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Abstract
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
7a-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.
Keywords
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Article info
Publication history
Accepted:
February 19,
1993
Received in revised form:
February 18,
1993
Received:
December 10,
1992
Identification
Copyright
© 1993 Published by Elsevier Inc.
