Hamman J H, Schultz C M, Kotzé A F
School of Pharmacy, Faculty of Health Sciences, Technikon Pretoria, Pretoria, South Africa.
Drug Dev Ind Pharm. 2003 Feb;29(2):161-72. doi: 10.1081/ddc-120016724.
N-trimethyl chitosan chloride (TMC) is a polycation that enhances drug transport across epithelia by opening tight junctions. The degree of quaternization of TMC determines the number of positive charges available on the molecule for interactions with the negatively charged sites on the epithelial membrane and thereby influences its drug absorption-enhancing properties. The effects of six different TMC polymers (degree of quarternization between 12% and 59%) on the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers and on the transport of hydrophilic and macromolecular model compounds across Caco-2 cells were determined. All the TMC polymers were able to decrease the TEER markedly in a slightly acidic environment (pH 6.2). However, only TMC polymers with higher degrees of quaternization (> 22%) were able to reduce the TEER in a neutral environment (pH 7.4). The maximum reduction in TEER (47.34 +/- 6.0% at a concentration of 0.5% w/v and pH 7.4) was reached with TMC with a degree of quaternization of 48%, and this effect did not increase further with higher degrees of quaternization of TMC. In agreement with the TEER results, the transport of model compounds across Caco-2 cell monolayers increased with an increase in the degree of quaternization of TMC. However, the transport reached a maximum for TMC with a degree of quaternization of 48% (25.3% of the initial dose for [14C]mannitol and 15.2% of the initial dose for [14C]PEG 4000), and this effect did not increase further with higher degrees of quaternization of TMC. Therefore, the increase in the effects of TMC on intestinal epithelia did not directly correlate up to the maximum quaternization degree of this polymer, but reached an optimum value already at an intermediate degree of quaternization (ca. 48%).
氯化N-三甲基壳聚糖（TMC）是一种聚阳离子，它通过打开紧密连接来增强药物跨上皮细胞的转运。TMC的季铵化程度决定了分子上可用于与上皮细胞膜上带负电荷位点相互作用的正电荷数量，从而影响其增强药物吸收的特性。测定了六种不同的TMC聚合物（季铵化程度在12%至59%之间）对Caco-2细胞单层跨上皮电阻（TEER）以及亲水性和大分子模型化合物跨Caco-2细胞转运的影响。所有TMC聚合物在微酸性环境（pH 6.2）中均能显著降低TEER。然而，只有季铵化程度较高（>22%）的TMC聚合物在中性环境（pH 7.4）中能够降低TEER。季铵化程度为48%的TMC在浓度为0.5% w/v且pH 7.4时使TEER达到最大降低值（47.34±6.0%），并且随着TMC季铵化程度的进一步提高，这种效果并未进一步增强。与TEER结果一致，模型化合物跨Caco-2细胞单层的转运随着TMC季铵化程度的增加而增加。然而，季铵化程度为48%的TMC转运达到最大值（[14C]甘露醇为初始剂量的25.3%，[14C]聚乙二醇4000为初始剂量的15.2%），并且随着TMC季铵化程度的进一步提高，这种效果并未进一步增强。因此，TMC对肠上皮细胞作用的增强在该聚合物的最大季铵化程度之前并非直接相关，而是在中间季铵化程度（约48%）时已达到最佳值。
