title: Development of a novel model for comparative evaluation of intranasal pharmacokinetics and effects of anti-allergic nasal sprays.
abstract: For locally acting drugs, an extended residence time in the nasal cavity is desirable and related to a prolonged effect. We sought to develop a model for comparative determination of intranasal pharmacokinetics. We embedded human respiratory tissue into a solid matrix and coated the surface with artificial nasal fluid. Nasal spray suspensions of fluticasone propionate (FP) and budesonide (Bud) as well as a solution of azelastine hydrochloride (AZ) were applied onto the surface and removed after 30 min to simulate mucociliary clearance. As exemplary anti-inflammatory measure, we evaluated the inhibition of IL-8 release from epithelial cells. FP and Bud were initially bound to the same extent to the tissue gel while AZ displayed a more 4-fold higher binding than FP or Bud. After equilibrium with plasma, approximately 5-fold higher tissue concentrations of AZ compared to FP and 77-fold higher levels in relation to Bud were determined. This tissue retention revealed an excellent correlation with the volume of distribution of the respective drugs (r=0.9999, p ≤ 0.05). The inhibitory effect of FP on IL-8 release was approximately 5-fold more pronounced compared to AZ. The present model realistically mirrors conditions in vivo where solubility and tissue absorption of intranasally applied drugs compete with mucociliary clearance mechanisms.
authors.affiliation: Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg, Würzburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baumann
authors.forename: Claus
authors.initials: C
authors.lastname: Bachert
authors.forename: Petra
authors.initials: P
authors.lastname: Högger
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000280:Administration, Inhalation; D000281:Administration, Intranasal / Q000379:methods; D000336:Aerosols / Q000008:administration & dosage / Q000493:pharmacokinetics; D000730:Androstadienes / Q000008:administration & dosage / Q000493:pharmacokinetics; D018926:Anti-Allergic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics; D019819:Budesonide / Q000008:administration & dosage / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000068298:Fluticasone; D005938:Glucocorticoids / Q000378:metabolism; D006633:Histamine Antagonists / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009079:Mucociliary Clearance; D017817:Nasal Lavage Fluid / Q000737:chemistry*; D059085:Nasal Sprays; D010793:Phthalazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D006255:Rhinitis, Allergic, Seasonal / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000336:Aerosols; D000730:Androstadienes; D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D005938:Glucocorticoids; D006633:Histamine Antagonists; D016209:Interleukin-8; D059085:Nasal Sprays; D010793:Phthalazines; D019819:Budesonide; D000068298:Fluticasone; C020976:azelastine