On the predictive value of experiments in vitro in the evaluation of the effect duration of bronchodilator drugs for local administration.

Abstract

Six bronchodilating beta-adrenoceptor agonists, clinically documented with respect to the duration of action after inhalation, were included in this study in vitro on the guinea-pig trachea. Relaxation of carbachol contracted trachea strip preparations and inhibition of contraction of a vagus nerve-tracheal tube preparation were measured. The relaxing effects of salbutamol and fenoterol (both with relatively short duration in man) were rapid in onset and easily reversed by washing in a drug-free medium. The relaxation by salmeterol (long duration) and D2343 (intermediate duration) developed more slowly, resisted washing but was reversed by propranolol. Formoterol (long duration) and salmefamol (intermediate duration) showed properties between these two extremes. All test compounds inhibited the vagally-induced contractions of tracheal concentration dependently. The EC50 values for the hydrophilic compounds salbutamol and fenoterol were higher with intra- as compared with extratracheal administration. For the more lipophilic compounds formoterol, salmefamol, salmeterol and D2343, this difference was less pronounced. A high lipophilicity and a retention by the tissue in vitro of a beta-adrenoceptor agonist may be factors contributing to a long effect duration after inhalation but a further selection has to be made in vivo since metabolic and circulatory effects may influence the effect kinetics.