Three Generations of Bile Acid Sequestrants

Cholestyramine, the first bile acid sequestrant to be marketed, has been in use for over 20 years. Despite its low potency, requiring 16-24 g of polymer to achieve 20% LDL cholesterol reduction in hypercholesterolemic individuals, only one other sequestrant, colestipol, has come to market in the ensuing period. GelTex Pharmaceuticals has been involved for over six years in the discovery and development of new, more potent polymeric sequestrants. Two binding mechanisms are presented — one that operates via an aggregate binding structure and one that is effective via a defined site binding structure. These two binding mechanisms are compared and contrasted through bile acid binding isotherms. The best of these new sequestrants bind bile acids through a combination of hydrophobicity and ion exchange. Optimization and balancing of each of these interactions led us to more potent materials. The first of these, colesevelam hydrochloride is expected to be three to four times more potent than cholestyramine. A third generation product is still in research at GelTex. With another twofold increase in potency possible, single tablet therapy may become a reality.