Institute of Pharmaceutical Sciences, ETH Zürich, Switzerland.
Eur J Pharm Sci. 2009 Dec 8;38(5):533-47. doi: 10.1016/j.ejps.2009.10.001. Epub 2009 Oct 9.
This study compares the lipid membrane interactions of indacaterol, an ultra long acting beta-2 agonist that is given once a day, to salmeterol, a twice a day beta-2 agonist, in order to elucidate the potential mechanisms leading to their different pharmacological properties. Salmeterol but not indacaterol perturbed dimyristoyl-phosphatidylcholine membranes. While the liposome partitioning of the two compounds was similar, independent of the lipid composition, the membrane affinity of indacaterol was two-fold greater than that of salmeterol when rafts, i.e. detergent-insoluble membrane domains, were used as the partition phase. The observed association kinetics with immobilized liposomes at physiological pH were two times faster for indacaterol than for salmeterol. A new model to explain the relationships between the drug/membrane interactions and drug's pharmacological properties considering multiple factors is proposed. The synergy between the higher partitioning of indacaterol into the raft micro domains and the faster membrane permeation of indacaterol could explain the faster onset and longer duration of therapeutic effect of indacaterol. The higher fluidizing effect of salmeterol on membrane fluidity may contribute to its lower intrinsic efficacy compared to indacaterol.
本研究比较了每天一次给予的超长效β2 激动剂茚达特罗与每日两次给予的β2 激动剂沙美特罗的脂质膜相互作用，以阐明导致它们具有不同药理学特性的潜在机制。沙美特罗而非茚达特罗扰乱了二肉豆蔻酰磷脂酰胆碱膜。虽然两种化合物的脂质体分配相似，与脂质组成无关，但当使用筏，即去污剂不可溶的膜域作为分配相时，茚达特罗的膜亲和力是沙美特罗的两倍。在生理 pH 值下与固定化脂质体的观察到的缔合动力学，茚达特罗比沙美特罗快两倍。提出了一个新的模型来解释考虑多种因素的药物/膜相互作用与药物的药理学特性之间的关系。茚达特罗向筏微域的更高分配与茚达特罗更快的膜渗透之间的协同作用可以解释茚达特罗更快的起效和更长的治疗效果持续时间。与茚达特罗相比，沙美特罗对膜流动性的更高的溶胀作用可能导致其内在功效较低。
