SK-AND-F 97426-A - A NOVEL BILE-ACID SEQUESTRANT WITH HIGHER AFFINITIES AND SLOWER DISSOCIATION RATES FOR BILE-ACIDS IN-VITRO THAN CHOLESTYRAMINE

SK&F 97426-A is a novel bile acid sequestrant that is threefold more p otent than cholestyramine at increasing bile acid excretion in the ham ster, SK&F: 97426-A is a quaternary alkylammonium polymethacrylate tha t was selected for comparison with cholestyramine in vivo because of i ts superior in vitro bile acid binding properties. Association, dissoc iation, affinity, and capacity experiments were performed under physio logically relevant conditions with the most abundant bile acids found in human bile. The bile acids came to equilibrium with SK&F 97426-A an d cholestyramine within similar to 30 min and 6 min, respectively, SK& F 97426-A and cholestyramine had similar capacities for all the bile a cids (between 2.5 and 4 mmol/g) and both had similar, very high affini ties and slow dissociation rates far the dihydroxy bile acids. However , SK&F 97426-A had much higher affinities for the trihydroxy bile acid s glycocholic acid and taurocholic acid than did cholestyramine. Disso ciation of glycocholic acid and taurocholic acid from SK&F 97426-A was also much slower (27 and 25%, respectively, dissociated after 60 min) than from cholestyramine (89 and 84%, respectively, dissociated after 60 min). The higher affinities and slower dissociation rates of the t rihydroxy bile acids for and from SK&F 97426-A probably account for th e increased potency of SK&F 97426-A over cholestyramine in vivo.