Cholesterol absorption inhibitor
Encyclopedia
Cholesterol absorption inhibitors are a class of compounds that prevents the uptake of cholesterol
from the small intestine into the circulatory system.
An example is ezetimibe
, previously known as "Sch-58235". Another example is Sch-48461
. The "Sch" is for Schering-Plough
, where these compounds were developed.
Phytosterols are also cholesterol absorption inhibitors.
emulsions, combines with bile salts
, to form bile salt micelles from which cholesterol can then be absorbed by the intestinal enterocyte
.
Once absorbed by the enterocyte, cholesterol is reassembled into large intestinal lipoproteins called chylomicrons. These chylomicron
s are then secreted into the lymphatics and circulated to the liver. These cholesterol particles are then secreted by the liver into the blood as VLDL particles, precursors to LDL.
As a class, cholesterol absorption inhibitors block the uptake of micellar cholesterol, thereby reducing the incorporation of cholesterol esters into chylomicron particles. By reducing the cholesterol content in chylomicrons and chylomicron remnants, cholesterol absorption inhibitors effectively reduce the amount of cholesterol that is delivered back to the liver.
The reduced delivery of cholesterol to the liver increases hepatic LDL receptor activity and thereby increases clearance of circulating LDL. The net result is a reduction in circulating LDL particles.
. Cholesterol absorption inhibitors are known to have a synergistic effect when combined a class of antihyperlipidemics called statins, to achieve an overall serum cholesterol target. For statin-resistant or statin-sensitive populations that are characterized by low one-year compliance rates, such a combination therapy is proving to be especially effective.
Partially due to the challenges of statin dose toxicity, cholesterol absorption inhibitors have emerged as a new class of anti-hyperlipidemics that is effective strategy for the treatment of hypercholesterolemia.
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
from the small intestine into the circulatory system.
An example is ezetimibe
Ezetimibe
Ezetimibe is a drug that lowers cholesterol. It acts by decreasing cholesterol absorption in the intestine. It may be used alone , when other cholesterol-lowering medications are not tolerated, or together with statins when statins alone do not control cholesterol.Even though ezetimibe decreases...
, previously known as "Sch-58235". Another example is Sch-48461
SCH-48461
SCH-48461 is a cholesterol absorption inhibitor....
. The "Sch" is for Schering-Plough
Schering-Plough
Schering-Plough Corporation was a United States-based pharmaceutical company. It was founded in 1851 by Ernst Christian Friedrich Schering as Schering AG in Germany. In 1971, the Schering Corporation merged with Plough to form Schering-Plough. On November 4, 2009 Merck & Co...
, where these compounds were developed.
Phytosterols are also cholesterol absorption inhibitors.
How they work
There are two sources of cholesterol in the upper intestine: dietary (from food) and biliary (from bile). Dietary cholesterol, in the form of lipidLipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
emulsions, combines with bile salts
Bile acid
Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids compounded with a cation, usually sodium. In humans, the salts of taurocholic acid and glycocholic acid represent approximately eighty percent of all bile salts. The two major bile acids are cholic...
, to form bile salt micelles from which cholesterol can then be absorbed by the intestinal enterocyte
Enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...
.
Once absorbed by the enterocyte, cholesterol is reassembled into large intestinal lipoproteins called chylomicrons. These chylomicron
Chylomicron
Chylomicrons are lipoprotein particles that consist of triglycerides , phospholipids , cholesterol and proteins .They transport dietary lipids from the intestines to other locations in the body...
s are then secreted into the lymphatics and circulated to the liver. These cholesterol particles are then secreted by the liver into the blood as VLDL particles, precursors to LDL.
As a class, cholesterol absorption inhibitors block the uptake of micellar cholesterol, thereby reducing the incorporation of cholesterol esters into chylomicron particles. By reducing the cholesterol content in chylomicrons and chylomicron remnants, cholesterol absorption inhibitors effectively reduce the amount of cholesterol that is delivered back to the liver.
The reduced delivery of cholesterol to the liver increases hepatic LDL receptor activity and thereby increases clearance of circulating LDL. The net result is a reduction in circulating LDL particles.
Importance
Managing cholesterol at the site of absorption is an increasingly popular strategy in the treatment of hypercholesterolemiaHypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
. Cholesterol absorption inhibitors are known to have a synergistic effect when combined a class of antihyperlipidemics called statins, to achieve an overall serum cholesterol target. For statin-resistant or statin-sensitive populations that are characterized by low one-year compliance rates, such a combination therapy is proving to be especially effective.
Partially due to the challenges of statin dose toxicity, cholesterol absorption inhibitors have emerged as a new class of anti-hyperlipidemics that is effective strategy for the treatment of hypercholesterolemia.