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

Prediction of In Vivo Rat Biliary Drug Clearance from an In Vitro Hepatocyte Efflux Model

Patrik Lundquist, Johan Lööf, Urban Fagerholm, Ingemo Sjögren, Jenny Johansson, Sveinn Briem, Janet Hoogstraate, Lovisa Afzelius and Tommy B. Andersson
Drug Metabolism and Disposition March 2014, 42 (3) 459-468; DOI: https://doi.org/10.1124/dmd.113.054155
Patrik Lundquist
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (P.L., J.L., U.F., I.S., J.J., S.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Johan Lööf
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (P.L., J.L., U.F., I.S., J.J., S.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Urban Fagerholm
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (P.L., J.L., U.F., I.S., J.J., S.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ingemo Sjögren
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (P.L., J.L., U.F., I.S., J.J., S.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jenny Johansson
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (P.L., J.L., U.F., I.S., J.J., S.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sveinn Briem
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (P.L., J.L., U.F., I.S., J.J., S.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Janet Hoogstraate
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (P.L., J.L., U.F., I.S., J.J., S.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lovisa Afzelius
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (P.L., J.L., U.F., I.S., J.J., S.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tommy B. Andersson
CNS and Pain Innovative Medicines DMPK, AstraZeneca R&D, Södertälje (P.L., J.L., U.F., I.S., J.J., S.B., J.H., L.A.); Cardiovascular and Metabolic Diseases Innovative Medicines DMPK, AstraZeneca R&D, Mölndal (P.L., T.B.A.); Department of Pharmacy, Uppsala University, Uppsala (P.L.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (T.B.A.), Sweden
  • 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

Well-established techniques are available to predict in vivo hepatic uptake and metabolism from in vitro data, but predictive models for biliary clearance remain elusive. Several studies have verified the expression and activity of ATP-binding cassette (ABC) efflux transporters central to biliary clearance in freshly isolated rat hepatocytes, raising the possibility of predicting biliary clearance from in vitro efflux measurements. In the present study, short-term plated rat hepatocytes were evaluated as a model to predict biliary clearance from in vitro efflux measurements before major changes in transporter expression known to take place in long-term hepatocyte cultures. The short-term cultures were carefully characterized for their uptake and metabolic properties using a set of model compounds. In vitro efflux was studied using digoxin, fexofenadine, napsagatran, and rosuvastatin, representing compounds with over 100-fold differences in efflux rates in vitro and 60-fold difference in measured in vivo biliary clearance. The predicted biliary clearances from short-term plated rat hepatocytes were within 2-fold of measured in vivo values. As in vitro efflux includes both basolateral and canalicular effluxes, pronounced basolateral efflux may introduce errors in predictions for some compounds. In addition, in vitro rat hepatocyte uptake rates corrected for simultaneous efflux predicted rat in vivo hepatic clearance of the biliary cleared compounds with less than 2-fold error. Short-term plated hepatocytes could thus be used to quantify hepatocyte uptake, metabolism, and efflux of compounds and considerably improve the prediction of hepatic clearance, especially for compounds with a large biliary clearance component.

Footnotes

    • Received August 9, 2013.
    • Accepted January 6, 2014.
  • dx.doi.org/10.1124/dmd.113.054155.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 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: 42 (3)
Drug Metabolism and Disposition
Vol. 42, Issue 3
1 Mar 2014
  • 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.
Prediction of In Vivo Rat Biliary Drug Clearance from an In Vitro Hepatocyte Efflux Model
(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

Prediction of Rat Biliary Clearance

Patrik Lundquist, Johan Lööf, Urban Fagerholm, Ingemo Sjögren, Jenny Johansson, Sveinn Briem, Janet Hoogstraate, Lovisa Afzelius and Tommy B. Andersson
Drug Metabolism and Disposition March 1, 2014, 42 (3) 459-468; DOI: https://doi.org/10.1124/dmd.113.054155

Citation Manager Formats

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

Share
Research ArticleArticle

Prediction of Rat Biliary Clearance

Patrik Lundquist, Johan Lööf, Urban Fagerholm, Ingemo Sjögren, Jenny Johansson, Sveinn Briem, Janet Hoogstraate, Lovisa Afzelius and Tommy B. Andersson
Drug Metabolism and Disposition March 1, 2014, 42 (3) 459-468; DOI: https://doi.org/10.1124/dmd.113.054155
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

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