Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • 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
  • 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
    • 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
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Preclinical Evaluation of the Metabolism and Disposition of RRx-001, a Novel Investigative Anticancer Agent

Jan Scicinski, Bryan Oronsky, Michael Taylor, Gang Luo, Timothy Musick, Joseph Marini, Christopher M. Adams and William L. Fitch
Drug Metabolism and Disposition September 2012, 40 (9) 1810-1816; DOI: https://doi.org/10.1124/dmd.112.046755
Jan Scicinski
RadioRx Inc., Mountain View, California (J.S., B.O.); Covance Laboratories Inc., Madison, Wisconsin (G.L., T.M., J.M.); NonClinical Safety Assessment, Mountain View, California (M.T.); and Departments of Anesthesiology (W.L.F.) and Chemistry (C.M.A.), Stanford University, Stanford, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bryan Oronsky
RadioRx Inc., Mountain View, California (J.S., B.O.); Covance Laboratories Inc., Madison, Wisconsin (G.L., T.M., J.M.); NonClinical Safety Assessment, Mountain View, California (M.T.); and Departments of Anesthesiology (W.L.F.) and Chemistry (C.M.A.), Stanford University, Stanford, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael Taylor
RadioRx Inc., Mountain View, California (J.S., B.O.); Covance Laboratories Inc., Madison, Wisconsin (G.L., T.M., J.M.); NonClinical Safety Assessment, Mountain View, California (M.T.); and Departments of Anesthesiology (W.L.F.) and Chemistry (C.M.A.), Stanford University, Stanford, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gang Luo
RadioRx Inc., Mountain View, California (J.S., B.O.); Covance Laboratories Inc., Madison, Wisconsin (G.L., T.M., J.M.); NonClinical Safety Assessment, Mountain View, California (M.T.); and Departments of Anesthesiology (W.L.F.) and Chemistry (C.M.A.), Stanford University, Stanford, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timothy Musick
RadioRx Inc., Mountain View, California (J.S., B.O.); Covance Laboratories Inc., Madison, Wisconsin (G.L., T.M., J.M.); NonClinical Safety Assessment, Mountain View, California (M.T.); and Departments of Anesthesiology (W.L.F.) and Chemistry (C.M.A.), Stanford University, Stanford, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joseph Marini
RadioRx Inc., Mountain View, California (J.S., B.O.); Covance Laboratories Inc., Madison, Wisconsin (G.L., T.M., J.M.); NonClinical Safety Assessment, Mountain View, California (M.T.); and Departments of Anesthesiology (W.L.F.) and Chemistry (C.M.A.), Stanford University, Stanford, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher M. Adams
RadioRx Inc., Mountain View, California (J.S., B.O.); Covance Laboratories Inc., Madison, Wisconsin (G.L., T.M., J.M.); NonClinical Safety Assessment, Mountain View, California (M.T.); and Departments of Anesthesiology (W.L.F.) and Chemistry (C.M.A.), Stanford University, Stanford, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William L. Fitch
RadioRx Inc., Mountain View, California (J.S., B.O.); Covance Laboratories Inc., Madison, Wisconsin (G.L., T.M., J.M.); NonClinical Safety Assessment, Mountain View, California (M.T.); and Departments of Anesthesiology (W.L.F.) and Chemistry (C.M.A.), Stanford University, Stanford, California
  • 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 + SI
  • PDF
Loading

Abstract

RRx-001 has shown promise as a novel cancer therapeutic agent. The disposition of RRx-001 was evaluated in vitro and after intravenous administration to rats. At both 24 and 168 h after a single intravenous administration of 14C-RRx-001 (10 mg/kg), the majority of radiolabel was in the blood. The recovery of label in excreta was quite low, but the major route of radiolabel excretion was via the kidney, with approximately 26% in the urine by the first 8 h and decreasing amounts in all subsequent collections to a total of 36.3% by 168 h. The partitioning of total radioactivity in red blood cells (RBCs) and plasma was determined after in vitro addition to human, rat, dog, and monkey whole blood at 1 and 20 μM. In rat, at 30 min, approximately 75% of the radioactivity is associated with RBCs and 25% with plasma. In human, at 30 min, approximately 25% of the radioactivity is associated with RBCs and 75% with plasma. Analysis by liquid chromatography/radiodetection/mass spectrometry showed that 14C-RRx-001 reacted rapidly with whole blood to give four major soluble metabolites: the GSH and Cys adducts of RRx-001 (M1 and M2) and the corresponding mononitro GSH and Cys adducts (M3 and M4). Human Hb was incubated with cold RRx-001 in buffer, and a standard proteomics protocol was used to separate and identify the tryptic peptides. Standard peptide collision-induced fragment ions supported the structure of the peptide GTFATLSELHCDK with the alkylation on the Cys-93 locus of the Hb β chain.

Footnotes

  • This work was supported by RadioRx.

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

    http://dx.doi.org/10.1124/dmd.112.046755.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    RRx-001
    ethanone, 2-bromo-1-(3,3-dinitro-1-azetidinyl)
    DTT
    dithiothreitol
    LC
    liquid chromatography
    MS
    mass spectrometry
    MS/MS
    tandem mass spectrometry
    NO
    nitric oxide
    QWBA
    quantitative whole-body autoradiography
    RBC
    red blood cell.

  • Received May 14, 2012.
  • Accepted June 14, 2012.
  • Copyright © 2012 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: 40 (9)
Drug Metabolism and Disposition
Vol. 40, Issue 9
1 Sep 2012
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • 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.
Preclinical Evaluation of the Metabolism and Disposition of RRx-001, a Novel Investigative Anticancer Agent
(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 DISPOSITION OF RRx-001

Jan Scicinski, Bryan Oronsky, Michael Taylor, Gang Luo, Timothy Musick, Joseph Marini, Christopher M. Adams and William L. Fitch
Drug Metabolism and Disposition September 1, 2012, 40 (9) 1810-1816; DOI: https://doi.org/10.1124/dmd.112.046755

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 DISPOSITION OF RRx-001

Jan Scicinski, Bryan Oronsky, Michael Taylor, Gang Luo, Timothy Musick, Joseph Marini, Christopher M. Adams and William L. Fitch
Drug Metabolism and Disposition September 1, 2012, 40 (9) 1810-1816; DOI: https://doi.org/10.1124/dmd.112.046755
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Retroconversion of PQ and Its N-Oxide Metabolites
  • Deoxycholate Oxidation Is Predictive of CYP3A Activity
  • REF vs RAF Prediction of Renal 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 © 2021 by the American Society for Pharmacology and Experimental Therapeutics