Abstract
Dalcetrapib, a modulator of the cholesteryl ester transfer protein has been studied clinically for cardiovascular risk reduction associated with an increase in HDL-cholesterol. In non-clinical studies in vitro, macrophages have been shown to take up lipids in the presence of dalcetrapib by a specific scavenger receptor, termed MARCO (Perez et al., 2010). This receptor shows extensive species and tissue distribution differences in its expression and therefore, differences in uptake between tissues and species have been recorded in vitro and in vivo. In vivo, mesenteric lymph node enlargement based due to lipid uptake by macrophages has been observed in mice and rats in a cumulative way. In monkeys, this lymph node enlargement has been less pronounced. However, the effect was of slow reversibility consistent with the life span of the macrophages. In order to assist assessment of the clinical relevance of these findings, magnetic resonance imaging of lymph nodes in the GI tract was done in an extended Phase II study with a duration of at least six months. This novel imaging approach supported the pre-clinical assessment of low relevance of the animal findings for the human situation.
References: Perez et al. (2010) MARCO, a macrophage scavenger receptor highly expressed in rodents, mediates the dalcetrapib-induced uptake of lipids by rat and mouse macrophages. Toxicology In Vitro 24, 745-750.
Stein et al. (2010) Safety and tolerability of dalcetrapib (RO4607381/JTT-705): Results from a 48-week trial. Eur Heart J, Feb;31(4):480-8
