Abstract 23016: Dalcetrapib Mediated Increase in Macrophage Reverse Cholesterol Transport Does Not Correlate with Raised HDL-C in Hamsters
Objectives: High-density lipoprotein (HDL) is suggested to play an important role through reverse cholesterol transport (RCT) towards reducing cardiovascular risk. Dalcetrapib selectively targets cholesteryl ester transfer protein (CETP) to increase HDL-cholesterol (HDL-C). We investigated dose-related effects of dalcetrapib in a hamster model of macrophage RCT and evaluated the relationship between the elimination of fecal sterols and HDL-C levels.
Methods: Golden Syrian hamsters (5 per group) were pretreated by daily gavage with dalcetrapib 30, 100 and 200 mg/kg BID for 7 days prior to injection of 3H-cholesterol-labeled autologous macrophages on Day 0. Following macrophage injection, dalcetrapib treatment was continued for 10 days, and levels of radioactivity in fecal sterols, liver cholesteryl esters (CE) and HDL were measured. Control animals received vehicle (0.5% methyl cellulose) for 17 days.
Results: Dalcetrapib increased plasma HDL-C levels on Day 0 (30 mg/kg: +13%, 100 mg/kg: +33%, 200 mg/kg: +33%, vs vehicle) and increased plasma HDL radioactivity on Day 10 (30 mg/kg: +10%, 100 mg/kg: +41%, 200 mg/kg: +16%, vs vehicle). Radioactivity of liver CE on Day 10 was decreased dose-dependently (30 mg/kg: −23%, 100 mg/kg: −38%, 200 mg/kg: −61%, vs vehicle), and radioactivity in fecal sterols, recovered over 10 days, increased dose-dependently (30 mg/kg: +10%, 100 mg/kg: +18%, 200 mg/kg: +30%, vs vehicle). Levels of radioactivity in fecal sterols did not correlate significantly with either HDL-C (r=−0.459, p=0.083) or HDL radioactivity (r=−0.171, p=0.435) but did correlate significantly with levels of radioactivity in liver CE (r=−0.875, p<0.001).
Conclusions: Although the potency of dalcetrapib to raise HDL-C reached a plateau between 100 and 200 mg/kg, a dose-dependent effect towards decreasing liver CE and increasing fecal sterols was observed. This data confirms that dalcetrapib not only increases HDL-C in this model but also promotes RCT through increased levels of functional HDL.
- © 2010 by American Heart Association, Inc.