Abstract 1271: The Effects of Dalcetrapib on Macrophage Reverse Cholesterol Transport in a Rodent Model
Objectives: To establish a model of reverse cholesterol transport (RCT) in a species that naturally expresses cholesteryl ester transfer protein (CETP), and assess the effects of 2 agents that target CETP in this system.
Methods: Golden Syrian hamsters were pretreated by daily gavage with dalcetrapib (DAL) 100 mg/kg BID or torcetrapib (TOR) 30 mg/kg QD for 7 days prior to injection of 3H-cholesterol-labeled autologous macrophages on Day 0. Treatment was continued for ≤10 days and 3H-sterols measured in plasma HDL, liver and feces. In a separate study, DAL 300 mg/kg or TOR 30 mg/kg was administered daily with food for 7 days. 3H-cholesterol-labeled macrophages were injected on Day 0 then fecal elimination of neutral sterols and bile acids was measured at Day 3.
Results: HDL-C level was significantly increased following pretreatment with DAL or TOR (102.1 or 112.7 mg/dL, respectively) vs vehicle (82.7 mg/dL, P<0.05). On Day 3, 3H-cholesterol in plasma HDL was significantly raised following treatment with DAL or TOR (each P<0.05 vs vehicle), and sustained at Day 10 for TOR. On Day 10, liver radioactivity was significantly reduced by DAL and TOR compared with vehicle (−42 and −28%, respectively; both P<0.01), and fecal elimination of 3H-sterols was significantly increased (+32 and +24% vs vehicle, both P<0.05). In a separate experiment, DAL 300 mg/kg also increased fecal radioactivity elimination at Day 3 (+24% vs vehicle, P<0.01). Both 3H-neutral sterols and 3H-bile acids were increased (+28 and +24% compared with vehicle, P<0.05 and P<0.01, respectively); In the same study TOR 30 mg/kg also increased fecal radioactivity elimination (+22%) but changes were not statistically significant compared with vehicle (P>0.1).
Conclusions: This is the first demonstration of DAL-induced RCT from autologous labeled macrophages in a species expressing CETP. DAL and TOR were associated with significant but different 3H-cholesterol transfer to HDL not proportional to fecal elimination. The clinical relevance of these findings remains to be determined but suggests differences in stimulating RCT not related to HDL-C-raising potency exist among agents that target CETP.