Avdeef Alex
pION INC., 5 Constitution Way, Woburn, MA 01801, USA.
Expert Opin Drug Metab Toxicol. 2005 Aug;1(2):325-42. doi: 10.1517/17425255.1.2.325.
The parallel artificial membrane permeability assay (PAMPA), as a passive-permeability screen, is a possible low-cost alternative to cellular models for the earliest ADME primary screening of research compounds. Its popularity in the industry has risen rapidly. This review examines state-of-the-art PAMPA methods. The various covered topics include: different lipid formulations, the quantitative relationships between hexadecane, dioyleyoylphosphatidycholine and Double-Sink PAMPA measurements, the use of individual-well stirring, issues of ultraviolet sensitivity, timing strategies, reproducibility of measurements, the correct pH to perform the measurement to avoid aqueous boundary layer problems, the pKa(flux) method for determining intrinsic permeability coefficients and the cosolvent method for very insoluble molecules. Examples of the determination of permeability of very difficult molecules, but molecules that are well absorbed, are given. Carefully gathered evidence in support of the use of the Double-Sink PAMPA model is presented. The review concludes with a binning strategy to predict human intestinal absorption, based on the use of the sum of permeability coefficients, measured at gradient pH 5.0, 6.2 and 7.4. Opinions regarding the future of PAMPA are offered.
平行人工膜通透性测定法（PAMPA）作为一种被动通透性筛选方法，是一种可能用于研究化合物早期ADME初步筛选的低成本细胞模型替代方法。它在行业中的受欢迎程度迅速上升。本综述探讨了PAMPA的最新方法。涵盖的各种主题包括：不同的脂质配方、十六烷、二油酰磷脂酰胆碱与双池PAMPA测量之间的定量关系、单孔搅拌的使用、紫外线敏感性问题、计时策略、测量的重现性、进行测量以避免水相边界层问题的正确pH值、用于确定内在通透性系数的pKa（通量）方法以及用于极难溶分子的助溶剂方法。给出了极难溶但吸收良好的分子的通透性测定示例。展示了支持使用双池PAMPA模型的精心收集的证据。综述最后提出了一种基于在pH 5.0、6.2和7.4梯度下测量的通透性系数总和来预测人体肠道吸收的分级策略。还提供了关于PAMPA未来发展方向的观点。
