Hochhaus G, Möllmann H
College of Pharmacy, University of Florida, Gainesville 32610.
Int J Clin Pharmacol Ther Toxicol. 1992 Sep;30(9):342-62.
The clinical pharmacokinetics and pharmacokinetic/dynamic properties of the beta-adrenergic drugs fenoterol, salbutamol and terbutaline are reviewed. Sulfate conjugates are the main metabolites in man. The protein binding of these derivatives is rather weak with most pronounced binding observed e.g. fenoterol (40%). Disposition after parenteral administration shows a multi-exponential behavior for all the substances with linear but also stereo-selective pharmacokinetics. After parenteral administration, the drugs are mainly eliminated by renal processes while after oral administration a pronounced metabolic clearance (high first pass effect) is responsible for a low bioavailability, especially for fenoterol (2%). The total clearance for fenoterol is about twice that of salbutamol and terbutaline. Seven to 15% of the delivered aerosol reach typically the systemic circulation. In patients with respiratory disorders, pulmonary absorption is however highly dependent on the disease state. Pharmacokinetics in children do not significantly differ from adults when expressed per kg body weight. Patients with renal failure but not asthmatics show changed pharmacokinetic profiles. Only insignificant interactions with other drugs have been found. Pharmacokinetic/dynamic modeling approaches indicated that fenoterol is 25 times more active at the site of action than salbutamol and terbutaline, but all three drugs show similar bronchopulmonary selectivities. When the overall clinical activity, determined by pharmacokinetic and dynamic properties is compared, the activity gap is reduced: fenoterol (8) greater than salbutamol (2) greater than terbutaline (1). Differences in the first pass effect even inverse the pattern after oral administration. PK/PD modeling quantified the pulmonary effect after inhalation and suggested that the higher incidence of side effects for fenoterol might be linked to an overdosing problem. The application of PK/PD principles may improve the clinical usage and therapy of beta-2-adrenergic drugs.
本文综述了β-肾上腺素能药物非诺特罗、沙丁胺醇和特布他林的临床药代动力学及药代动力学/药效学特性。硫酸酯结合物是人体中的主要代谢产物。这些衍生物的蛋白结合力较弱，例如非诺特罗的结合力最为明显（40%）。肠胃外给药后的处置显示，所有物质均呈现多指数行为，具有线性但也有立体选择性药代动力学。肠胃外给药后，药物主要通过肾脏过程消除，而口服给药后，显著的代谢清除率（高首过效应）导致生物利用度较低，尤其是非诺特罗（2%）。非诺特罗的总清除率约为沙丁胺醇和特布他林的两倍。通常有7%至15%的递送气雾剂到达体循环。然而，在患有呼吸系统疾病的患者中，肺部吸收高度依赖于疾病状态。按每千克体重计算，儿童的药代动力学与成人无显著差异。肾衰竭患者而非哮喘患者的药代动力学特征发生了变化。仅发现与其他药物的相互作用不显著。药代动力学/药效学建模方法表明，非诺特罗在作用部位的活性比沙丁胺醇和特布他林高25倍，但这三种药物的支气管肺选择性相似。当比较由药代动力学和药效学特性决定的总体临床活性时，活性差距减小：非诺特罗（8）＞沙丁胺醇（2）＞特布他林（1）。首过效应的差异甚至使口服给药后的模式相反。PK/PD建模量化了吸入后的肺部效应，并表明非诺特罗副作用发生率较高可能与用药过量问题有关。PK/PD原理的应用可能会改善β2-肾上腺素能药物的临床使用和治疗。
