Polli J E, Amidon G L
College of Pharmacy, University of Michigan, Ann Arbor 48109, USA.
J Pharm Sci. 1995 Dec;84(12):1446-54. doi: 10.1002/jps.2600841212.
In large doses, cholestyramine resin lowers blood serum cholesterol by binding bile salts in the intestinal lumen and thus increases the fecal excretion of bile salts. In order to gain a better understanding of the low in vivo potency of cholestyramine, mathematical models estimating the amount of glycocholate bound per gram of cholestyramine and the free glycocholate concentration were derived and employ the capacity-corrected molar selectivity coefficient. Predictions of the quantity of glycocholate bound per gram of cholestyramine and of the free glycocholate concentration matched observed values (r2 = 0.993 and r2 = 0.998, respectively) over a wide range of conditions. Simulated binding studies indicated the relative importance of several biopharmaceutical parameters for improved resin in vivo performance. Increasing resin selectivity of glycocholate over chloride has greatest therapeutic impact if bile salt sequestering is most important in the upper portion of the intestines. Furthermore, ion exchange phenomena was subjected to dimensional analysis and revealed the controlling factors as components of two dimensionless numbers, GC* and Cl*. Placing physiologic limits on values of GC* and Cl* suggests requisite selectivity properties of more potent bile acid sequestrants and dosing strategies to optimize current resin therapy.
大剂量时，消胆胺树脂通过在肠腔内结合胆盐来降低血清胆固醇，从而增加胆盐的粪便排泄量。为了更好地理解消胆胺在体内的低效性，推导了估计每克消胆胺结合的甘氨胆酸盐量和游离甘氨胆酸盐浓度的数学模型，并采用了容量校正摩尔选择性系数。在广泛的条件下，每克消胆胺结合的甘氨胆酸盐量和游离甘氨胆酸盐浓度的预测值与观测值相符（分别为r2 = 0.993和r2 = 0.998）。模拟结合研究表明了几个生物制药参数对改善树脂体内性能的相对重要性。如果胆盐螯合在小肠上部最为重要，那么提高树脂对甘氨胆酸盐相对于氯化物的选择性具有最大的治疗影响。此外，对离子交换现象进行了量纲分析，揭示了控制因素为两个无量纲数GC和Cl的组成部分。对GC和Cl的值设定生理限度，表明了更有效的胆汁酸螯合剂所需的选择性特性以及优化当前树脂治疗的给药策略。
