Objective: Nicotine replacement therapy (NRT) involving delivery of nicotine trans-mucosally and trans-dermally is an important adjunct for smoking cessation. It is generally assumed that nicotine flux is concentration dependent, but a recent report suggests an inverse relationship (Nielsen and Rassing, Eur J Pharm Sci, 16,151, 2002). The goal of this investigation is to further examine the effect of nicotine concentration on flux across various oral mucosae and skin.

Methods: Gingiva, buccal mucosa, sublingual mucosa, and skin from freshly slaughtered pigs were mounted in continuous-flow perfusion chambers maintained at 37°C; 5%, O.5% and 0.05% nicotine in phosphate-buffered saline (pH 7.5) with 2µCi tritiated nicotine applied directly to the epithelial surface. Perfusate was collected at 1hr intervals for 12 hours and dpm counted. Values were calculated for flux (dpm/sq cm/min) and K_p (cm/min).

Results: K_p values for nicotine were in descending order for the tissues as follows: sublingual mucosa>buccal mucosa>gingiva>skin. Concentration influenced Kp differently within each tissue; sublingual and buccal mucosae showed a significant (p<0.05) inverse relationship between K_p and concentration. In gingival, K_p is not concentration dependent and for skin, K_p increased significantly (p<0.05) with concentration. Conclusions: The differences in flux of nicotine across oral mucosae and skin reflect structural and compositional differences between the permeability barriers. Epidermis contains extensive and well-organized neutral lipids whereas non-keratinizing oral epithelia contain relatively few disordered lipids that offer less resistance to diffusion. The inverse relationship between K_p and nicotine concentration at pH 7.5 may be due to electrostatic repulsion of cationic forms of nicotine within the intercellular space. This electrostatic repulsion would most likely involve protonated lysine, arginine and histidine groups from intercellular proteins. These effects raise important questions about the formulation of NRT such as skin patches and chewing gum intended for delivery at different tissue sites.

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