Luner P E, Amidon G L
College of Pharmacy, University of Michigan, Ann Arbor 48109.
Pharm Res. 1992 May;9(5):670-6. doi: 10.1023/a:1015862329303.
In vitro bile salt binding equilibria and kinetic studies were performed with cholestyramine to determine how these factors influence bile sequestrant efficacy in vivo. Chloride ion at physiologic concentrations caused more than a twofold reduction in glycocholate (GCH) binding, compared to binding in the absence of salt, over a range of GCH concentrations and was also observed to displace bound GCH. In addition, chloride ion displaced from cholestyramine as a result of bile salt binding was measured using a chloride selective electrode, and the results show that bile salt binding is due to ion exchange. Comparison of the results of the equilibrium binding experiments to human data shows that the effect of anion binding competition alone cannot account for the lack of efficacy of cholestyramine. Consideration of other effects, such as additional binding competition or poor availability for binding, based on data from the literature, shows that adequate bile salt binding potential exists and that these interferences are not major factors influencing resin efficacy. In kinetic studies, both binding uptake of GCH and displacement of GCH from cholestyramine by chloride ion were relatively rapid, indicating that cholestyramine should equilibrate rapidly with bile salts in the GI tract. Based on these findings, it is suggested that the low efficacy of cholestyramine is a result mainly of its relatively poor ability to prevent bile salt reabsorption in the ileum.
对消胆胺进行了体外胆汁盐结合平衡和动力学研究，以确定这些因素如何影响体内胆汁螯合剂的疗效。在一系列甘胆酸盐（GCH）浓度范围内，与无盐情况下的结合相比，生理浓度的氯离子使GCH结合减少了两倍多，并且还观察到其能置换结合的GCH。此外，使用氯离子选择性电极测量了由于胆汁盐结合而从消胆胺中置换出的氯离子，结果表明胆汁盐结合是由于离子交换。将平衡结合实验结果与人体数据进行比较表明，仅阴离子结合竞争的影响不能解释消胆胺疗效不佳的原因。根据文献数据考虑其他影响，如额外的结合竞争或结合可用性差，结果表明存在足够的胆汁盐结合潜力，并且这些干扰不是影响树脂疗效的主要因素。在动力学研究中，GCH的结合摄取和氯离子从消胆胺中置换GCH的过程都相对较快，这表明消胆胺在胃肠道中应能迅速与胆汁盐达到平衡。基于这些发现，有人提出消胆胺疗效低主要是由于其在回肠中防止胆汁盐重吸收的能力相对较差。
