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
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
    • 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 In Vivo Hepatic Clearance and Half-Life of Drug Candidates in Human Using Chimeric Mice with Humanized Liver

Seigo Sanoh, Aya Horiguchi, Kazumi Sugihara, Yaichiro Kotake, Yoshitaka Tayama, Hiroki Ohshita, Chise Tateno, Toru Horie, Shigeyuki Kitamura and Shigeru Ohta
Drug Metabolism and Disposition February 2012, 40 (2) 322-328; DOI: https://doi.org/10.1124/dmd.111.040923
Seigo Sanoh
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Aya Horiguchi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kazumi Sugihara
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yaichiro Kotake
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yoshitaka Tayama
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hiroki Ohshita
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chise Tateno
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Toru Horie
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shigeyuki Kitamura
  • 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 + SI
  • PDF
Loading

Abstract

Accurate prediction of pharmacokinetics (PK) parameters in humans from animal data is difficult for various reasons, including species differences. However, chimeric mice with humanized liver (PXB mice; urokinase-type plasminogen activator/severe combined immunodeficiency mice repopulated with approximately 80% human hepatocytes) have been developed. The expression levels and metabolic activities of cytochrome P450 (P450) and non-P450 enzymes in the livers of PXB mice are similar to those in humans. In this study, we examined the predictability for human PK parameters from data obtained in PXB mice. Elimination of selected drugs involves multiple metabolic pathways mediated not only by P450 but also by non-P450 enzymes, such as UDP-glucuronosyltransferase, sulfotransferase, and aldehyde oxidase in liver. Direct comparison between in vitro intrinsic clearance (CLint,in vitro) in PXB mice hepatocytes and in vivo intrinsic clearance (CLint,in vivo) in humans, calculated based on a well stirred model, showed a moderate correlation (r2 = 0.475, p = 0.009). However, when CLint,in vivo values in humans and PXB mice were compared similarly, there was a good correlation (r2 = 0.754, p = 1.174 × 10−4). Elimination half-life (t1/2) after intravenous administration also showed a good correlation (r2 = 0.886, p = 1.506 × 10−4) between humans and PXB mice. The rank order of CL and t1/2 in human could be predicted at least, although it may not be possible to predict absolute values due to rather large prediction errors. Our results indicate that in vitro and in vivo experiments with PXB mice should be useful at least for semiquantitative prediction of the PK characteristics of candidate drugs in humans.

Footnotes

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

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

    doi:http://dx.doi.org/10.1124/dmd.111.040923.

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

  • ABBREVIATIONS:

    PK
    pharmacokinetics
    CL
    clearance
    AO
    aldehyde oxidase
    CLint,in vitro
    in vitro intrinsic clearance
    CLint,in vivo
    in vitro intrinsic clearance
    CLoral
    oral clearance
    CLt
    total clearance
    P450
    cytochrome P450
    DMSO
    dimethyl sulfoxide
    fu
    plasma unbound fraction
    h-hepatocytes
    PXB mice hepatocytes
    LC/MS/MS
    liquid chromatography tandem mass spectrometry
    NAT
    N-acetyltransferase
    PXB mice
    chimeric mice with humanized liver
    Q
    hepatic blood flow
    Rb
    blood/plasma concentration ratio
    RI
    replacement index
    SULT
    sulfotransferase
    t1/2
    half-life
    UGT
    UDP-glucuronosyltransferase
    AUCiv
    area under the concentration versus time curve by intravenous administration.

  • Received August 5, 2011.
  • Accepted November 2, 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 (2)
Drug Metabolism and Disposition
Vol. 40, Issue 2
1 Feb 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 In Vivo Hepatic Clearance and Half-Life of Drug Candidates in Human Using Chimeric Mice with Humanized Liver
(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 PK PARAMETERS USING HUMAN LIVER CHIMERIC MICE

Seigo Sanoh, Aya Horiguchi, Kazumi Sugihara, Yaichiro Kotake, Yoshitaka Tayama, Hiroki Ohshita, Chise Tateno, Toru Horie, Shigeyuki Kitamura and Shigeru Ohta
Drug Metabolism and Disposition February 1, 2012, 40 (2) 322-328; DOI: https://doi.org/10.1124/dmd.111.040923

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 PK PARAMETERS USING HUMAN LIVER CHIMERIC MICE

Seigo Sanoh, Aya Horiguchi, Kazumi Sugihara, Yaichiro Kotake, Yoshitaka Tayama, Hiroki Ohshita, Chise Tateno, Toru Horie, Shigeyuki Kitamura and Shigeru Ohta
Drug Metabolism and Disposition February 1, 2012, 40 (2) 322-328; DOI: https://doi.org/10.1124/dmd.111.040923
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
    • Acknowledgments
    • 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