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Research ArticleArticle

Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice

Georgy Hartmann, Sanjeev Kumar, Douglas Johns, Ferdous Gheyas, David Gutstein, Xiaolan Shen, Aimee Burton, Harmony Lederman, Ryan Lutz, Tonya Jackson, Cynthia Chavez-Eng and Kaushik Mitra
Drug Metabolism and Disposition March 2016, 44 (3) 428-434; DOI: https://doi.org/10.1124/dmd.115.067736
Georgy Hartmann
Merck & Co., Inc., Kenilworth, New Jersey.
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Sanjeev Kumar
Merck & Co., Inc., Kenilworth, New Jersey.
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Douglas Johns
Merck & Co., Inc., Kenilworth, New Jersey.
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Ferdous Gheyas
Merck & Co., Inc., Kenilworth, New Jersey.
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David Gutstein
Merck & Co., Inc., Kenilworth, New Jersey.
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Xiaolan Shen
Merck & Co., Inc., Kenilworth, New Jersey.
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Aimee Burton
Merck & Co., Inc., Kenilworth, New Jersey.
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Harmony Lederman
Merck & Co., Inc., Kenilworth, New Jersey.
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Ryan Lutz
Merck & Co., Inc., Kenilworth, New Jersey.
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Tonya Jackson
Merck & Co., Inc., Kenilworth, New Jersey.
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Cynthia Chavez-Eng
Merck & Co., Inc., Kenilworth, New Jersey.
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Kaushik Mitra
Merck & Co., Inc., Kenilworth, New Jersey.
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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.

Footnotes

    • Received October 8, 2015.
    • Accepted December 23, 2015.
  • ↵1 Current affiliation: Vertex Pharmaceuticals Inc., Boston, MA.

  • Funding for this research was provided by Merck & Co., Inc., Kenilworth, NJ.

  • dx.doi.org/10.1124/dmd.115.067736.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (3)
Drug Metabolism and Disposition
Vol. 44, Issue 3
1 Mar 2016
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Research ArticleArticle

Accumulation and Elimination Kinetics of Anacetrapib

Georgy Hartmann, Sanjeev Kumar, Douglas Johns, Ferdous Gheyas, David Gutstein, Xiaolan Shen, Aimee Burton, Harmony Lederman, Ryan Lutz, Tonya Jackson, Cynthia Chavez-Eng and Kaushik Mitra
Drug Metabolism and Disposition March 1, 2016, 44 (3) 428-434; DOI: https://doi.org/10.1124/dmd.115.067736

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Research ArticleArticle

Accumulation and Elimination Kinetics of Anacetrapib

Georgy Hartmann, Sanjeev Kumar, Douglas Johns, Ferdous Gheyas, David Gutstein, Xiaolan Shen, Aimee Burton, Harmony Lederman, Ryan Lutz, Tonya Jackson, Cynthia Chavez-Eng and Kaushik Mitra
Drug Metabolism and Disposition March 1, 2016, 44 (3) 428-434; DOI: https://doi.org/10.1124/dmd.115.067736
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