title: In vivo effects of anacetrapib on preβ HDL: improvement in HDL remodeling without effects on cholesterol absorption.
abstract: Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester and triglyceride between HDL and apoB-containing lipoproteins. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol and lowers LDL cholesterol in dyslipidemic patients. We previously demonstrated that ANA increases macrophage-to-feces reverse cholesterol transport and fecal cholesterol excretion in hamsters, and increased preβ HDL-dependent cholesterol efflux via ABCA1 in vitro. However, the effects of ANA on in vivo preβ HDL have not been characterized. In vitro, ANA inhibited the formation of preβ, however in ANA-treated dyslipidemic hamsters, preβ HDL levels (measured by two-dimensional gel electrophoresis) were increased, in contrast to in vitro findings. Because changes in plasma preβ HDL have been proposed to potentially affect markers of cholesterol absorption with other CETP inhibitors, a dual stable isotope method was used to directly measure cholesterol absorption in hamsters. ANA treatment of hamsters (on either dyslipidemic or normal diet) had no effect on cholesterol absorption, while dalcetrapib-treated hamsters displayed an increase in cholesterol absorption. Taken together, these data support the notion that ANA promotes preβ HDL functionality in vivo, with no effects on cholesterol absorption.
authors.affiliation: Department of Atherosclerosis, Merck Research Laboratories, Rahway, NJ 07065.
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Wang
authors.forename: Erin
authors.initials: E
authors.lastname: Daniels
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Jose
authors.initials: J
authors.lastname: Castro-Perez
authors.forename: Haihong
authors.initials: H
authors.lastname: Zhou
authors.forename: Karen O
authors.initials: KO
authors.lastname: Akinsanya
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Previs
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Roddy
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Johns
mesh_terms: D000577:Amides; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D001384:Azetidines / Q000494:pharmacology / Q000627:therapeutic use; D002784:Cholesterol / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006224:Cricetinae; D059305:Diet, High-Fat / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D004952:Esters; D000069438:Ezetimibe; D053442:High-Density Lipoproteins, Pre-beta / Q000097:blood*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D008647:Mesocricetus; D023303:Oxazolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D013438:Sulfhydryl Compounds / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000577:Amides; D000924:Anticholesteremic Agents; D001384:Azetidines; D053480:Cholesterol Ester Transfer Proteins; D004952:Esters; D053442:High-Density Lipoproteins, Pre-beta; D023303:Oxazolidinones; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; D002784:Cholesterol; D000069438:Ezetimibe; C530884:anacetrapib
keywords: anacetrapib; apolipoprotein A1; cholesteryl ester transfer protein; dalcetrapib; high density lipoprotein
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