Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Drug Metabolism & Disposition
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans

Sanjeev Kumar, Eugene Y. Tan, Georgy Hartmann, Zachary Biddle, Arthur J. Bergman, James Dru, Jonathan Z. Ho, Allen N. Jones, Steve J. Staskiewicz, Matthew P. Braun, Bindhu Karanam, Dennis C. Dean, Isaias Noel Gendrano, Mark W. Graves, John A. Wagner and Rajesh Krishna
Drug Metabolism and Disposition March 2010, 38 (3) 474-483; DOI: https://doi.org/10.1124/dmd.109.028704
Sanjeev Kumar
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eugene Y. Tan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Georgy Hartmann
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zachary Biddle
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Arthur J. Bergman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James Dru
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jonathan Z. Ho
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Allen N. Jones
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steve J. Staskiewicz
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew P. Braun
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bindhu Karanam
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dennis C. Dean
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Isaias Noel Gendrano
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark W. Graves
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John A. Wagner
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rajesh Krishna
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

Anacetrapib is a novel cholesteryl ester transfer protein inhibitor being developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The absorption, distribution, metabolism, and excretion of anacetrapib were investigated in an open-label study in which six healthy male subjects received a single oral dose of 150 mg and 165 μCi of [14C]anacetrapib. Plasma, urine, and fecal samples were collected at predetermined times for up to 14 days postdose and were analyzed for total radioactivity, the parent compound, and metabolites. The majority of the administered radioactivity (87%) was eliminated by fecal excretion, with negligible amounts present in urine (0.1%). The peak level of radioactivity in plasma (∼2 μM equivalents of [14C]anacetrapib) was achieved ∼4 h postdose. The parent compound was the major radioactive component (79–94% of total radioactivity) in both plasma and feces. Three oxidative metabolites, M1, M2, and M3, were detected in plasma and feces and were identified as the O-demethylated species (M1) and two secondary hydroxylated derivatives of M1 (M2 and M3). Each metabolite was detected at low levels, representing ≤14% of the radioactivity in plasma or fecal samples. In vitro data indicated that anacetrapib is metabolized mainly by CYP3A4 to form M1, M2, and M3. Overall, these data, along with those from other preclinical and clinical studies, indicate that anacetrapib probably exhibits a low-to-moderate degree of oral absorption in humans and the absorbed fraction of the dose is eliminated largely via CYP3A4-catalyzed oxidative metabolism, followed by excretion of metabolites by the biliary-fecal route.

Footnotes

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

    doi:10.1124/dmd.109.028704.

  • ABBREVIATIONS:

    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
    CETP
    cholesteryl ester transfer protein
    HDL
    high-density lipoprotein
    LDL
    low-density lipoprotein
    MRL
    Merck Research Laboratories
    P450
    cytochrome P450
    LC
    liquid chromatography
    MS
    mass spectrometry
    CID
    collision-induced dissociation
    MS/MS
    tandem mass spectrometry
    TFA
    trifluoroacetic acid
    AUC
    area under plasma concentration versus time curve
    HPLC
    high-performance liquid chromatography.

    • Received June 2, 2009.
    • Accepted December 16, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

 

DMD articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 38 (3)
Drug Metabolism and Disposition
Vol. 38, Issue 3
1 Mar 2010
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Drug Metabolism & Disposition article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans

Sanjeev Kumar, Eugene Y. Tan, Georgy Hartmann, Zachary Biddle, Arthur J. Bergman, James Dru, Jonathan Z. Ho, Allen N. Jones, Steve J. Staskiewicz, Matthew P. Braun, Bindhu Karanam, Dennis C. Dean, Isaias Noel Gendrano, Mark W. Graves, John A. Wagner and Rajesh Krishna
Drug Metabolism and Disposition March 1, 2010, 38 (3) 474-483; DOI: https://doi.org/10.1124/dmd.109.028704

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans

Sanjeev Kumar, Eugene Y. Tan, Georgy Hartmann, Zachary Biddle, Arthur J. Bergman, James Dru, Jonathan Z. Ho, Allen N. Jones, Steve J. Staskiewicz, Matthew P. Braun, Bindhu Karanam, Dennis C. Dean, Isaias Noel Gendrano, Mark W. Graves, John A. Wagner and Rajesh Krishna
Drug Metabolism and Disposition March 1, 2010, 38 (3) 474-483; DOI: https://doi.org/10.1124/dmd.109.028704
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments.
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Determination of Acyl-, O-, and N-Glucuronide
  • TMDD Affects PK of IL-10 Fc-fusion Proteins
  • Uptake as the RDS in Pevonedistat Hepatic Clearance
Show more Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About DMD
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

Copyright © 2022 by the American Society for Pharmacology and Experimental Therapeutics