Abstract

The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibits a long terminal half-life (t_½) in humans; however, the dispositional mechanisms that lead to this long t_½ are still being elucidated. As it is hypothesized that disposition into adipose tissue and binding to CETP might play a role, we sought to delineate the relative importance of these factors using a preclinical animal model. A multiple-dose pharmacokinetic study was conducted in C57BL6 wild-type (WT) lean, WT diet-induced obese (DIO), natural flanking region (NFR) CETP-transgenic lean, and NFR-DIO mice. Mice were dosed orally with 10 mg/kg anacetrapib daily for 42 days. Drug concentrations in blood, brown and white adipose tissue, liver, and brain were measured up to 35 weeks postdose. During dosing, a 3- to 9-fold accumulation in 72-hour postdose blood concentrations of anacetrapib was observed. Drug concentrations in white adipose tissue accumulated ∼20- to 40-fold, whereas 10- to 17-fold accumulation occurred in brown adipose and approximately 4-fold in liver. Brain levels were very low (<0.1 μM), and a trend of accumulation was not seen. The presence of CETP as well as adiposity seems to play a role in determining the blood concentrations of anacetrapib. The highest blood concentrations were observed in NFR DIO mice, whereas the lowest concentrations were seen in WT lean mice. In adipose and liver tissue, higher concentrations were seen in DIO mice, irrespective of the presence of CETP. This finding suggests that white adipose tissue serves as a potential depot and that disposition into adipose tissue governs the long-term kinetics of anacetrapib in vivo.