Mathematical model and dimensional analysis of glycocholate binding to cholestyramine resin: implications for in vivo resin performance

• Published in: Journal of pharmaceutical sciences Vol. 84; no. 12; p. 1446
• Main Authors: Polli, J E, Amidon, G L
• Format: Journal Article
• Language: English
• Published: United States 01.12.1995
• Subjects: Binding Sites; Cholestyramine Resin - chemistry; Glycocholic Acid - chemistry; Mathematics; Models, Chemical; Resins, Plant - chemistry
• ISSN: 0022-3549; 1520-6017
• 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.