Wiedmann T S, Kvanbeck K, Han C H, Roongta V
University of Minnesota, College of Pharmacy, Minneapolis, USA.
Pharm Res. 1997 Nov;14(11):1574-82. doi: 10.1023/a:1012178318128.
The aqueous solubility and the extent of solubilization and ionization constant in sodium taurodeoxycholate (NaTDC) solutions of a series of benzoic acid and aniline derivatives were measured as a basis to characterize and thereby help predict the nature of the interaction of drugs with bile aggregates.
The aqueous solubility and the solubilization of two series of compounds, 4-alkyl benzoic acids and 4-alkyl anilines, was measured as a function of NaTDC in 0 and 150 mM NaCl. The ionization constants were determined in water and in 50 mM NaTDC at sodium chloride concentration of 0, 75 and 150 mM by spectrophotometric titration. The diffusion coefficients of NaTDC and the solutes were measured by pulsed-field gradient spin echo NMR spectroscopy.
The aqueous solubilities decreased with increasing alkyl chain length in both series, and the aniline derivatives had larger solubilities than the benzoic acid derivatives. The number of moles of solute solubilized per mole of bile salt ranged from 0.17 to 0.31 for the benzoic acid derivatives and from 1.3 to 3.0 for the aniline derivatives. The pKa values of the benzoic acid derivatives in the presence of NaTDC were higher relative to the controls, and the difference in the pKa (delta pKa,obs) increased with increasing chain length. With the aniline derivatives, the pKa values were also shifted to higher values in NaTDC relative to the control but only in the absence of salt. The presence of the solute caused a decrease in the diffusion coefficient of NaTDC, and the diffusion coefficients of the solutes decreased with increasing alkyl chain length. With the hexyl derivative, the diffusion coefficient of the solute was smaller than the diffusion coefficient of the bile salt. The chemical shift of the protons attached to carbon 18 and 19 of the salt were decreased to a greater extent in the presence of the solutes than the protons attached to carbon 26.
Both the solubilization and ionization behavior of solutes were affected by the presence of bile salt aggregates. The surface potential and effective polarity of NaTDC aggregates were found to be dependent on the alkyl chain length for these two homologous series of solutes. The solubilization ratio was largely independent of alkyl chain length, but the unitary partition coefficient was dependent on both alkyl chain length as well as ionization state. The derivatives reduced the diffusivity of the micelles suggesting the formation of larger size aggregates and the solutes (hexyl derivatives) appear to favor association with the larger sized aggregates. The phenyl ring of the solutes appears to be oriented parallel to the plane of the steroid frame with preferential positioning near the hydrophobic rings.
测定一系列苯甲酸和苯胺衍生物在牛磺脱氧胆酸钠（NaTDC）溶液中的水溶性、增溶程度和电离常数，以此为基础来表征并帮助预测药物与胆汁聚集体的相互作用性质。
测定了两个系列化合物（4-烷基苯甲酸和4-烷基苯胺）在0和150 mM氯化钠中随NaTDC变化的水溶性和增溶情况。通过分光光度滴定法测定了在氯化钠浓度为0、75和150 mM的水以及50 mM NaTDC中的电离常数。通过脉冲场梯度自旋回波核磁共振光谱法测定了NaTDC和溶质的扩散系数。
两个系列中，水溶性均随烷基链长度增加而降低，且苯胺衍生物的溶解度大于苯甲酸衍生物。每摩尔胆盐增溶的溶质摩尔数，苯甲酸衍生物为0.17至0.31，苯胺衍生物为1.3至3.0。在存在NaTDC的情况下，苯甲酸衍生物的pKa值相对于对照更高，且pKa差值（δpKa,obs）随链长增加而增大。对于苯胺衍生物，相对于对照，在NaTDC中pKa值也向更高值移动，但仅在无盐时如此。溶质的存在导致NaTDC的扩散系数降低，且溶质的扩散系数随烷基链长度增加而降低。对于己基衍生物，溶质的扩散系数小于胆盐的扩散系数。在存在溶质的情况下，与盐的碳18和19相连的质子的化学位移比与碳26相连的质子的化学位移降低程度更大。
胆盐聚集体的存在影响了溶质的增溶和电离行为。发现对于这两个同系物系列的溶质，NaTDC聚集体的表面电位和有效极性取决于烷基链长度。增溶比在很大程度上与烷基链长度无关，但单一分配系数取决于烷基链长度以及电离状态。衍生物降低了胶束的扩散率，表明形成了更大尺寸的聚集体，且溶质（己基衍生物）似乎更倾向于与更大尺寸的聚集体缔合。溶质的苯环似乎与甾体骨架平面平行排列，且优先定位在疏水环附近。
