida H, Kamiya A, Okumura K, Hori R (1989) Contribution of monoamine oxidase (MAO) to the binding of tertiaty basic drugs in lung mitochondria. Pharm Res 6: 877–882PubMedCrossRefGoogle Scholar
  22. 22.
    Ishida H, Okumura K, Hori R (1990) Contribution of monoamine oxidase (MAO) to the binding of tertiary basic drugs in isolated perfused rat lung. Pharm Res 7: 398–401CrossRefGoogle Scholar
  23. 23.
    Reasor MJ, Koshut RA, Castranova V (1979) Biochemical characteristics of rat alveolar macrophages with chlorophentermine-induced phospholipidosis: Variations with increased cell size. Exp Mol Pathol 31: 297–307PubMedCrossRefGoogle Scholar
  24. 24.
    Smith LL (1985) The identification and characterization of a polyamine-accumulating system in the lung. Biochem Soc Trans 13: 332–334PubMedGoogle Scholar
  25. 25.
    Anderson MW, Orton TC, Picket RD, Eling TE (1974) Accumulation of amines in the isolated perfused rabbit lung. J Pharmacol Exp Ther 189: 456–466PubMedGoogle Scholar
  26. 26.
    Orton TC, Anderson MW, Picket RD, Eling TE, Fouts JR (1973) Xenobiotic accumulation and metabolism by isolated perfused rabbit lung. J Pharmacol Exp Ther 186: 482–487Google Scholar
  27. 27.
    Fowler JS, Gallagher BM, MacGregor RR, Wolf AP (1976) Carbon-11 labeled aliphatic amines in lung uptake and metabolism studies: potential for dynamic measurements in vivo. J Pharmacol Exp Ther 198: 133–145PubMedGoogle Scholar
  28. 28.
    Ryrfeldt Å, Nilsson E, Tunek A, Svensson L-Å (1988) Bambuterol: Uptake and metabolism in guinea pig isolated lungs. Pharm Res 5: 151–155PubMedCrossRefGoogle Scholar
  29. 29.
    Levin E, Tegnér K (Manuscript in preparation)Google Scholar
  30. 30.
    Gnosspelius Y, Olsson H (Manuscript in preparation)Google Scholar

Copyright information

© Springer-Verlag/Wien 1998

Authors and Affiliations

  • Leif-Ake Svensson
    • 1
  1. 1.Department of Medicinal ChemistryAstra Draco ABLundSweden

Personalised recommendations