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

Effect of Experimental Kidney Disease on the Functional Expression of Hepatic Reductases

Osama Y. Alshogran, Judith Naud, Andrew J. Ocque, François A. Leblond, Vincent Pichette and Thomas D. Nolin
Drug Metabolism and Disposition January 2015, 43 (1) 100-106; DOI: https://doi.org/10.1124/dmd.114.061150
Osama Y. Alshogran
Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Judith Naud
Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew J. Ocque
Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
François A. Leblond
Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vincent Pichette
Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas D. Nolin
Center for Clinical Pharmaceutical Sciences (O.Y.A., A.J.O., T.D.N.), Department of Pharmaceutical Sciences (O.Y.A.) and Department of Pharmacy and Therapeutics (T.D.N.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; and Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont (J.N., F.A.L., V.P.), Département de Pharmacologie (V.P.), Université de Montréal, Montréal, Québec, Canada
  • 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

Chronic kidney disease (CKD) affects the nonrenal clearance of drugs by modulating the functional expression of hepatic drug–metabolizing enzymes and transporters. The impact of CKD on oxidative and conjugative metabolism has been extensively studied. However, its effect on hepatic drug reduction, an important phase I drug–metabolism pathway, has not been investigated. We aimed to assess the effect of experimental CKD on hepatic reduction using warfarin as a pharmacological probe substrate. Cytosolic and microsomal cellular fractions were isolated from liver tissue harvested from five-sixths-nephrectomized and control rats (n = 10 per group). The enzyme kinetics for warfarin reduction were evaluated in both fractions, and formation of warfarin alcohols was used as an indicator of hepatic reductase activity. Selective inhibitors were employed to identify reductases involved in warfarin reduction. Gene and protein expression of reductases were determined using quantitative real-time polymerase chain reaction and Western blotting, respectively. Formation of RS/SR-warfarin alcohol was decreased by 39% (P < 0.001) and 43% (P < 0.01) in cytosol and microsomes, respectively, in CKD rats versus controls. However, RR/SS-warfarin alcohol formation was unchanged in the cytosol, and a trend toward its decreased production was observed in microsomes. Gene and protein expression of cytosolic carbonyl reductase 1 and aldo-keto reductase 1C3/18, and microsomal 11β-hydroxysteroid dehydrogenase type 1 were significantly reduced by >30% (P < 0.05) in CKD rats compared with controls. Collectively, these results suggest that the functional expression of hepatic reductases is selectively decreased in kidney disease. Our findings may explain one mechanism for altered nonrenal clearance, exposure, and response of drugs in CKD patients.

Footnotes

    • Received September 17, 2014.
    • Accepted October 20, 2014.
  • This work was supported in part by the La Néphrologie et Son Impact.

  • This study was presented in part at the 2013 Annual Meeting of the American College of Clinical Pharmacology, Bethesda, MD, September 22–24, 2013; and as an abstract: Alshogran O, Ocque A, Zhao J, Day B, Leblond F, Pichette V, Nolin T (2013). Effect of experimental kidney failure on warfarin reduction in rats. Clin Pharmacol Drug Dev 2013; 2(S1):20-21. DOI: 10.1002/cpdd.62 (Abstract # 1707846).

  • dx.doi.org/10.1124/dmd.114.061150.

  • 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: 43 (1)
Drug Metabolism and Disposition
Vol. 43, Issue 1
1 Jan 2015
  • 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.
Effect of Experimental Kidney Disease on the Functional Expression of Hepatic Reductases
(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

Effect of Kidney Disease on Hepatic Reduction in Rats

Osama Y. Alshogran, Judith Naud, Andrew J. Ocque, François A. Leblond, Vincent Pichette and Thomas D. Nolin
Drug Metabolism and Disposition January 1, 2015, 43 (1) 100-106; DOI: https://doi.org/10.1124/dmd.114.061150

Citation Manager Formats

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

Share
Research ArticleArticle

Effect of Kidney Disease on Hepatic Reduction in Rats

Osama Y. Alshogran, Judith Naud, Andrew J. Ocque, François A. Leblond, Vincent Pichette and Thomas D. Nolin
Drug Metabolism and Disposition January 1, 2015, 43 (1) 100-106; DOI: https://doi.org/10.1124/dmd.114.061150
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Improved CYP Reaction Phenotyping
  • Multiple-Concentration Chemical Inhibition Design
  • New Dog P450 3A98 in Gut
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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics