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
  • Log out
  • 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
  • Log out
  • 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

Prediction of the Overall Renal Tubular Secretion and Hepatic Clearance of Anionic Drugs and a Renal Drug-Drug Interaction Involving Organic Anion Transporter 3 in Humans by In Vitro Uptake Experiments

Takao Watanabe, Hiroyuki Kusuhara, Tomoko Watanabe, Yasuyuki Debori, Kazuya Maeda, Tsunenori Kondo, Hideki Nakayama, Shigeru Horita, Brian W. Ogilvie, Andrew Parkinson, Zhuohan Hu and Yuichi Sugiyama
Drug Metabolism and Disposition June 2011, 39 (6) 1031-1038; DOI: https://doi.org/10.1124/dmd.110.036129
Takao Watanabe
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hiroyuki Kusuhara
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tomoko Watanabe
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yasuyuki Debori
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kazuya Maeda
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tsunenori Kondo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hideki Nakayama
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shigeru Horita
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brian W. Ogilvie
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew Parkinson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zhuohan Hu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuichi Sugiyama
  • 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

The present study investigated prediction of the overall renal tubular secretion and hepatic clearances of anionic drugs based on in vitro transport studies. The saturable uptake of eight drugs, most of which were OAT3 substrates (rosuvastatin, pravastatin, pitavastatin, valsartan, olmesartan, trichlormethiazide, p-aminohippurate, and benzylpenicillin) by freshly prepared human kidney slices underestimated the overall intrinsic clearance of the tubular secretion; therefore, a scaling factor of 10 was required for in vitro-in vivo extrapolation. We examined the effect of gemfibrozil and its metabolites, gemfibrozil glucuronide and the carboxylic metabolite, gemfibrozil M3, on pravastatin uptake by human kidney slices. The inhibition study using human kidney slices suggests that OAT3 plays a predominant role in the renal uptake of pravastatin. Comparison of unbound concentrations and Ki values (1.5, 9.1, and 4.0 μM, for gemfibrozil, gemfibrozil glucuronide, and gemfibrozil M3, respectively) suggests that the mechanism of the interaction is due mainly to inhibition by gemfibrozil and gemfibrozil glucuronide. Furthermore, extrapolation of saturable uptake by cryopreserved human hepatocytes predicts clearance comparable with the observed hepatic clearance although fluvastatin and rosuvastatin required a scaling factor of 11 and 6.9, respectively. This study suggests that in vitro uptake assays using human kidney slices and hepatocytes provide a good prediction of the overall tubular secretion and hepatic clearances of anionic drugs and renal drug-drug interactions. It is also recommended that in vitro-in vivo extrapolation be performed in animals to obtain more reliable prediction.

Footnotes

  • This study was supported in part by a Grant-in-Aid for Scientific Research (A) [Grant 20249008] (to Y.S.); and Mandom International Research Grants for Alternatives to Animal Experiments (to H.K.).

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

    doi:10.1124/dmd.110.036129.

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

  • ABBREVIATIONS:

    OAT
    organic anion transporter
    DDI
    drug-drug interaction
    PAH
    p-aminohippurate
    LC
    liquid chromatography
    MS
    mass spectrometry
    IVIVE
    in vitro-in vivo extrapolation.

  • Received August 28, 2010.
  • Accepted February 23, 2011.
  • Copyright © 2011 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: 39 (6)
Drug Metabolism and Disposition
Vol. 39, Issue 6
1 Jun 2011
  • 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.
Prediction of the Overall Renal Tubular Secretion and Hepatic Clearance of Anionic Drugs and a Renal Drug-Drug Interaction Involving Organic Anion Transporter 3 in Humans by In Vitro Uptake Experiments
(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 the Overall Renal Tubular Secretion and Hepatic Clearance of Anionic Drugs and a Renal Drug-Drug Interaction Involving Organic Anion Transporter 3 in Humans by In Vitro Uptake Experiments

Takao Watanabe, Hiroyuki Kusuhara, Tomoko Watanabe, Yasuyuki Debori, Kazuya Maeda, Tsunenori Kondo, Hideki Nakayama, Shigeru Horita, Brian W. Ogilvie, Andrew Parkinson, Zhuohan Hu and Yuichi Sugiyama
Drug Metabolism and Disposition June 1, 2011, 39 (6) 1031-1038; DOI: https://doi.org/10.1124/dmd.110.036129

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 the Overall Renal Tubular Secretion and Hepatic Clearance of Anionic Drugs and a Renal Drug-Drug Interaction Involving Organic Anion Transporter 3 in Humans by In Vitro Uptake Experiments

Takao Watanabe, Hiroyuki Kusuhara, Tomoko Watanabe, Yasuyuki Debori, Kazuya Maeda, Tsunenori Kondo, Hideki Nakayama, Shigeru Horita, Brian W. Ogilvie, Andrew Parkinson, Zhuohan Hu and Yuichi Sugiyama
Drug Metabolism and Disposition June 1, 2011, 39 (6) 1031-1038; DOI: https://doi.org/10.1124/dmd.110.036129
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
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • In Vivo Functional Effects of CYP2C9 M1L
  • Clearance pathways: fevipiprant with probenecid perpetrator
  • Predicting Volume of Distribution from In Vitro Parameters
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