Jeppsson A B, Roos C, Waldeck B, Widmark E
Research and Development Department, AB Draco, Lund, Sweden.
Pharmacol Toxicol. 1989 Jan;64(1):58-63. doi: 10.1111/j.1600-0773.1989.tb00602.x.
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.
采用豚鼠离体迷走神经 - 气管插管标本，研究支气管扩张β - 肾上腺素能受体激动剂的效应动力学。将受试化合物加入充满液体的管腔或外部介质中，它们均能剂量依赖性地完全抑制迷走神经诱导的收缩。与气管外给药相比，亲水性化合物异丙肾上腺素、沙丁胺醇和特布他林气管内给药时效力低得多，表明其透过上皮层的转运缓慢。对于亲脂性化合物D2489（沙美特罗的间苯二酚衍生物），这种差异不太明显。当特布他林以其亲脂性二异丁酸酯前药异丁特罗给药时，给药途径之间的差异基本消除。特布他林（而非D2489）的抑制作用经冲洗后很容易逆转。气管内给予化合物后，对气管组织和外部介质中的特布他林和D2489进行测量，支持以下观点：亲水性化合物缓慢通过上皮层且不保留在组织中，而亲脂性化合物迅速通过上皮层并被组织保留。豚鼠离体迷走神经 - 气管插管标本非常适合同时研究支气管扩张药物的药效学和药代动力学特性。
