Skip to main content
  • AACR Publications
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

  • Register
  • Log in
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
  • AACR Publications
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in

Search

  • Advanced search
Cancer Research
Cancer Research

Advanced Search

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
Experimental and Molecular Therapeutics 18: Pharmacogenomics, Preclinical Toxicology, Pharmacokinetics

Toxicity of single-dose oral gemcitibine in mice.

Noel D. Horton, Jamie K. Young, Everett J. Perkins and Lewis L. Truex
Noel D. Horton
Eli Lilly and Company, Greenfield, IN and Eli Lilly and Company, Indianapolis, IN.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jamie K. Young
Eli Lilly and Company, Greenfield, IN and Eli Lilly and Company, Indianapolis, IN.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Everett J. Perkins
Eli Lilly and Company, Greenfield, IN and Eli Lilly and Company, Indianapolis, IN.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lewis L. Truex
Eli Lilly and Company, Greenfield, IN and Eli Lilly and Company, Indianapolis, IN.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI:  Published April 2004
  • Article
  • Info & Metrics
Loading
Proc Amer Assoc Cancer Res, Volume 45, 2004

Abstract

2115

The present study was conducted to determine the single-dose toxicity and toxicokinetics of gemcitabine when administered orally to mice. Gemcitabine hydrochloride, an intravenously administered chemotherapeutic antimetabolite, is a potent and specific oncolytic used for the treatment of cancer. The antiproliferative mechanism of the drug involves inhibition of DNA replication and repair by inhibiting DNA synthesis and by blocking repair mechanisms through masked chain termination. CD-1 mice (10/sex/group) were given a single oral (gavage) gemcitabine dose of 167, 333, or 500 mg/kg, and mice were euthanized 4 or 14 days postdose to determine the acute cytotoxic effects and the reversibility of compound-related effects, respectively. Data from this study were compared to data from previously conducted toxicology studies. Orally administered gemcitabine was rapidly absorbed with a time-to-peak plasma concentration of approximately 0.5 to 1.0 hours. Consistent with IV administration, metabolism of gemcitabine to difluorodeoxyuridine (dFdU) after a single-oral dose was extensive, with high plasma concentrations of dFdU relative to gemcitabine. There were no consistent gender-related differences in gemcitabine toxicokinetics. Exposure (area under the concentration vs. time curve) and maximum plasma concentration values for both gemcitabine and dFdU were not dose proportional in the dose range examined. Compound-related deaths in mice given 333 or 500 mg/kg occurred 3 to 5 days after dosing. The mortality seen in this study was attributed to adverse intestinal lesions characterized by moderate-to-marked loss of mucosal epithelium (atrophic enteropathy) throughout the entire length of the intestinal tract. Comparable exposures via IV dosing in previous mouse studies did not result in death or gastrointestinal toxicity. The enteropathy was dose-responsive in incidence and severity, but with marked variation among individual mice within compound-treated groups. In some mice that were euthanized and necropsied 4 days postdose, the intestinal changes were characterized by mucosal epithelial regeneration resulting in a normal mucosal thickness. Due to the severity of the intestinal lesions, suspected acute time of onset, and marked variation among individual mice within dose groups, it is likely that local effects due to the route of administration were important for development of the enteropathy. The systemic toxicities observed in this study were typical of those seen at these exposure levels. In summary, a single-oral dose of gemcitabine at 167, 333, or 500 mg/kg caused dose-responsive adverse intestinal lesions at exposures that were previously tolerated when the compound was adminstered IV. Toxicokinetics and systemic toxicity were consistent with data from earlier IV mouse studies.

  • American Association for Cancer Research
Previous
Back to top
April 2004
Volume 64, Issue 7 Supplement
  • Table of Contents
  • Index by Author

Sign up for alerts

Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Research 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.
Toxicity of single-dose oral gemcitibine in mice.
(Your Name) has forwarded a page to you from Cancer Research
(Your Name) thought you would be interested in this article in Cancer Research.
Citation Tools
Toxicity of single-dose oral gemcitibine in mice.
Noel D. Horton, Jamie K. Young, Everett J. Perkins and Lewis L. Truex
Cancer Res April 1 2004 (64) (7 Supplement) 486-487;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Toxicity of single-dose oral gemcitibine in mice.
Noel D. Horton, Jamie K. Young, Everett J. Perkins and Lewis L. Truex
Cancer Res April 1 2004 (64) (7 Supplement) 486-487;
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
  • Info & Metrics
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • The stability of PX-478 in human blood and plasma.
  • In vitro metabolism and interaction studies with celecoxib and lovastatin.
  • Evaluation of in vitro hematotoxicity of c-1311, mitoxantrone and oxaliplatin to FU-GM committed neutrophil-monocyte progenitors from human and rat.
Show more Experimental and Molecular Therapeutics 18: Pharmacogenomics, Preclinical Toxicology, Pharmacokinetics
  • Home
  • Alerts
  • Feedback
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians
  • Reviewers

About Cancer Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2018 by the American Association for Cancer Research.

Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
American Journal of Cancer ISSN: 0099-7374

Advertisement