Balon K, Riebesehl B U, Müller B W
Lilly Forschung GmbH, Pharmaceutical Product Development, Hamburg, Germany.
Pharm Res. 1999 Jun;16(6):882-8. doi: 10.1023/a:1018882221008.
Appropriate physicochemical parameters are desired for the prediction of passive intestinal drug absorption during lead compound selection and drug development.
Liposome distribution coefficients measured titrimetrically and solubility data at pH 6.8 were used to characterize 21 structurally diverse ionizable drugs covering a range from <5% to almost complete absorption.
A sigmoidal relationship was found between the percentage of human passive intestinal absorption and a new absorption potential parameter calculated from liposome distribution data and the solubility-dose ratio. In contrast, the human absorption data did not correlate with an octanol-based absorption potential or partitioning data alone. Poor correlations were found between liposome and octanol partitioning of ionic species or nonionic bases indicating the profound differences of the partitioning systems.
Liposome distribution coefficients of ionizable drugs derived by a pH-metric titration were successfully used to calculate a parameter that correlates with the percentage of passive intestinal absorption in humans. Profound differences between liposome and octanol partitioning were found for a highly diverse set of species. This titration technique may serve to generate liposome partitioning data for the selection and optimization of lead compounds and in drug development.
在先导化合物筛选和药物研发过程中，需要合适的物理化学参数来预测药物在肠道的被动吸收情况。
通过滴定法测定的脂质体分配系数以及pH 6.8时的溶解度数据，用于表征21种结构各异的可电离药物，这些药物的吸收范围从小于5%到几乎完全吸收。
发现人体被动肠道吸收百分比与根据脂质体分配数据和溶解度-剂量比计算出的新吸收潜力参数之间呈S形关系。相比之下，人体吸收数据与基于正辛醇的吸收潜力或单独的分配数据并无相关性。在离子型物种或非离子型碱的脂质体和正辛醇分配之间发现相关性较差，这表明分配系统存在显著差异。
通过pH滴定法得到的可电离药物的脂质体分配系数成功用于计算一个与人体被动肠道吸收百分比相关的参数。对于种类繁多的物种，发现脂质体和正辛醇分配存在显著差异。这种滴定技术可用于生成脂质体分配数据，以用于先导化合物的筛选和优化以及药物研发。
