The Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, Biomedical Center P.O. Box 580, SE-751 23 Uppsala, Sweden.
Mol Pharm. 2010 Oct 4;7(5):1478-87. doi: 10.1021/mp100124f. Epub 2010 Sep 1.
In this study, the influence of physiologically relevant media on the compound position in a biopharmaceutical classification system (BCS) which resembled the intestinal absorption was investigated. Both solubility and permeability limited compounds (n = 22) were included to analyze the importance of each of these on the final absorption. Solubility was determined in three different dissolution media, phosphate buffer pH 6.5 (PhB 6.5), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) at 37 °C, and permeability values were determined using the 2/4/A1 cell line. The solubility data and membrane permeability values were used for sorting the compounds into a BCS modified to reflect the fasted and fed state. Three of the seven compounds sorted as BCS II in PhB 6.5 (high permeability, low solubility) changed their position to BCS I when dissolved in FaSSIF and/or FeSSIF (high permeability, high solubility). These were low dosed (20 mg or less) lipophilic molecules displaying solvation limited solubility. In contrast, compounds having solid-state limited solubility had a minor increase in solubility when dissolved in FaSSIF and/or FeSSIF. Although further studies are needed to enable general cutoff values, our study indicates that low dosed BCS Class II compounds which have solubility normally restricted by poor solvation may behave as BCS Class I compounds in vivo. The large series of compounds investigated herein reveals the importance of investigating solubility and dissolution under physiologically relevant conditions in all stages of the drug discovery process to push suitable compounds forward, to select proper formulations, and to reduce the risk of food effects.
在这项研究中，研究了在类似于肠道吸收的生物制药分类系统 (BCS) 中，生理相关介质对化合物位置的影响。本研究纳入了具有溶解度和渗透性限制的化合物（n = 22），以分析这些因素对最终吸收的重要性。溶解度在三种不同的溶解介质中进行测定，即磷酸盐缓冲液 pH 6.5（PhB 6.5）、空腹状态模拟肠液（FaSSIF）和进食状态模拟肠液（FeSSIF），温度为 37°C，而渗透性值则使用 2/4/A1 细胞系进行测定。溶解度数据和膜渗透性值用于将化合物分类到反映空腹和进食状态的 BCS 中。在 PhB 6.5 中被分类为 BCS II 的七种化合物中的三种（高渗透性，低溶解度），当溶解在 FaSSIF 和/或 FeSSIF 中时，其位置变为 BCS I（高渗透性，高溶解度）。这些是低剂量（20 毫克或更少）的亲脂性分子，显示出溶剂化限制的溶解度。相比之下，当溶解在 FaSSIF 和/或 FeSSIF 中时，具有固态限制溶解度的化合物的溶解度仅略有增加。尽管还需要进一步的研究来确定一般的截止值，但我们的研究表明，正常溶解度受到较差溶剂化限制的低剂量 BCS II 类化合物在体内可能表现为 BCS I 类化合物。本文研究的大量化合物揭示了在药物发现过程的所有阶段研究溶解度和溶解在生理相关条件下的重要性，以推动合适的化合物前进，选择合适的配方，并降低食物效应的风险。
