SK-AND-F 97426-A A MORE POTENT BILE-ACID SEQUESTRANT AND HYPOCHOLESTEROLEMIC AGENT THAN CHOLESTYRAMINE IN THE HAMSTER

SK&F 97426-A is a novel bile acid sequestrant which was selected for c omparison with cholestyramine in vivo because of its superior in vitro bile acid binding properties. The effects of the two sequestrants on faecal bile acid excretion, plasma total cholesterol, VLDL + LDL and H DL cholesterol and triglyceride concentrations and on liver enzymes in volved in the synthesis and metabolism of cholesterol were investigate d in normocholesterolaemic hamsters. Four studies were conducted to de termine the relative potencies of the two resins using a range of dose s of the sequestrants over treatment periods of up to 2 weeks. Curves fitted to the resulting data allowed common maximum responses and sepa rate ED50s to be calculated for each sequestrant. The maximum response of both sequestrants was to increase bile acid excretion by 352% and lower plasma total cholesterol by 37-58%. LDL + VLDL and HDL cholester ol were reduced by 56-75% and 25-41%, respectively. SK&F 97426-A was 3 times more potent than cholestyramine at increasing the excretion of bile acids in the faeces and 2.1-3.4-fold and 2.3-3.2-fold more potent at lowering total plasma cholesterol and LDL plus VLDL cholesterol, r espectively. In some of the experiments SK&F 97426-A was also more pot ent than cholestyramine at lowering HDL cholesterol. Plasma triglyceri des were also lowered by both sequestrants by up to 3 1 % after 1 week but the relative potency could not be determined. These HDL cholester ol and total triglyceride lowering effects of bile acid sequestrants i n the hamster are known not to occur in people treated with cholestyra mine. There were minimal differences between hamsters treated for 1 or 2 weeks in the relative potencies or ED50s calculated for the total p lasma cholesterol, LDL + VLDL and HDL cholesterol. Both sequestrants m ay have been slightly more efficacious on these parameters after 2 wee ks of treatment. Liver weights were reduced by about 15% by both seque strants at 2% (w/w) in the diet for 1 week. The activities of the live r HMG-CoA reductase and cholesterol 7alpha-hydroxylase were increased as expected, whilst the activity of the acyl-CoA:cholesterol acyltrans ferase was reduced by both sequestrants at this dose. SK&F 97426-A was , therefore, 2-3-fold more potent as a bile acid sequestrant and hypoc holesterolaemic agent than cholestyramine when tested in the hamster.