Fagerberg Jonas H, Sjögren Erik, Bergström Christel A S
Department of Pharmacy, Uppsala Biomedical Center, Uppsala University, P.O. Box 580, SE-751 23 Uppsala, Sweden.
Department of Pharmacy, Uppsala Biomedical Center, Uppsala University, P.O. Box 580, SE-751 23 Uppsala, Sweden.
Eur J Pharm Sci. 2015 Jan 25;67:12-20. doi: 10.1016/j.ejps.2014.10.017. Epub 2014 Oct 31.
Ethanol can increase the solubility of poorly soluble and hence present a higher drug concentration in the gastrointestinal tract. This may produce a faster and more effective absorption resulting in variable and/or high drug plasma concentrations, both of which can lead to adverse drug reactions. In this work we therefore studied the solubility and absorption effects of nine diverse compounds when ethanol was present. The apparent solubility was measured using the μDiss Profiler Plus (pION, MA) in four media representing gastric conditions with and without ethanol. The solubility results were combined with in-house data on solubility in intestinal fluids (with and without ethanol) and pharmacokinetic parameters extracted from the literature and used as input in compartmental absorption simulations using the software GI-Sim. Apparent solubility increased more than 7-fold for non-ionized compounds in simulated gastric fluid containing 20% ethanol. Compounds with weak base functions (cinnarizine, dipyridamole and terfenadine) were completely ionized at the studied gastric pH and their solubility was therefore unaffected by ethanol. Compounds with low solubility in intestinal media and a pronounced solubility increase due to ethanol in the upper gastric compartments showed an increased absorption in the simulations. The rate of absorption of the acidic compounds indomethacin and indoprofen was slightly increased but the extent of absorption was unaffected as the complete doses were readily absorbed even without ethanol. This was likely due to a high apparent solubility in the intestinal compartment where the weak acids are ionized. The absorption of the studied non-ionizable compounds increased when ethanol was present in the gastric and intestinal media. These results indicate that concomitant intake of alcohol may significantly increase the solubility and hence, the plasma concentration for non-ionizable, lipophilic compounds with the potential of adverse drug reactions to occur.
乙醇可增加难溶性药物的溶解度，从而使胃肠道中的药物浓度更高。这可能会产生更快、更有效的吸收，导致药物血浆浓度变化不定和/或升高，而这两者都可能导致药物不良反应。因此，在本研究中，我们研究了九种不同化合物在有乙醇存在时的溶解度和吸收效果。使用μDiss Profiler Plus（pION，马萨诸塞州）在四种模拟有或无乙醇的胃环境的介质中测量表观溶解度。将溶解度结果与内部关于在肠液中（有和无乙醇）的溶解度数据以及从文献中提取的药代动力学参数相结合，并用作使用GI-Sim软件进行房室吸收模拟的输入。在含有20%乙醇的模拟胃液中，非离子化化合物的表观溶解度增加了7倍多。具有弱碱功能的化合物（桂利嗪、双嘧达莫和特非那定）在所研究的胃pH值下完全离子化，因此它们的溶解度不受乙醇影响。在肠介质中溶解度低且由于乙醇在上部胃腔中溶解度显著增加的化合物在模拟中显示吸收增加。酸性化合物吲哚美辛和吲哚洛芬的吸收速率略有增加，但吸收程度未受影响，因为即使没有乙醇，完整剂量也很容易被吸收。这可能是由于弱酸在肠腔中离子化时具有较高的表观溶解度。当胃和肠介质中存在乙醇时，所研究的非离子化化合物的吸收增加。这些结果表明，同时摄入酒精可能会显著增加非离子化、亲脂性化合物的溶解度，从而增加其血浆浓度，有可能引发药物不良反应。
