Mechanistic analysis of bile acid sequestrant performance.

Abstract

Bile acid sequestrants bind with bile salts in the intestinal lumen to increase the fecal excretion of bile salts and, thus, lower blood cholesterol. This dissertation is a mechanistic investigation of the in vitro performance of various sequestrants. These results will facilitate our understanding of the biopharmaceutics of the sequestrants, aid in the rational design of more potent sequestrants, and suggest bioequivalency specifications for marketed sequestrants. In vitro equilibrium binding studies, water sorption studies, and resin capacity measurements were performed using several bile acid sequestrants and the bile salt sodium glycocholate. The bile acid sequestrants studied included cholestyramine resin USP, colestipol hydrochloride USP, and a series of Dowex 1 resins which varied in extent of cross-linking and particle size. For all resins except colestipol, the practical specific capacity for glycocholate was lower than the practical specific capacity for chloride. This difference suggests the rigid, bulky bile salt was pore excluded from portions of the resins. A fundamental parameter called the capacity-corrected molar selectivity coefficient was postulated to describe the underlying binding phenomena. This selectivity coefficient ranged from 9.8 ($\pm$0.7) to 18.6 ($\pm$0.2) for cholestyramine. The molar selectivity coefficient of colestipol ranged from 1.10 ($\pm$0.06) to 10.6 ($\pm$0.3) and increased as the resin was converted more to the glycocholate form, suggesting positive binding cooperativity among glycocholate molecules. In the Dowex 1 series, the capacity-corrected molar selectivity coefficient for glycocholate over chloride ranged from 3.4 to 16 ($\pm$1.2). The extent of cross-linkage qualitatively and quantitatively modulated the dependence of selectivity on the ionic composition of the resin. The capacity-corrected molar selectivity coefficient was employed to simulate the in vivo performance of resins. Prediction of the quantity of glycocholate bound per gram of resin and of the free glycocholate concentration matched observed values. This simulation approach suggested the requisite properties of a novel, potent bile acid sequestrant and regimen strategies to improve therapy. Increasing resin selectivity has greatest impact if bile salt sequestering is most important in the upper portion of the intestines. Furthermore, ion exchange was subjected to dimensional analysis and revealed the controlling factors as components of two dimensionless numbers, the Glycocholate Number, GC*, and the Chloride Number, Cl*.