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

Role of P-Glycoprotein and the Intestine in the Excretion of DPC 333 [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] in Rodents

C. Edwin Garner, Eric Solon, Chii-Ming Lai, Jianrong Lin, Gang Luo, Kevin Jones, Jingwu Duan, Carl P. Decicco, Thomas Maduskuie, Stephen E. Mercer, Lian-Shen Gan, Mingxin Qian, Shimoga Prakash, Huey-Shin Shen and Frank W. Lee
Drug Metabolism and Disposition June 2008, 36 (6) 1102-1110; DOI: https://doi.org/10.1124/dmd.107.017038
C. Edwin Garner
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eric Solon
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chii-Ming Lai
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jianrong Lin
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gang Luo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevin Jones
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jingwu Duan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carl P. Decicco
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas Maduskuie
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen E. Mercer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lian-Shen Gan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mingxin Qian
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shimoga Prakash
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Huey-Shin Shen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frank W. Lee
  • 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

The role of the intestine in the elimination of (2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide (DPC 333), a potent inhibitor of tissue necrosis factor α–converting enzyme, was investigated in mice and rats in vivo and in vitro. In Madine-Darby canine kidney cells stably transfected with P-glycoprotein (P-gp) and DPC 333, the transport from B→A reservoirs exceeded the transport from A→B by approximately 7-fold. In Caco-2 monolayers and isolated rat ileal mucosa, DPC 333 was transported from basolateral to apical reservoirs in a concentration-dependent, saturable manner, and transport was blocked by N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), confirming the contribution of P-gp/breast cancer resistance protein in B→A efflux of DPC 333. In quantitative whole body autoradiography studies with [14C]DPC 333 in mice and rats, radioactivity was distributed throughout the small intestine in both species. In GF120918-pretreated bile duct–cannulated rats, radioactivity in feces was reduced 60%. Using the in situ perfused rat intestine model, ∼20% of an i.v. dose of [14C]DPC 333 was measured in the intestinal lumen within 3 h postdose, 12% as parent. Kinetic analysis of data suggested that excreted DPC 333 may be further metabolized in the gut. Intestinal clearance was 0.2 to 0.35 l/h/kg. The above data suggest that in the rodent the intestine serves as an organ of DPC 333 excretion, mediated in part by the transporter P-gp.

Footnotes

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

  • doi:10.1124/dmd.107.017038.

  • ABBREVIATIONS: P-gp, P-glycoprotein; MDR, multidrug resistance; BCRP, breast cancer resistance protein; GF120918, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; DPC 333, (2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide; TEER, transepithelial electronical resistance; MDCK, Madine-Darby canine kidney; HPLC, high-performance liquid chromatography; QWBA, quantitative whole body autoradiography; IP, imaging plate; GI, gastrointestinal.

    • Received July 6, 2007.
    • Accepted March 13, 2008.
  • 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: 36 (6)
Drug Metabolism and Disposition
Vol. 36, Issue 6
1 Jun 2008
  • 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.
Role of P-Glycoprotein and the Intestine in the Excretion of DPC 333 [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] in Rodents
(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

Role of P-Glycoprotein and the Intestine in the Excretion of DPC 333 [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] in Rodents

C. Edwin Garner, Eric Solon, Chii-Ming Lai, Jianrong Lin, Gang Luo, Kevin Jones, Jingwu Duan, Carl P. Decicco, Thomas Maduskuie, Stephen E. Mercer, Lian-Shen Gan, Mingxin Qian, Shimoga Prakash, Huey-Shin Shen and Frank W. Lee
Drug Metabolism and Disposition June 1, 2008, 36 (6) 1102-1110; DOI: https://doi.org/10.1124/dmd.107.017038

Citation Manager Formats

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

Role of P-Glycoprotein and the Intestine in the Excretion of DPC 333 [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] in Rodents

C. Edwin Garner, Eric Solon, Chii-Ming Lai, Jianrong Lin, Gang Luo, Kevin Jones, Jingwu Duan, Carl P. Decicco, Thomas Maduskuie, Stephen E. Mercer, Lian-Shen Gan, Mingxin Qian, Shimoga Prakash, Huey-Shin Shen and Frank W. Lee
Drug Metabolism and Disposition June 1, 2008, 36 (6) 1102-1110; DOI: https://doi.org/10.1124/dmd.107.017038
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
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Candesartan glucuronide serves as a CYP2C8 inhibitor
  • Role of AADAC on eslicarbazepine acetate hydrolysis
  • Gene expression profile of human intestinal epithelial cells
Show more Articles

Similar Articles

  • 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