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

Disposition and Metabolism of Radiolabeled Casopitant in Humans

Mario Pellegatti, Ellenia Bordini, Patrizia Fizzotti, Andy Roberts and Brendan M. Johnson
Drug Metabolism and Disposition August 2009, 37 (8) 1635-1645; DOI: https://doi.org/10.1124/dmd.109.026781
Mario Pellegatti
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ellenia Bordini
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patrizia Fizzotti
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andy Roberts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brendan M. Johnson
  • 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

Casopitant [1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S)-(GW679769)] is a novel neurokinin-1 receptor antagonist being developed for the prevention of chemotherapy-induced and postoperative nausea and vomiting. The disposition of [14C]casopitant was determined in a single-sequence study in six healthy male subjects after single-dose 90-mg i.v. and 150-mg oral administration. Blood, urine, and feces were collected at frequent intervals after dosing. Plasma, urine, and fecal samples were analyzed by high-performance liquid chromatography/mass spectrometry coupled with off-line radiodetection for metabolite profiling. Moreover, urine was also analyzed with 1H-NMR to further characterize metabolites. Plasma pharmacokinetic parameters for casopitant, a major metabolite (M13, coded as GSK525060), and total radioactivity were determined. Absorption of radioactivity after oral administration appeared to be nearly complete; elimination was principally via the feces both after oral and intravenous administration. Urinary elimination accounted for only <8% of total radioactivity. The main circulating metabolites were a hydroxylated derivative, M13 (coded as GSK525060), and, after oral administration, a deacetylated and oxidized metabolite, M12 (coded as GSK631832). In addition, many other metabolites were identified in plasma and excreta: the principal route of metabolism included multiple oxidations, loss of the N-acetyl group, modifications or loss of the piperazine group, and cleavage of the molecule. Casopitant was extensively metabolized, and only negligible amounts were excreted as unchanged compound. Some phase II metabolites were also observed, particularly in urine.

Footnotes

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

  • doi:10.1124/dmd.109.026781.

  • ABBREVIATIONS: GW679769, 1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S)-; NK-1, neurokinin-1; CINV, chemotherapy-induced nausea and vomiting; HPLC, high-performance liquid chromatography; HPLC-MS/MS, HPLC tandem mass spectrometry; QC, quality control; SPE, solid-phase extraction; AUC, area under the plasma concentration-time curve; Cmax, maximal plasma concentration; tmax, time to reach Cmax; CL, systemic plasma clearance; Vdss, steady-state volume of distribution.

    • Accepted May 4, 2009.
    • Received January 27, 2009.
  • 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: 37 (8)
Drug Metabolism and Disposition
Vol. 37, Issue 8
1 Aug 2009
  • 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.
Disposition and Metabolism of Radiolabeled Casopitant 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

Disposition and Metabolism of Radiolabeled Casopitant in Humans

Mario Pellegatti, Ellenia Bordini, Patrizia Fizzotti, Andy Roberts and Brendan M. Johnson
Drug Metabolism and Disposition August 1, 2009, 37 (8) 1635-1645; DOI: https://doi.org/10.1124/dmd.109.026781

Citation Manager Formats

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

Share
Research ArticleArticle

Disposition and Metabolism of Radiolabeled Casopitant in Humans

Mario Pellegatti, Ellenia Bordini, Patrizia Fizzotti, Andy Roberts and Brendan M. Johnson
Drug Metabolism and Disposition August 1, 2009, 37 (8) 1635-1645; DOI: https://doi.org/10.1124/dmd.109.026781
Reddit logo Twitter logo Facebook 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

  • Olanzapine Glucuronidation in Humanized Mice
  • rs2242480 Regulates the Expression of CYP3A4 and CYP3A5
  • Absorption, Metabolism, and Excretion of Taselisib
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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics