Mathematical model and dimensional analysis of glycocholate binding to cholestyramine resin: implications for in vivo resin performance.
Mathematical model and dimensional analysis of glycocholate binding to cholestyramine resin: implications for in vivo resin performance.
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DOI：
10.1002/jps.2600841212
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发表时间：
1995-12
影响因子：
3.8
通讯作者：
J. Polli;G. Amidon
中科院分区：
文献类型：
--
作者：
J. Polli;G. Amidon
在大剂量下，考来烯胺树脂通过结合肠腔中的胆汁盐来降低血清胆固醇，从而增加胆汁盐的粪便排泄。为了更好地了解考来烯胺的体内低效价，推导出估计每克考来烯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，并采用容量校正的摩尔选择性系数。预测每克考来烯胺结合的甘氨胆酸盐的量和游离甘氨胆酸盐浓度在很宽的条件范围内与观察值（分别为r2 = 0.993和r2 = 0.998）相匹配。模拟结合研究表明，几个生物制药参数的相对重要性，改善树脂在体内的性能。如果胆盐螯合在肠的上部是最重要的，则增加甘氨胆酸盐相对于氯化物的树脂选择性具有最大的治疗影响。此外，离子交换现象进行了量纲分析，并揭示了控制因素的两个无量纲数，GC* 和Cl* 的组件。对GC* 和Cl* 的值设置生理限制表明更有效的胆汁酸螯合剂的必要选择性特性和优化当前树脂治疗的给药策略。
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.