Abstract 508: Plasma Kinetics of 3H-Cholesterol from Labeled Macrophages in Hamsters Treated with Dalcetrapib, Torcetrapib and Anacetrapib
Introduction: A model using hamsters injected intraperitoneally with cholesterol-labeled macrophages has been developed for the study of reverse cholesterol transport following treatment with compounds affecting CETP activity e.g., the CETP modulator dalcetrapib or the CETP inhibitors torcetrapib and anacetrapib.
Hypothesis: Contrary to torcetrapib and anacetrapib, dalcetrapib allows CETP-induced remodeling of HDL and the formation of pre-β-HDL in vitro; these compounds may differentially alter the kinetics of efflux of 3H-cholesterol (3H-C) from macrophages to plasma HDL and elimination from plasma HDL.
Methods: Male Golden Syrian hamsters were fed a chow diet and received dalcetrapib 150 mg/kg bid, n=10; torcetrapib 30 mg/kg qd, n=10; anacetrapib 30 mg/kg qd, n=10; or vehicle (0.5% HPMC), n=8, for 10 days. On Day 7, all animals were administered ip 3H-C-labeled J774 macrophages and treated as above for a further 3 days. The appearance of 3H-C in plasma HDL (24, 48 and 72 h), liver and in feces was measured and 3H-C specific activity (SA) calculated.
Results: Compared to vehicle, torcetrapib and dalcetrapib raised plasma total cholesterol by 14% and anacetrapib by 21% with a similar trend for HDL-C. At 24, 48 and 72 h, HDL 3H-C SA was -22.3, +4.9 and -0.5% (p<0.01, NS, NS) for torcetrapib, -16.7, -1.7 and -3.0% (p<0.05, NS, NS) for anacetrapib and +35.3, +36.4 and +8.7% (p<0.007, 0.012, NS) for dalcetrapib compared to vehicle. At sacrifice the percentage of injected dose in liver did not differ between treatment and vehicle for torcetrapib, anacetrapib and dalcetrapib. The SA of 3H-C in fecal cholesterol was +19.8, +0.5 and +44.8% (NS, NS, p<0.05 vs vehicle) and in fecal bile acids was +49.7, +7.8 and +56.0% (p<0.03, NS, NS vs vehicle) respectively.
Conclusions: The SA of HDL 3H-C from labeled macrophages is significantly higher for dalcetrapib at 24 and 48 h but lower for torcetrapib and anacetrapib at 24 h in treated hamsters compared to vehicle. A comparable SA to vehicle at later time points suggests an active mechanism of 3H-C removal from macrophages and elimination for dalcetrapib, while 3H-C for torcetrapib and anacetrapib is initially diluted in the HDL-C pool followed by attainment of equilibrium in this pool.
- © 2012 by American Heart Association, Inc.