AZD-4818

A validated method to predict lung deposition for inhaled medication from in vitro data is lacking in spite of many attempts to correlate in vitro and in vivo outcomes. By using an in vivo-like in vitro setup and analyzing inhalers from the same batches, both in vitro and in vivo, we wanted to create a situation where information from the in vitro and in vivo outcomes could be analyzed at the same time.

Nine inhalation products containing either budesonide or AZD4818 were evaluated. These comprised two pressurized metered dose inhalers (pMDIs), a pMDI plus a spacer, four dry powder inhalers, and two dosimetric nebulizers. In vitro, an in vivo-like setup consisting of anatomically correct inlet throats were linked to a flow system that could replay actual inhalation flow profiles through the throat to a filter or to an impactor. In vivo, total lung deposition was measured in healthy adults by pharmacokinetic methods.

We could show that the amount of drug escaping filtration in a realistic throat model under realistic delivery conditions predicts the typical total lung deposition in trained healthy adult subjects in the absence of significant exhaled mass. We could further show that by using combinations of throat models and flow profiles that represent realistic deviations from the typical case, variations in ex-cast deposition reflect between-subject variation in lung deposition. Further, we have demonstrated that ex-cast deposition collected either by a simple filter or by a cascade impactor operated at a fixed flow rate using a mixing inlet, to accommodate a variable flow profile through the inhaler, predicts equally well the lung deposited dose. Additionally, the ex-cast particle size distribution measured by this method may be relevant for predicting exhaled fraction and regional lung deposition by computational models.

The CC chemokine receptor 1 (CCR1) is linked to the pathogenesis of chronic inflammatory diseases and is an attractive target for drug discovery research.On the basis of the high-resolution crystal structure of CXC4 chemokine receptor, 3D structure of the human CCR1 was developed by homol. modeling.Nine representative antagonists were applied to binding site study with the rational model through mol. docking.Three hydrophobic sites, especially Phe89, Trp90; Trp99, Tyr113; Tyr114 and Cys183, were identified to be essential for their strong hydrophobic interactions with antagonists.Lys94 and Glu287 have been identified as major contributor to ligand binding by H-bond interaction and salt-bridge interaction, resp.Two hydrophobic sub-pockets (Regions A and B) and Glu287 may be crucial binding sites for chemokine receptors, whereas Tyr93 and Lys94 may be crucial binding sites of the subtype selectivity for CCR1.They are important in stabilizing CCR1-antagonist complexes.Thus, these studies should provide novel insights into the CCR1-antagonist interactions and guide further drug design and mutagenesis studies.