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Research ArticleArticle

Pharmacokinetics, Metabolism, and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Rats and Rhesus Monkeys

Eugene Y. Tan, Georgy Hartmann, Qing Chen, Antonio Pereira, Scott Bradley, George Doss, Andy Shiqiang Zhang, Jonathan Z. Ho, Matthew P. Braun, Dennis C. Dean, Wei Tang and Sanjeev Kumar
Drug Metabolism and Disposition March 2010, 38 (3) 459-473; DOI: https://doi.org/10.1124/dmd.109.028696
Eugene Y. Tan
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Georgy Hartmann
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Qing Chen
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Antonio Pereira
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Scott Bradley
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George Doss
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Andy Shiqiang Zhang
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Jonathan Z. Ho
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Matthew P. Braun
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Dennis C. Dean
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Wei Tang
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Sanjeev Kumar
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Abstract

The pharmacokinetics and metabolism of anacetrapib (MK-0859), a novel cholesteryl ester transfer protein inhibitor, were examined in rats and rhesus monkeys. Anacetrapib exhibited a low clearance in both species and a moderate oral bioavailability of ∼38% in rats and ∼13% in monkeys. The area under the plasma concentration-time curve in both species increased in a less than dose-proportional manner over an oral dose range of 1 to 500 mg/kg. After oral administration of [14C]anacetrapib at 10 mg/kg, ∼80 and 90% of the radioactive dose was recovered over 48 h postdose from rats and monkeys, respectively. The majority of the administered radioactive dose was excreted unchanged in feces in both species. Biliary excretion of radioactivity accounted for ∼15% and urinary excretion for less than 2% of the dose. Thirteen metabolites, resulting from oxidative and secondary glucuronic acid conjugation, were identified in rat and monkey bile. The main metabolic pathways consisted of O-demethylation (M1) and hydroxylation on the biphenyl moiety (M2) and hydroxylation on the isopropyl side chain (M3); these hydroxylations were followed by O-glucuronidation of these metabolites. A glutathione adduct (M9), an olefin metabolite (M10), and a propionic acid metabolite (M11) also were identified. In addition to parent anacetrapib, M1, M2, and M3 metabolites were detected in rat but not in monkey plasma. Overall, it appears that anacetrapib exhibits a low-to-moderate degree of absorption after oral dosing and majority of the absorbed dose is eliminated via oxidation to a series of hydroxylated metabolites that undergo conjugation with glucuronic acid before excretion into bile.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.109.028696.

  • ABBREVIATIONS:

    LDL
    low-density lipoprotein
    HDL
    high-density lipoprotein
    CETP
    cholesteryl ester transfer protein
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    HPLC
    high-performance liquid chromatography
    MRL
    Merck Research Laboratories
    AUC
    area under the plasma concentration versus time curve
    MS
    mass spectrometry
    CID
    collision-induced dissociation
    amu
    atomic mass units
    MK-0859
    [4S,5R]-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-methoxy-5′-(propan-2-yl)-4-(trifluoromethyl)[1,1′-biphenyl]-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.

    • Received June 1, 2009.
    • Accepted December 16, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (3)
Drug Metabolism and Disposition
Vol. 38, Issue 3
1 Mar 2010
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Research ArticleArticle

Pharmacokinetics, Metabolism, and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Rats and Rhesus Monkeys

Eugene Y. Tan, Georgy Hartmann, Qing Chen, Antonio Pereira, Scott Bradley, George Doss, Andy Shiqiang Zhang, Jonathan Z. Ho, Matthew P. Braun, Dennis C. Dean, Wei Tang and Sanjeev Kumar
Drug Metabolism and Disposition March 1, 2010, 38 (3) 459-473; DOI: https://doi.org/10.1124/dmd.109.028696

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Research ArticleArticle

Pharmacokinetics, Metabolism, and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Rats and Rhesus Monkeys

Eugene Y. Tan, Georgy Hartmann, Qing Chen, Antonio Pereira, Scott Bradley, George Doss, Andy Shiqiang Zhang, Jonathan Z. Ho, Matthew P. Braun, Dennis C. Dean, Wei Tang and Sanjeev Kumar
Drug Metabolism and Disposition March 1, 2010, 38 (3) 459-473; DOI: https://doi.org/10.1124/dmd.109.028696
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