Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden.
Mol Pharm. 2012 Jul 2;9(7):1942-52. doi: 10.1021/mp2006467. Epub 2012 Jun 20.
Ethanol intake can lead to an unexpected and possibly problematic increase in the bioavailability of druglike compounds. In this work we investigated the effect of ethanol on the apparent solubility and dissolution rate of poorly soluble compounds in simulated intestinal fluid representing a preprandial state. A series of 22 structurally diverse, poorly soluble compounds were measured for apparent solubility and intrinsic dissolution rate (37 °C) in phosphate buffer pH 6.5 (PhB6.5) and fasted state simulated intestinal fluid (FaSSIF, pH 6.5) with and without ethanol at 5% v/v or 20% v/v. The obtained data were used to understand for which molecules ethanol results in an increased apparent solubility and, therefore, may increase the amount of drug absorbed. In FaSSIF20%ethanol 59% of the compounds displayed >3-fold higher apparent solubility than in pure FaSSIF, whereas the effects of 5% ethanol on solubility, in most cases, were negligible. Acidic and neutral compounds were more solubilized by the addition of ethanol than by lecithin/taurocholate aggregates, whereas bases showed a more substance-specific response to the additives in the buffer. The stronger solubilizing capacity of ethanol as compared to the mixed lipid aggregates in FaSSIF was further identified through Spearman rank analyses, which showed a stronger relationship between FaSSIF20%ethanol and PhB6.5,20%ethanol (rS of 0.97) than FaSSIF20%ethanol and FaSSIF (rS of 0.86). No relationships were found between solubility changes in media containing ethanol and single physicochemical properties, but multivariate data analysis showed that inclusion of ethanol significantly reduced the negative effect of compound lipophilicity on solubility. For this data set the higher concentration of ethanol gave a dose number (Do) <1 for 30% of the compounds that showed incomplete dissolution in FaSSIF. Significant differences were shown in the melting point, lipophilicity, and dose profiles between the compounds having a Do < 1 and Do > 1, with the latter having higher absolute values in all three parameters. In conclusion, this study showed that significant effects of ethanol on apparent solubility in the preprandial state can be expected for lipophilic compounds. The results herein indicate that acidic and neutral compounds are more sensitive to the addition of ethanol than to the mixed lipid aggregates present in the fasted intestine.
乙醇摄入可导致药物类似物的生物利用度意外增加，且可能存在问题。在这项工作中，我们研究了乙醇对模拟肠液中不良溶性化合物的表观溶解度和溶解速率的影响，该模拟肠液代表空腹状态。我们用磷酸盐缓冲液 pH6.5（PhB6.5）和空腹状态模拟肠液（FaSSIF，pH6.5）测量了一系列 22 种结构多样、不良溶性的化合物的表观溶解度和内在溶解速率（37°C），并分别在 5%v/v 和 20%v/v 乙醇存在和不存在的条件下进行测量。所得数据用于了解对于哪些分子，乙醇会导致表观溶解度增加，从而可能增加吸收的药物量。在 FaSSIF20%乙醇中，有 59%的化合物的表观溶解度比在纯 FaSSIF 中高 3 倍以上，而 5%乙醇对溶解度的影响在大多数情况下可以忽略不计。与混合脂质胶束相比，添加乙醇可使酸性和中性化合物的溶解度更高，而碱性化合物对缓冲液中的添加剂表现出更具物质特异性的响应。通过 Spearman 秩分析进一步确定了乙醇与 FaSSIF 中的混合脂质胶束相比具有更强的溶解能力，结果表明 FaSSIF20%乙醇与 PhB6.5,20%乙醇（rS 为 0.97）之间的关系比 FaSSIF20%乙醇与 FaSSIF（rS 为 0.86）之间的关系更强。在含有乙醇的介质中，溶解度变化与单个物理化学性质之间未发现关系，但多元数据分析表明，包含乙醇可显著降低化合物亲脂性对溶解度的负面影响。对于该数据集，在 FaSSIF 中不完全溶解的化合物中，有 30%的化合物的乙醇浓度更高，剂量数（Do）<1。具有 Do<1 和 Do>1 的化合物之间在熔点、亲脂性和剂量分布方面存在显著差异，后者在所有三个参数中具有更高的绝对值。总之，这项研究表明，在空腹状态下，乙醇对亲脂性化合物的表观溶解度可能会产生显著影响。结果表明，与空腹肠内存在的混合脂质胶束相比，酸性和中性化合物对添加乙醇更为敏感。
