Anacetrapib and dalcetrapib differentially alters HDL metabolism and macrophage-to-feces reverse cholesterol transport at similar levels of CETP inhibition in hamsters

Cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and anacetrapib differentially alter LDLand 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 similar to 60%. After injection of H-3-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 H-3-tracer fecal excretion by 30% (P < 0.05 vs. vehicle). After H-3-cholesterol labeled macrophage intraperitoneal injection, anacetrapib stimulated 3H-tracer appearance in HDL, but both drugs did not promote macrophage-derived H-3-tracer fecal excretion. In dyslipidemic hamsters, both anacetrapib 1 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by similar to 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 H-3-cholesterol labeled macrophage injection, only anacetrapib 1 mg/kg QD stimulated macrophage-derived H-3-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 H-3-tracer fecal excretion. In contrast, dalcetrapib 200 mg/kg BID reduced macrophage-derived H-3-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. (C) 2014 Elsevier B.V. All rights reserved.