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
Journal of Pharmacology and Experimental Therapeutics
  • 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
Journal of Pharmacology and Experimental Therapeutics

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 jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Hepatobiliary Disposition of Troglitazone and Metabolites in Rat and Human Sandwich-Cultured Hepatocytes: Use of Monte Carlo Simulations to Assess the Impact of Changes in Biliary Excretion on Troglitazone Sulfate Accumulation

Jin Kyung Lee, Tracy L. Marion, Koji Abe, Changwon Lim, Gary M. Pollock and Kim L. R. Brouwer
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 26-34; DOI: https://doi.org/10.1124/jpet.109.156653
Jin Kyung Lee
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tracy L. Marion
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Koji Abe
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Changwon Lim
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gary M. Pollock
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kim L. R. Brouwer
  • 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

This study examined the hepatobiliary disposition of troglitazone (TGZ) and metabolites [TGZ sulfate (TS), TGZ glucuronide (TG), and TGZ quinone (TQ)] over time in rat and human sandwich-cultured hepatocytes (SCH). Cells were incubated with TGZ; samples were analyzed for TGZ and metabolites by liquid chromatography-tandem mass spectrometry. SCH mimicked the disposition of TGZ/metabolites in vivo in rats and humans; TGZ was metabolized primarily to TS and to a lesser extent to TG and TQ. In human SCH, the biliary excretion index (BEI) was negligible for TGZ and TQ, ∼16% for TS, and ∼43% for TG over the incubation period; in rat SCH, the BEI for TS and TG was ∼13 and ∼41%, respectively. Hepatocyte accumulation of TS was extensive, with intracellular concentrations ranging from 132 to 222 μM in rat SCH; intracellular TGZ concentrations ranged from 7.22 to 47.7 μM. In human SCH, intracellular TS and TGZ concentrations ranged from 136 to 160 μM and from 49.4 to 84.7 μM, respectively. Pharmacokinetic modeling and Monte Carlo simulations were used to evaluate the impact of modulating the biliary excretion rate constant (Kbile) for TS on TS accumulation in hepatocytes and medium. Simulations demonstrated that intracellular concentrations of TS may increase up to 3.1- and 5.7-fold when biliary excretion of TS was decreased 2- and 10-fold, respectively. It is important to note that altered hepatobiliary transport and the extent of hepatocyte exposure may not always be evident based on medium concentrations (analogous to systemic exposure in vivo). Pharmacokinetic modeling/simulation with data from SCH is a useful approach to examine the impact of altered hepatobiliary transport on hepatocyte accumulation of drug/metabolites.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant GM41935] (to K.L.R.B); and the National Institutes of Health National Institute of Environmental Health Sciences [Grant T32-ES007126] (to T.L.M.).

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

    doi:10.1124/jpet.109.156653

  • ABBREVIATIONS:

    TGZ
    troglitazone
    BSEP/Bsep
    bile salt export pump
    TS
    troglitazone sulfate
    AUCss
    area under the plasma concentration versus time curve at steady state
    AUC
    area under the plasma concentration versus time curve
    SCH
    sandwich-cultured hepatocyte(s)
    DEX
    dexamethasone
    HBSS
    Hanks' balanced salts solution
    MEM
    minimal essential medium
    DMEM
    Dulbecco's modified Eagle's medium
    TG
    troglitazone glucuronide
    TQ
    troglitazone quinone
    BEI
    biliary excretion index
    M
    medium
    C
    hepatocytes
    B
    bile.

    • Received May 25, 2009.
    • Accepted October 1, 2009.
  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET 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

Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 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 Journal of Pharmacology and Experimental Therapeutics 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.
Hepatobiliary Disposition of Troglitazone and Metabolites in Rat and Human Sandwich-Cultured Hepatocytes: Use of Monte Carlo Simulations to Assess the Impact of Changes in Biliary Excretion on Troglitazone Sulfate Accumulation
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Hepatobiliary Disposition of Troglitazone and Metabolites in Rat and Human Sandwich-Cultured Hepatocytes: Use of Monte Carlo Simulations to Assess the Impact of Changes in Biliary Excretion on Troglitazone Sulfate Accumulation

Jin Kyung Lee, Tracy L. Marion, Koji Abe, Changwon Lim, Gary M. Pollock and Kim L. R. Brouwer
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 26-34; DOI: https://doi.org/10.1124/jpet.109.156653

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Hepatobiliary Disposition of Troglitazone and Metabolites in Rat and Human Sandwich-Cultured Hepatocytes: Use of Monte Carlo Simulations to Assess the Impact of Changes in Biliary Excretion on Troglitazone Sulfate Accumulation

Jin Kyung Lee, Tracy L. Marion, Koji Abe, Changwon Lim, Gary M. Pollock and Kim L. R. Brouwer
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 26-34; DOI: https://doi.org/10.1124/jpet.109.156653
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

  • HDL Mimetic 4F Modulates Aβ Distribution in Brain and Plasma
  • AOX1 Inhibition by Gefitinib, Erlotinib, and Metabolites
  • Catalytic Activity of CYP2C9 Variants
Show more Metabolism, Transport, and Pharmacogenomics

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

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics