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 Human Metabolism of FK3453 by Aldehyde Oxidase Using Chimeric Mice Transplanted with Human or Rat Hepatocytes

Seigo Sanoh, Kazuyoshi Nozaki, Hidetsugu Murai, Shigeyuki Terashita, Toshio Teramura and Shigeru Ohta
Drug Metabolism and Disposition January 2012, 40 (1) 76-82; DOI: https://doi.org/10.1124/dmd.111.041954
Seigo Sanoh
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kazuyoshi Nozaki
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hidetsugu Murai
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shigeyuki Terashita
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Toshio Teramura
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shigeru Ohta
  • 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

During drug development, it is important to predict the activities of multiple metabolic enzymes, not only cytochrome P450 (P450) but also non-P450 enzymes, such as conjugative enzymes and aldehyde oxidase (AO). In this study, we focused on prediction of AO-mediated human metabolism and pharmacokinetics (PK) of 6-(2-amino-4-phenylpyrimidine-5-yl)-2-isopropylpyridazin-3(2H)-one (FK3453) (Astellas Pharma Inc.), the development of which was suspended due to extremely low exposure in human, despite good oral bioavailability in rat and dog. We examined species difference in oxidative metabolism of the aminopyrimidine moiety of FK3453, catalyzed by AO, using human-chimeric mice with humanized liver (h-PXB mice) and rat-chimeric mice (r-PXB mice) transplanted with rat hepatocytes. AO activity of h-PXB mouse hepatocytes was higher than that of r-PXB mouse hepatocytes. Moreover, higher concentrations of human-specific AO-generated FK3453 metabolite A-M were detected in urine and feces after administration of FK3453 to h-PXB mice versus r-PXB mice. The total clearance of h-PXB mice was 2-fold higher than that of r-PXB mice. These results agreed reasonably well with the metabolism and PK profiles of FK3453 in human and rat. Our results indicated that h-PXB mice should be helpful for predicting the metabolic profile of drugs in humans, and the use of both h-PXB and r-PXB mice should be helpful for evaluation of species differences of AO metabolic activity.

Footnotes

  • This work was supported by a Grant-in-Aid for Young Scientists (B) from Japan Society for the Promotion of Science [Grant 22790109].

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

    http://dx.doi.org/10.1124/dmd.111.041954.

  • ABBREVIATIONS:

    PK
    pharmacokinetics
    UGT
    UDP-glucuronosyltransferase
    P450
    cytochrome P450
    AO
    aldehyde oxidase
    FK3453
    6-(2-amino-4-phenylpyrimidine-5-yl)-2-isopropylpyridazin-3(2H)-one
    A-M
    AO-generated metabolite
    SCID
    severe combined immunodeficiency
    h-PXB mice
    chimeric mice with humanized liver
    r-PXB mice
    chimeric mice transplanted with rat hepatocytes
    SD
    Sprague-Dawley
    RI
    replacement index
    h-hepatocytes
    h-PXB mice hepatocytes
    r-hepatocytes
    r-PXB mice hepatocytes
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    PEG400
    polyethylene glycol 400
    HPLC
    high-performance liquid chromatography
    Cmax
    the maximum plasma concentration
    tmax
    the time at which Cmax was achieved
    AUC
    the area under the plasma concentration-time curve
    CLt
    total clearance
    i.v.
    intravenous administration
    CLoral
    oral clearance
    p.o.
    oral administration
    t1/2
    half-life
    F
    the oral bioavailability
    CLint, in vitro
    in vitro intrinsic clearance
    SGX523
    6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinoline
    RO1
    6-(2,4-difluoro-phenoxy)-2-((R)-2-hydroxy-1-methyl-ethylamino)-8-((S)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one.

  • Received August 5, 2011.
  • Accepted October 7, 2011.
  • Copyright © 2012 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: 40 (1)
Drug Metabolism and Disposition
Vol. 40, Issue 1
1 Jan 2012
  • 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 Human Metabolism of FK3453 by Aldehyde Oxidase Using Chimeric Mice Transplanted with Human or Rat Hepatocytes
(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

METABOLISM BY ALDEHYDE OXIDASE IN HUMAN LIVER CHIMERIC MICE

Seigo Sanoh, Kazuyoshi Nozaki, Hidetsugu Murai, Shigeyuki Terashita, Toshio Teramura and Shigeru Ohta
Drug Metabolism and Disposition January 1, 2012, 40 (1) 76-82; DOI: https://doi.org/10.1124/dmd.111.041954

Citation Manager Formats

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

Share
Research ArticleArticle

METABOLISM BY ALDEHYDE OXIDASE IN HUMAN LIVER CHIMERIC MICE

Seigo Sanoh, Kazuyoshi Nozaki, Hidetsugu Murai, Shigeyuki Terashita, Toshio Teramura and Shigeru Ohta
Drug Metabolism and Disposition January 1, 2012, 40 (1) 76-82; DOI: https://doi.org/10.1124/dmd.111.041954
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
    • Results
    • Discussion
    • Authorship Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Oral PBPK Modeling of Vismodegib
  • Transporter-enzyme interplay in PK of PF-06835919
  • PBPK Model of Vit D3 and Metabolites
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