文摘
The hypotheses of this study are that the permeation of ionizable molecules follows the pH-partition theory, that the preferred transport pathway for penetrants depends on their charge status and that transport resistance is related to the membrane-coating granules (MCG). Transcellular resistance is believed to be proportional to the volume of MCG in the intracellular space while paracellular resistance is believed to result from the extrusion of the lipid contents of the MCG into the intercellular space. Nicotine, an ionizable model compound with two pKa values (3.4 and 8.2), was chosen as a molecular probe to investigate the pH-partition theory on permeation through porcine oramucosae, to characterize the differences in permeability among various oramucosae, and to explore the preferred transport pathways of each nicotine species through oramucosae. The pH-partition theory was proved from the observations that permeability, partition coefficient and diffusivity of nicotine varied as a function of pH. The keratinized gingiva was found to have greater permeability than the non-keratinized buccal and sublingual mucosae. The neutral nicotine species had a higher permeability than the ionized species due to its higher partition coefficient and diffusivity. A mechanistic analysis (permeability ratio-pH profile) was conducted to determine the preferred transport pathway of each nicotine species. The permeability of neutral nicotine was found to be proportional to the occupied volume of MCG in the intracellular space. This indicates that the preferred transport pathway for neutral nicotine is transcellular. As the solution pH was decreased, and a greater fraction of nicotine became protonated, the transport of hydrophilic, charged nicotine species along the intercellular pathway was preferred.