RT Journal Article
SR Electronic
T1 Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 428
OP 434
DO 10.1124/dmd.115.067736
VO 44
IS 3
A1 Hartmann, Georgy
A1 Kumar, Sanjeev
A1 Johns, Douglas
A1 Gheyas, Ferdous
A1 Gutstein, David
A1 Shen, Xiaolan
A1 Burton, Aimee
A1 Lederman, Harmony
A1 Lutz, Ryan
A1 Jackson, Tonya
A1 Chavez-Eng, Cynthia
A1 Mitra, Kaushik
YR 2016
UL http://dmd.aspetjournals.org/content/44/3/428.abstract
AB The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibits a long terminal half-life (t½) in humans; however, the dispositional mechanisms that lead to this long t½ 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.