SK&F 97426-A a more potent bile acid sequestrant and hypocholesterolaemic agent than cholestyramine in the hamster.
SK&F 97426-A is a novel bile acid sequestrant which was selected for comparison 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 HDL cholesterol and triglyceride concentrations and on liver enzymes involved in the synthesis and metabolism of cholesterol were investigated in normocholesterolaemic hamsters. Four studies were conducted to determine the relative potencies of the two resins using a range of doses of the sequestrants over treatment periods of up to 2 weeks. Curves fitted to the resulting data allowed common maximum responses and separate 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 cholesterol 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, respectively. In some of the experiments SK&F 97426-A was also more potent than cholestyramine at lowering HDL cholesterol. Plasma triglycerides were also lowered by both sequestrants by up to 31% after 1 week but the relative potency could not be determined. These HDL cholesterol and total triglyceride lowering effects of bile acid sequestrants in the hamster are known not to occur in people treated with cholestyramine. There were minimal differences between hamsters treated for 1 or 2 weeks in the relative potencies or ED50s calculated for the total plasma cholesterol, LDL + VLDL and HDL cholesterol. Both sequestrants may have been slightly more efficacious on these parameters after 2 weeks of treatment. Liver weights were reduced by about 15% by both sequestrants at 2% (w/w) in the diet for 1 week. The activities of the liver HMG-CoA reductase and cholesterol 7 alpha-hydroxylase were increased as expected, whilst the activity of the acyl-CoA:cholesterol acyltransferase 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 hypocholesterolaemic agent than cholestyramine when tested in the hamster.
Benson
G M
GM
SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts, UK.
Alston
D R
DR
Bond
B C
BC
Gee
A N
AN
Glen
A
A
Haynes
C
C
Hickey
D M
DM
Iqbal
S
S
Jackson
B
B
Jaxa-Chamiec
A A
AA
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D002792:Cholestyramine Resin / Q000494:pharmacology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000201:enzymology; D011109:Polymethacrylic Acids / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D008074:Lipoproteins; D011109:Polymethacrylic Acids; C083681:SK&F 97426-A; D014280:Triglycerides; C030104:lipoprotein cholesterol; D002792:Cholestyramine Resin; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase