Abstract
Two new lipophilic terbutaline ester prodrugs – the biscarbamate bambuterol (pINN) and the cascade ester D 2438 – have been designed with the goal to achieve enhanced absorption and high hydrolytic stability during first-pass in order to prolong the effect duration of the parent compound. Bambuterol, the bis-N,N-dimethyl-carbamate of terbutaline, displays improved hydrolytic stability, partly by inhibition of its own hydrolysis, and has been shown to survive first-pass hydrolysis in the dog to a high degree. Bambuterol per se is inactive; however, after oral administration to guinea-pigs, the ED50 value for protection from histamine-induced bronchospasm is similar to that of terbutaline. Moreover, the terbutaline plasma level-time profile after oral doses of bambuterol in dogs is significantly prolonged. The cascade ester of terbutaline (D 2438), derived from p-pivaloyloxybenzoic acid, was designed to undergo first-pass hydrolysis and conjugation at the p-pivaloyloxybenzoic acid moiety; i. e. distal from the active resorcinol moiety in terbutaline. The prodrug itself is active in the isolated guinea-pig trachea and displays prolonged effect duration both after inhalation in guinea-pigs and after oral administration in dogs. The cascade ester prodrug (D 2438) has a somewhat shorter effect duration than bambuterol in these species.
Similar content being viewed by others
References
Nilsson, H. T., Tegnér, K. (1972) Xenobiotica 2, 363–373.
Davies, D. S., George, C. F., Blackwell, E., Conolly, M. E., Dollery, C. T. (1974) Br. J. Clin. Pharmacol. 1, 129–136.
Wetterlin, K. I. L., Svensson, L. Å. (1976) US Patent 3 937 838.
Hörnblad, Y., Ripe, E., Magnusson, P. O., Tegnér, K. (1976) Eur. J. Clin. Pharmacol. 10, 9–18.
Gilette, J. R. (1974) in: Pharmacology & Pharmacokinetics (Teorell, T., ed.) pp. 209–231, Plenum Press, New York.
Ryrfeld, Å., Nilsson, E. (1978) Biochem. Pharmacol. 27, 301–305.
Kristoffersson, J., Svensson, L. Å., Tegnér, K. (1974) Acta Pharm. Suecica 11, 427–438.
Olsson, O. A. T., Svensson, L. Å., Wetterlin, K. I. L. (1981) Patent applications EPO 81 850 118.1 and EPO 81 850 117.3.
Olsson, O. A. T., Ahlquist, B., Gustavsson, B. (1981) Acta pharmacol. toxicol. 48, 340–348.
Olsson, O. A. T. (1971) Acta allergologica 26, 438–447.
Jacobsson, S. E., Jönsson, S., Lindberg, C., Svensson, L. Å. (1980) Biomed. Mass spectrom. 7, 265–268.
Olsson, O. A. T., Persson, C. G. A., Persson, H., Sörenby, L. (1974) Acta pharmacol. toxicol. 35, 76–90.
Rights and permissions
About this article
Cite this article
Olsson, O.A.T., Svensson, LÅ. New Lipophilic Terbutaline Ester Prodrugs with Long Effect Duration. Pharm Res 1, 19–23 (1984). https://doi.org/10.1023/A:1016322524471
Issue Date:
DOI: https://doi.org/10.1023/A:1016322524471