Anacetrapib
At matched CETP inhibition, only anacetrapib boosts macrophage-to-feces cholesterol excretion in dyslipidemic hamsters (Eur J Pharmacol 2014)
Original title: Anacetrapib and dalcetrapib differentially alters HDL metabolism and macrophage-to-feces reverse cholesterol transport at similar levels of CETP inhibition in hamsters
To test whether anacetrapib and dalcetrapib differ in effect beyond their potency at inhibiting CETP, both drugs were dosed to achieve similar CETP inhibition in hamsters and their effects on macrophage-to-feces reverse cholesterol transport compared. In normolipidemic hamsters, anacetrapib 30 mg/kg and dalcetrapib 200 mg/kg both inhibited CETP activity by approximately 60% and reduced HDL cholesteryl ester fractional catabolic rate by 30% and 26% (both P less than 0.001), but only dalcetrapib increased fecal excretion of HDL-derived tracer, by 30% (P less than 0.05). In dyslipidemic hamsters at approximately 65% CETP inhibition, both drugs reduced HDL cholesteryl ester catabolic rate by 36% (P less than 0.001), but only anacetrapib significantly increased HDL-derived fecal tracer excretion, by 39%, and stimulated macrophage-derived tracer appearance in HDL, while dalcetrapib instead reduced macrophage-derived fecal tracer excretion by 23% (P less than 0.05), indicating stronger CETP inhibition is needed to promote reverse cholesterol transport in dyslipidemic states.
Original 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.
anacetrapibdalcetrapibmechanisms
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.