In vitro cell models to study nasal mucosal permeability and metabolism

Whereas in vivo studies represent the most crucial test for any nasal drug application or formulation, mechanistic aspects of nasal absorption may be more clearly approached by well defined and controlled in vitro studies. In this review the progress of nasal in vitro models to investigate drug permeation and metabolism in the epithelium is summarized and their potential and limitations are discussed. The following subjects will be covered: (i) primary cell cultures of human nasal epithelium, including sampling techniques and culture conditions, (ii) human nasal cell lines (in particular the human nasal cell line RPMI 2650), and (iii) excised nasal epithelium (rabbit, bovine, ovine, canine, human), also summarizing suitable preparation techniques and tissue characterization, test media, tissue equilibration, viability testing, and integrity tests. Furthermore, an overview on the various experimental set-ups suitable for in vitro transport studies (permeation rates; identification of permeation pathways; mechanisms and toxicity of absorption enhancers) and for metabolism studies (rates, saturation and pathways of enzymatic cleavage) is presented. Some attention is given to identify potential endocytotic uptake mechanisms. To date, the permeation and metabolic barrier function of excised nasal tissue derived from various animals has shown to mimic the in vivo situation 'ex vivo' at the highest degree possible. Supply of human tissue will continue to be short. Therefore, further studies are necessary to evaluate and improve culture conditions, handling, performance and physiologic relevance of primary human cell and cell line cultures.