Oja Mare, Maran Uko
Institute of Chemistry, University of Tartu, Tartu, Estonia.
SAR QSAR Environ Res. 2016 Oct;27(10):813-832. doi: 10.1080/1062936X.2016.1238408. Epub 2016 Oct 17.
Human intestinal absorption is a key property for orally administered drugs and is dependent on pH. This study focuses on neutral and amphoteric compounds and their membrane permeabilities across the range of pH values found in the human intestine. The membrane permeability values for 15 neutral and 60 amphoteric compounds at pH 3, 5, 7.4 and 9 were measured using the parallel artificial membrane permeability assay (PAMPA). For each data series the quantitative structure-permeability relationships were developed and analysed. The results show that the membrane permeability of neutral compounds is attributed to a single structural characteristic, the hydrogen bond donor ability. Amphoteric compounds are more complex because of their chemical constitution, and therefore require three-parameter models to describe and predict membrane permeability. Analysis of the models for amphoteric compounds reveals that membrane permeability depends on multiple structural characteristics: the partition coefficient, hydrogen bond properties and the shape of the molecules. In addition to conventional validation strategies, two external compounds (isradipine and omeprazole) were tested and revealed very good agreement of pH profiles between experimental and predicted membrane permeability for all of the developed models. Selected QSAR models are available at the QsarDB repository (http://dx.doi.org/10.15152/QDB.184).
人体肠道吸收是口服药物的关键特性，且取决于pH值。本研究聚焦于中性和两性化合物及其在人体肠道内不同pH值范围内的膜通透性。使用平行人工膜通透性测定法（PAMPA）测量了15种中性化合物和60种两性化合物在pH 3、5、7.4和9时的膜通透性值。针对每个数据系列建立并分析了定量构效关系。结果表明，中性化合物的膜通透性归因于单一结构特征，即氢键供体能力。两性化合物因其化学组成更为复杂，因此需要三参数模型来描述和预测膜通透性。对两性化合物模型的分析表明，膜通透性取决于多种结构特征：分配系数、氢键性质和分子形状。除了传统的验证策略外，还测试了两种外部化合物（伊拉地平和平拉唑），结果表明所有已建立的模型在实验和预测的膜通透性pH曲线之间都具有很好的一致性。选定的QSAR模型可在QSarDB数据库（http://dx.doi.org/10.15152/QDB.184）中获取。
