title: Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice.
abstract: 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.
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey. georgy_hartmann@merck.com.
authors.forename: Georgy
authors.initials: G
authors.lastname: Hartmann
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Douglas
authors.initials: D
authors.lastname: Johns
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Ferdous
authors.initials: F
authors.lastname: Gheyas
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: David
authors.initials: D
authors.lastname: Gutstein
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Shen
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Aimee
authors.initials: A
authors.lastname: Burton
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Harmony
authors.initials: H
authors.lastname: Lederman
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Ryan
authors.initials: R
authors.lastname: Lutz
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Tonya
authors.initials: T
authors.lastname: Jackson
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Chavez-Eng
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Mitra
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004032:Diet; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D023303:Oxazolidinones / Q000378:metabolism*
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D023303:Oxazolidinones; C530884:anacetrapib