SK&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 potent than cholestyramine at increasing bile acid excretion in the hamster. SK&F 97426-A is a quaternary alkylammonium polymethacrylate that was selected for comparison with cholestyramine in vivo because of its superior in vitro bile acid binding properties. Association, dissociation, affinity, and capacity experiments were performed under physiologically relevant conditions with the most abundant bile acids found in human bile. The bile acids came to equilibrium with SK&F 97426-A and cholestyramine within approximately 30 min and 6 min, respectively. SK&F 97426-A and cholestyramine had similar capacities for all the bile acids (between 2.5 and 4 mmol/g) and both had similar, very high affinities and slow dissociation rates for the dihydroxy bile acids. However, SK&F 97426-A had much higher affinities for the trihydroxy bile acids glycocholic acid and taurocholic acid than did cholestyramine. Dissociation 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 trihydroxy bile acids for and from SK&F 97426-A probably account for the increased potency of SK&F 97426-A over cholestyramine in vivo.
Benson
G M
GM
SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts, U.K.
Alston
D R
DR
Hickey
D M
DM
Jaxa-Chamiec
A A
AA
Whittaker
C M
CM
Haynes
C
C
Glen
A
A
Blanchard
S
S
Cresswell
S R
SR
Suckling
K E
KE
D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001647:Bile Acids and Salts / Q000378:metabolism*; D002792:Cholestyramine Resin / Q000378:metabolism* / Q000493:pharmacokinetics; D006224:Cricetinae; D006801:Humans; D011109:Polymethacrylic Acids / Q000378:metabolism* / Q000493:pharmacokinetics
D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D011109:Polymethacrylic Acids; C083681:SK&F 97426-A; D002792:Cholestyramine Resin