Cholesterol absorption inhibitor

Cholesterol absorption inhibitors are a class of compounds that prevents the uptake of cholesterol from the small intestine into the circulatory system. Most of these molecules are monobactams but show no antibiotic activity. An example is ezetimibe (SCH 58235)^[1][2][3][4] Another example is Sch-48461.^[5] The "Sch" is for Schering-Plough, where these compounds were developed. Phytosterols are also cholesterol absorption inhibitors.

Physiology

There are two sources of cholesterol in the upper intestine: dietary (from food) and biliary (from bile). Dietary cholesterol, in the form of lipid 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 intestinal lipoproteins called chylomicrons. These chylomicrons 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 hypercholesterolemia . 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 .

References

1. Patrick JE, Kosoglou T, Stauber KL; et al. (April 2002). "Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects". Drug Metab. Dispos. 30 (4): 430–7. doi:10.1124/dmd.30.4.430. PMID 11901097.
2. Dujovne CA, Ettinger MP, McNeer JF; et al. (November 2002). "Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia". Am. J. Cardiol. 90 (10): 1092–7. doi:10.1016/S0002-9149(02)02798-4. PMID 12423709.
3. Rosenblum SB, Huynh T, Afonso A; et al. (March 1998). "Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption". J. Med. Chem. 41 (6): 973–80. doi:10.1021/jm970701f. PMID 9526571.
4. Jeu L, Cheng JW (September 2003). "Pharmacology and therapeutics of ezetimibe (SCH 58235), a cholesterol-absorption inhibitor". Clin Ther 25 (9): 2352–87. doi:10.1016/S0149-2918(03)80281-3. PMID 14604738.
5. Salisbury BG, Davis HR, Burrier RE; et al. (May 1995). "Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461". Atherosclerosis 115 (1): 45–63. doi:10.1016/0021-9150(94)05499-9. PMID 7669087.