title: Inhibition of cholesterol absorption: targeting the intestine.
abstract: Atherosclerosis, the gradual formation of a lipid-rich plaque in the arterial wall is the primary cause of Coronary Artery Disease (CAD), the leading cause of mortality worldwide. Hypercholesterolemia, elevated circulating cholesterol, was identified as a key risk factor for CAD in epidemiological studies. Since the approval of Mevacor in 1987, the primary therapeutic intervention for hypercholesterolemia has been statins, drugs that inhibit the biosynthesis of cholesterol. With improved understanding of the risks associated with elevated cholesterol levels, health agencies are recommending reductions in cholesterol that are not achievable in every patient with statins alone, underlying the need for improved combination therapies. The whole body cholesterol pool is derived from two sources, biosynthesis and diet. Although statins are effective at reducing the biosynthesis of cholesterol, they do not inhibit the absorption of cholesterol, making this an attractive target for adjunct therapies. This report summarizes the efforts to target the gastrointestinal absorption of cholesterol, with emphasis on specifically targeting the gastrointestinal tract to avoid the off-target effects sometimes associated with systemic exposure.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, British Columbia, V6T 1Z3, Canada. Stephen.Lee@alumni.ubc.ca
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Lee
authors.forename: Pavel
authors.initials: P
authors.lastname: Gershkovich
authors.forename: Jerald W
authors.initials: JW
authors.lastname: Darlington
authors.forename: Kishor M
authors.initials: KM
authors.lastname: Wasan
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism; D001384:Azetidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D000069438:Ezetimibe; D006331:Heart Diseases / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D000071518:Liver X Receptors; D058990:Molecular Targeted Therapy / Q000379:methods*; D057093:Orphan Nuclear Receptors / Q000819:agonists; D010840:Phytosterols / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D001384:Azetidines; D001647:Bile Acids and Salts; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010840:Phytosterols; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D000069438:Ezetimibe