Analysis of bile acid sequestrants performance through mechanistic and animal model approaches.

Abstract

Colestipol and cholestyramine resins are bile acid sequestrants which bind with bile salts in the intestinal lumen to increase fecal excretion of bile salts. Depletion of bile salts triggers enhanced uptake of LDL cholesterol and increases hepatic conversion of cholesterol to bile salts, thereby lowering plasma and LDL cholesterol. Both colestipol and cholestyramine show good in vitro binding capacity for bile salts; the in vivo binding efficiency, however, is less than expected. The consequence of such low binding efficiency is the binding requirement for large doses in order to achieve the targeted lowering of plasma cholesterol. Mechanistic and animal model approaches were used to determine how resins perform in the simulated duodenal condition and in the small intestine of hamster treated with colestipol, respectively. The mechanistic approach focused on binding affinity of individual bile salts with resins and possible interfering factors. The effect of isotonic Sorensen buffer on bile salt binding to resins indicated that total phosphate anions reduced the capacity of colestipol to more than 70% whereas its effect on cholestyramine was less than 15%. The calculation of capacity-corrected molar selectivity suggested that improvement on the selectivity for resin binding should focus on the trihydroxyl bile salts because the selectivity for dihydroxyl bile salts is at least 5 times higher than trihydroxyl bile salts. There is no direct in vitro evidence of cation interference for bile salt binding to resins from calcium and magnesium at their physiological range. The animal model approach is based on the similarity of hamster and human GI physiology and bile salt metabolism. Characterization of in vivo spatial binding to colestipol by bile salts and the resulting pharmacological change due to resin therapy were evaluated. Bile salt binding to resins in vivo, which is demonstrated by the in vivo/in vitro ratio, was optimal injejunum (0.6% for glycocholate or GC, 0.2% for taurocholate or TC) of hamsters and least effective in the ileum (close to 0 for both GC and TC). A dose response effect suggested that colestipol tends to be more effective on reducing intraluminal GC (ED$\sb{50}$ = 0.030 g) than TC (ED$\sb{50}$ = 0.059 g). Considering the higher percentage of TC (37%) to GC (28%) in the bile salt pool of hamsters, binding preference suggests that improvement on colestipol-TC binding would have a greater effect on the in vivo efficiency. The hamster model can be used for evaluating novel resins since the pharmacological effect of colestipol treatment resulted in decreasing cholesterol in the apo B containing lipoprotein fractions. Thus, colestipol treatment is effective on both LDL cholesterol and plasma total cholesterol level.