Pharmacodynamic and pharmacokinetic aspects on the transport of bronchodilator drugs through the tracheal epithelium of the guinea-pig.

An isolated vagus nerve-trachea tube preparation from guinea-pig was used to study the effect kinetics of bronchodilating beta-adrenoceptor agonists. The test compounds were added either into the fluid-filled lumen or into the external medium and they all inhibited, dose-dependently and completely, the vagally induced contractions. The hydrophilic compounds isoprenaline, salbutamol and terbutaline were much less potent when administered intratracheally as compared with extratracheal administration indicating a slow transport through the epithelial layer. For the lipophilic compound, D2489 (the resorcinol derivative of salmeterol), this difference was less pronounced. When terbutaline was administered as its lipophilic diisobutyrate ester prodrug, ibuterol, the difference between the routes of administration was largely eliminated. The inhibitory effect of terbutaline, but not D2489, was readily reversed by washing. Measurements of terbutaline and D2489 in the tracheal tissue and in the external medium after the intratracheal administration of the compounds support the view that a hydrophilic compound slowly passes the epithelium and is not retained in the tissue, whereas a lipophilic compound rapidly passes the epithelium and is retained by the tissue. The isolated vagus nerve-trachea tube preparation of the guinea-pig is well suited for the concommitant study of pharmacodynamic and pharmacokinetic properties of bronchodilator drugs.