title: Anacetrapib and dalcetrapib differentially alters HDL metabolism and macrophage-to-feces reverse cholesterol transport at similar levels of CETP inhibition in hamsters.
abstract: Cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and anacetrapib differentially alter LDL- and HDL-cholesterol levels, which might be related to the potency of each drug to inhibit CETP activity. We evaluated the effects of both drugs at similar levels of CETP inhibition on macrophage-to-feces reverse cholesterol transport (RCT) in hamsters. In normolipidemic hamsters, both anacetrapib 30 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~60%. After injection of 3H-cholesteryl oleate labeled HDL, anacetrapib and dalcetrapib reduced HDL-cholesteryl esters fractional catabolic rate (FCR) by 30% and 26% (both P<0.001 vs. vehicle) respectively, but only dalcetrapib increased HDL-derived 3H-tracer fecal excretion by 30% (P<0.05 vs. vehicle). After 3H-cholesterol labeled macrophage intraperitoneal injection, anacetrapib stimulated 3H-tracer appearance in HDL, but both drugs did not promote macrophage-derived 3H-tracer fecal excretion. In dyslipidemic hamsters, both anacetrapib 1 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~65% and reduced HDL-cholesteryl ester FCR by 36% (both P<0.001 vs. vehicle), but only anacetrapib increased HDL-derived 3H-tracer fecal excretion significantly by 39%. After 3H-cholesterol labeled macrophage injection, only anacetrapib 1 mg/kg QD stimulated macrophage-derived 3H-tracer appearance in HDL. These effects remained weaker than those observed with anacetrapib 60 mg/kg QD, which induced a maximal inhibition of CETP and stimulation of macrophage-derived 3H-tracer fecal excretion. In contrast, dalcetrapib 200 mg/kg BID reduced macrophage-derived 3H-tracer fecal excretion by 23% (P<0.05 vs. vehicle). In conclusion, anacetrapib and dalcetrapib differentially alter HDL metabolism and RCT in hamsters. A stronger inhibition of CETP may be required to promote macrophage-to-feces reverse cholesterol transport in dyslipidemic hamsters.
authors.affiliation: Physiogenex SAS, Prologue Biotech, Labège, France.
authors.forename: François
authors.initials: F
authors.lastname: Briand
authors.affiliation: Physiogenex SAS, Prologue Biotech, Labège, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Thieblemont
authors.affiliation: Physiogenex SAS, Prologue Biotech, Labège, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Muzotte
authors.affiliation: Physiogenex SAS, Prologue Biotech, Labège, France.
authors.forename: Noémie
authors.initials: N
authors.lastname: Burr
authors.affiliation: Physiogenex SAS, Prologue Biotech, Labège, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Urbain
authors.affiliation: Physiogenex SAS, Prologue Biotech, Labège, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Sulpice
authors.affiliation: Department of Cardiovascular Diseases, Atherosclerosis, Merck Research Laboratories, Rahway, NJ, USA. Electronic address: Douglas_Johns@merck.com.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Johns
mesh_terms: D000577:Amides; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001692:Biological Transport; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors / Q000097:blood; D006224:Cricetinae; D050171:Dyslipidemias / Q000097:blood / Q000378:metabolism; D004952:Esters; D005243:Feces / Q000737:chemistry*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D023303:Oxazolidinones / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: D000577:Amides; D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D004952:Esters; D023303:Oxazolidinones; D013438:Sulfhydryl Compounds; D014280:Triglycerides; C411602:dalcetrapib; D002784:Cholesterol; C530884:anacetrapib
keywords: Cholesteryl ester transfer protein inhibition; Hamster; High density lipoprotein; Reverse cholesterol transport