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%).