Lipid membrane interactions of indacaterol and salmeterol: do they influence their pharmacological properties?
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Lombardi, Dario, Cuenoud, Bernard, Kramer, Stephanie D and Trifilieff, Alexandre (2009) Lipid membrane interactions of indacaterol and salmeterol: do they influence their pharmacological properties? European Journal of Pharmaceutical Sciences, 38 (5). pp. 533-547. ISSN 0928-0987
Abstract
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.
| Item Type: | Article |
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| Additional Information: | Author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
| Keywords: | Indacaterol; Salmeterol; Partitioning; Liposomes; Surface Plasmon Resonance (SPR); Kinetics; Membrane fluidity; Beta-2-adrenoceptor agonist; Rafts |
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| Date Deposited: | 13 Oct 2015 13:17 |
| Last Modified: | 13 Oct 2015 13:17 |
| URI: | https://oak.novartis.com/id/eprint/1067 |