N-trimethyl chitosan chloride:: Optimum degree of quaternization for drug absorption enhancement across epithelial cells
N-trimethyl chitosan chloride:: Optimum degree of quaternization for drug absorption enhancement across epithelial cells
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DOI：
10.1081/ddc-120016724
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发表时间：
2003-01-01
影响因子：
3.4
通讯作者：
Kotzé, AF
中科院分区：
文献类型：
--
作者：
Hamman, JH;Schultz, CM;Kotzé, AF
N-三甲基壳聚糖氯(TMC)是一种聚阳离子，通过打开紧密的连接来增强药物在上皮细胞中的转运。TMC的季铵化程度决定了分子上可与上皮膜上带负电荷的位置相互作用的正电荷的数量，从而影响其药物吸收促进性能。测定了6种不同的TMC聚合物(季节化程度在12%~59%之间)对Caco-2细胞单层的跨上皮电阻(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。在弱酸性环境(pH 6.2)中，所有TMC聚合物均能显著降低TEER。然而，只有季铵化程度较高(>；22%)的TMC聚合物才能在中性环境(pH 7.4)中降低TEER。季铵盐化程度为48%的TMC对TEER的降幅最大(在0.5%w/v、pH为7.4时为47.3+/-6.0%)，且随着TMC季胺化程度的增加，这一效应不再进一步增强。与TEER结果一致的是，随着TMC季节化程度的增加，模型化合物在Caco-2细胞单层中的转运增加。当TMC季节化程度为48%时，TMC的转运达到最大值([C-14]甘露醇为初始剂量的25.3%，[C-14]PEG4000为初始剂量的15.2%)，且这种影响不会随着TMC季节化程度的增加而进一步增强。因此，TMC对肠上皮细胞作用的增加并不直接与该聚合物的最大季节化程度相关，而是在中等季节化程度(约48%)时已达到最佳值。
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 (47.3 +/- 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 [C-14]mannitol and 15.2% of the initial dose for [C-14]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%).