CLINICAL PHARMACOLOGY
Cholesterol is the major, and probably the sole precursor
of bile acids. During normal digestion, bile acids are
secreted via the bile from the liver and gall bladder
into the intestines. Bile acids emulsify the fat and lipid
materials present in food, thus facilitating absorption.
A major portion of the bile acids secreted is reabsorbed
from the intestines and returned via the portal circulation
to the liver, thus completing the enterohepatic cycle.
Only very small amounts of bile acids are found in normal
serum.
Colestipol hydrochloride binds bile acids in the intestine
forming a complex that is excreted in the feces. This
nonsystemic action results in a partial removal of the
bile acids from the enterohepatic circulation, preventing
their reabsorption. Since colestipol hydrochloride is
an anion exchange resin, the chloride anions of the resin
can be replaced by other anions, usually those with a
greater affinity for the resin than the chloride ion.
Colestipol hydrochloride is hydrophilic, but it is virtually
water insoluble (99.75%) and it is not hydrolyzed by digestive
enzymes. The high molecular weight polymer in colestipol
hydrochloride apparently is not absorbed. In humans, less
than 0.17% of a single 14Clabeled colestipol hydrochloride
dose is excreted in the urine when given following 60
days of dosing of 20 grams of colestipol hydrochloride
per day.
The increased fecal loss of bile acids due to colestipol
hydrochloride administration leads to an increased oxidation
of cholesterol to bile acids. This results in an increase
in the number of low- density lipoprotein (LDL) receptors,
increased hepatic uptake of LDL and a decrease in beta
lipoprotein or LDL serum levels, and a decrease in serum
cholesterol levels. Although colestipol hydrochloride
produces an increase in the hepatic synthesis of cholesterol
in man, serum cholesterol levels fall.
There is evidence to show that this fall in cholesterol
is secondary to an increased rate of clearance of cholesterol-rich
lipoproteins (beta or low-density lipoproteins) from the
plasma. Serum triglyceride levels may increase or remain
unchanged in colestipol hydrochloride treated patients.
The decline in serum cholesterol levels with colestipol
hydrochloride treatment is usually evident by one month.
When colestipol hydrochloride is discontinued, serum cholesterol
levels usually return to baseline levels within one month.
Periodic determinations of serum cholesterol levels as
outlined in the National Cholesterol Education Program
(NCEP) guidelines, should be done to confirm a favorable
initial and long- term response.
In a large, placebo- controlled, multiclinic study, the
LRC- CPPT2, hypercholesterolemic subjects treated with
cholestyramine, a bile-acid sequestrant with a mechanism
of action and an effect on serum cholesterol similar to
that of colestipol hydrochloride, had reductions in total
and LDL- C. Over the 7- year study period the cholestyramine
group experienced a 19% reduction (relative to the incidence
in the placebo group) in the combined rate of coronary
heart disease (CHD) death plus nonfatal myocardial infarction
(cumulative incidences of 7% cholestyramine and 8.6% placebo).
The subjects included in the study were middle-aged men
(aged 35-59) with serum cholesterol levels above 265 mg/
dL, LDL-C above 175 mg/ dL on a moderate cholesterol-lowering
diet, and no history of heart disease. It is not clear
to what extent these findings can be extrapolated to other
segments of the hypercholesterolemic population not studied.
Treatment with colestipol results in a significant increase
in lipoprotein LpAl. Lipoprotein LpAl is one of the two
major lipoprotein particles within the high-density lipoprotein
(HDL) density range3, and has been shown in cell culture
to promote cholesterol efflux or removal from cells4.
Although the significance of this finding has not been
established in clinical studies, the elevation of the
lipoprotein LpAl particle within the HDL fraction is consistent
with an antiatherogenic effect of colestipol hydrochloride,
even though little change is observed in HDL cholesterol
(HDL-C).
In patients with heterozygous familial hypercholesterolemia
who have not obtained an optimal response to colestipol
hydrochloride alone in maximal doses, the combination
of colestipol hydrochloride and nicotinic acid has been
shown to further lower serum cholesterol, triglyceride,
and LDL-cholesterol (LDL-C) values. Simultaneously, HDL-C
values increased significantly. In many such patients
it is possible to normalize serum lipid values.
Preliminary evidence suggests that the cholesterol lowering
effects of lovastatin and the bile acid sequestrant, colestipol
hydrochloride, are additive. The effect of intensive lipid-towering
therapy on coronary atherosclerosis has been assessed
by arteriography in hyperlipidemic patients. In these
randomized, controlled clinical trials, patients were
treated for two to four years by either conventional measures
(diet, placebo, or in some cases low-dose resin), or with
intensive combination therapy using diet and COLESTID
Granules plus either nicotinic acid or lovastatin. When
compared to conventional measures, intensive lipid-lowering
combination therapy significantly reduced the frequency
of progression and increased the frequency of regression
of coronary atherosclerotic lesions in patients with or
at risk for coronary artery disease.
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