Identification of membrane transporters to facilitate intranasal drug delivery using tissue-based and pharmacokinetic approaches.

摘要

Nasal drug delivery has been broadly investigated in the past three decades. In addition to an effective therapeutic route for local illness, the nasal cavity presents a potential absorption site for systemic and direct CNS absorption. Since permeation of drug molecules across nasal membrane represents the rate limiting step in nasal absorption, especially for hydrophilic drug molecules, utilization and modification of membrane transporters located within nasal epithelium may facilitate absorption and enhance the bioavailability of drug compounds administered intranasally.;In vitro methods to evaluate drug transport mechanisms and concurrent metabolism are frequently used in pre-clinical drug development. These systems separate the permeation step from the following absorption cascades which occur in vivo, and allow the permeation step to be studied under well-controlled conditions. The permeability of various compounds across excised nasal mucosal tissues was studied, and linear, non-saturable and non-polarized flux was observed for cocaine and baclofen. In contrast, saturable and polarized flux was observed for L-phenylalanine. The presence of the large amino acid transporter system (LAT-1) was speculated to be responsible for L-phenylalanine uptake, and the transporter was further identified using immunohistochemistry and Western blotting techniques.;The systemic absorption of baclofen, an antispastic agent with a similar chemical structure to phenylalanine, was also investigated using in vivo absorption studies in rats. Baclofen was administered following intravenous and intranasal administration, and the resulting pharmacokinetic profile in the blood was studied. Similar pharmacokinetic profiles were observed between R- and S-baclofen following both intravenous and intranasal administration, and significant nasal absorption was observed for both enantiomers following nasal administration.;In an effort to use the permeability across excised nasal mucosal tissues to predict absorption, the cumulative nasal absorption was estimated for a number of nasally administered compounds using a deconvolution method. Correlation of the calculated absorption rate and measured permeation rate was attempted for nine small, hydrophilic compounds, and a close linear correlation was observed. These results suggest that the permeability obtained from in vitro studies can be used to predict nasal absorption and bioavailability following intranasal drug delivery.