Compliance is a major obstacle in the treatment and management of chronic respiratory diseases such as chronic obstructive pulmonary disease, hence the need to develop long acting (>24 h duration) agents. Casarosa et al. investigated a new long acting β agonist, olodaterol (BI1744CL), to determine the mechanism responsible for its long duration of action. An increase in lipophilicity of salmeterol and lateral diffusion out of the lipid bilayer may be responsible for its slow onset and long duration of action (microkinetic model). In contrast, olodaterol displays a rapid onset of action and long duration that is not associated with significant accumulation in the lipid bilayer. However, kinetic and binding studies demonstrated a dissociation half-life of 17.8 h that is associated with the formation of a stable ternary complex of agonist-β2AR-G protein. Functional data after extensive washout also support this tight binding model for olodaterol; however, as a result of moderate accumulation of olodaterol in the lipid bilayer, a contribution of the microkinetic model cannot be ruled out. Taken together, these results provide the rationale behind the ability for once a day dosing of olodaterol in clinical trials.
See article at J Pharmacol Exp Ther 2011, 337:600–609
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics