Abstract：
Zwitterions contain both positively and negatively charged functional groups, resulting in an overall net neutral charge. Nevertheless, the membrane permeability of the zwitterionic form of a compound is assumed to be much lower than the permeability of the uncharged neutral form. Although a significant proportion of pharmaceuticals are zwitterionic, it has not been clear so far whether their permeability is dominated by the permeation of the zwitterionic or the neutral form, since neutral fractions are often quite low as compared to the zwitterionic fraction. This complicates the in silico prediction of the permeability of zwitterionic compounds. In this work, we re-evaluated existing in vitro permeability data from literature measured with Caco-2/MDCK cell assays, using more strict exclusion criteria for effects like diffusion limitation by the aqueous boundary layers, paracellular transport, active transport and retention. Using this re-evaluated data set, we show that extracted intrinsic permeabilities of the neutral fraction are well predicted by the solubility-diffusion model (RMSE = 1.21; n = 18) if the permeability of the zwitterionic species is assumed negligible. Our work thus suggests that only the neutral species is relevant for the membrane permeability of zwitterionic compounds, and that membrane permeability of zwitterionic compounds is indeed predictable by the solubility-diffusion model.
摘要：
两性离子包含带正电荷和负电荷的官能团，导致整体净中性电荷。然而，认为化合物的两性离子形式的膜渗透性远低于不带电的中性形式的渗透性。虽然很大一部分药物是两性离子的，到目前为止，还不清楚它们的渗透性是由两性离子形式还是中性形式的渗透所主导，因为中性部分与两性离子部分相比通常相当低。这使两性离子化合物渗透性的计算机预测复杂化。在这项工作中,我们重新评估现有的体外通透性数据从文献测量与Caco-2/MDCK细胞试验，使用更严格的排除标准，例如水边界层的扩散限制，细胞旁转运,主动运输和保留。使用这个重新评估的数据集，我们表明，如果假定两性离子物种的渗透率可以忽略不计，则可以通过溶解度-扩散模型（RMSE=1.21；n=18）很好地预测中性部分的固有渗透率。因此，我们的工作表明，只有中性物质与两性离子化合物的膜通透性有关，两性离子化合物的膜通透性确实可以通过溶解度-扩散模型预测。
