Laboratory of Biopharmaceutics and Pharmacokinetics, National and Kapodistrian University of Athens, Athens, Greece.
Biopharm Drug Dispos. 2009 Sep;30(6):318-25. doi: 10.1002/bdd.670.
The suitability of various media to forecast the solubility of ketoconazole and dipyridamole in the fed stomach at various periods after meal administration was evaluated. Solubilities were measured with the shake-flask method in gastric fluids aspirated 30, 60 and 120 min after administration of 500 ml Ensure plus to healthy fasted adults, in three sets of simulated gastric fluids based on milk, and in simple aqueous buffered media. Simple aqueous buffered media vastly underestimated the intragastric solubility of model compounds in the fed state. When using undigested milk-based media, the solubilities of model compounds in aspirates were also underestimated by a factor of 2.5-27. Solubility in milk digested with pepsin was useful for estimating the intragastric solubility of ketoconazole (within 20%) but overestimated the intragastric values of dipyridamole by a factor of 2-19. For both drugs, the solubility in milk digested with pepsin and lipase predicted the solubility in aspirates collected 60 min after meal administration, whereas at other times it overestimated the intragastric solubility (by a factor of <5). Both the use of biorelevant media and simulation of intragastric digestion are necessary for the prediction of drug solubility in the fed stomach. Milk digested with pepsin and lipase enabled the estimation of the intragastric solubility of dipyridamole and ketoconazole at 1 h after meal intake. Simulation of vesicle/micellar structures seems to be key for the prediction of intragastric solubility in the fed stomach.
评估了各种介质在进食后不同时间预测酮康唑和双嘧达莫在进食胃中溶解度的适用性。在健康禁食成年人服用 500 毫升 Ensure plus 后 30、60 和 120 分钟，用摇瓶法在三种基于牛奶的模拟胃液中以及在简单的水缓冲介质中测量溶解度。简单的水缓冲介质大大低估了模型化合物在进食状态下的胃内溶解度。当使用未消化的基于牛奶的介质时，模型化合物在抽吸物中的溶解度也被低估了 2.5-27 倍。用胃蛋白酶消化的牛奶的溶解度可用于估计酮康唑的胃内溶解度（在 20%以内），但双嘧达莫的胃内值高估了 2-19 倍。对于这两种药物，用胃蛋白酶和脂肪酶消化的牛奶的溶解度可预测餐后 60 分钟收集的抽吸物中的溶解度，而在其他时间则高估了胃内溶解度（<5 倍）。生物相关介质的使用和胃内消化的模拟对于预测进食胃中药物的溶解度都是必要的。用胃蛋白酶和脂肪酶消化的牛奶可以估计双嘧达莫和酮康唑在餐后 1 小时的胃内溶解度。模拟囊泡/胶束结构似乎是预测进食胃中胃内溶解度的关键。
