Chen L L, Chetty D J, Chien Y W
Controlled Drug-Delivery Research Center, College of Pharmacy, Rutgers University, 41 Gordon Road, Suite D, Piscataway, NJ 08854-8067, USA.
Int J Pharm. 1999 Jul 5;184(1):63-72. doi: 10.1016/s0378-5173(99)00091-5.
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 pK(a) 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.
可电离分子的渗透遵循pH分配理论，渗透物的首选转运途径取决于其电荷状态，且转运阻力与膜包被颗粒（MCG）有关。据信，跨细胞阻力与细胞内空间中MCG的体积成正比，而细胞旁阻力据信是由于MCG的脂质成分被挤出到细胞间空间所致。尼古丁是一种具有两个pK(a)值（3.4和8.2）的可电离模型化合物，被选作分子探针，以研究通过猪口腔黏膜渗透的pH分配理论，表征各种口腔黏膜之间渗透性的差异，并探索每种尼古丁物种通过口腔黏膜的首选转运途径。从尼古丁的渗透率、分配系数和扩散率随pH变化的观察结果证明了pH分配理论。发现角化牙龈比非角化颊黏膜和舌下黏膜具有更高的渗透性。中性尼古丁物种由于其更高的分配系数和扩散率，比离子化物种具有更高的渗透性。进行了机理分析（渗透率比-pH曲线）以确定每种尼古丁物种的首选转运途径。发现中性尼古丁的渗透率与细胞内空间中MCG的占据体积成正比。这表明中性尼古丁的首选转运途径是跨细胞的。随着溶液pH降低，越来越多的尼古丁质子化，亲水性带电尼古丁物种沿细胞间途径的转运成为首选。
