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

THE CHIMPANZEE (PAN TROGLODYTES) AS A PHARMACOKINETIC MODEL FOR SELECTION OF DRUG CANDIDATES: MODEL CHARACTERIZATION AND APPLICATION

Harvey Wong, Scott J. Grossman, Stephen A. Bai, Sharon Diamond, Matthew R. Wright, James E. Grace Jr., Mingxin Qian, Kan He, Krishnaswamy Yeleswaram and David D. Christ
Drug Metabolism and Disposition December 2004, 32 (12) 1359-1369; DOI: https://doi.org/10.1124/dmd.104.000943
Harvey Wong
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Scott J. Grossman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen A. Bai
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sharon Diamond
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew R. Wright
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James E. Grace Jr.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mingxin Qian
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kan He
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Krishnaswamy Yeleswaram
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David D. Christ
  • 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

The chimpanzee (CHP) was evaluated as a pharmacokinetic model for humans (HUMs) using propranolol, verapamil, theophylline, and 12 proprietary compounds. Species differences were observed in the systemic clearance of theophylline (∼5-fold higher in CHPs), a low clearance compound, and the bioavailability of propranolol and verapamil (lower in CHPs), both high clearance compounds. The systemic clearance of propranolol (∼1.53 l/h/kg) suggested that the hepatic blood flow in CHPs is comparable to that in humans. No substantial differences were observed in the in vitro protein binding. A preliminary attempt was made to characterize cytochrome P450 (P450) activities in CHP and HUM liver microsomes. Testosterone 6β-hydroxylation and tolbutamide methylhydroxylation activities were comparable in CHP and HUM liver microsomes. In contrast, dextromethorphan O-demethylation and phenacetin O-deethylation activities were ∼10-fold higher (per mg protein) in CHP liver microsomes. Intrinsic clearance estimates in CHP liver microsomes were higher for propranolol (∼10-fold) and theophylline (∼5-fold) and similar for verapamil. Of the 12 proprietary compounds, 3 had oral clearances that differed in the two species by more than 3-fold, an acceptable range for biological variability. Most of the observed differences are consistent with species differences in P450 enzyme activity. Oral clearances of proprietary compounds in HUMs were significantly correlated to those from CHPs (r = 0.68; p = 0.015), but not to estimates from rat, dog, and monkey. In summary, the chimpanzee serves as a valuable surrogate model for human pharmacokinetics, especially when species differences in P450 enzyme activity are considered.

Footnotes

  • ↵1 Current address: Incyte Corporation, Newark, DE.

  • ↵2 Current address: Gilead, Foster City, CA.

  • ↵3 Current address: Adolor Corporation, Exton, PA.

  • doi:10.1124/dmd.104.000943.

  • ABBREVIATIONS: P450, cytochrome P450; AUC, area under the plasma concentration-time profile; CLint microsomal, microsomal intrinsic clearance; CLs, systemic clearance; CLs in vitro, predicted systemic clearance based upon microsome data; CLs/F, oral clearance; Cmax, maximum observed concentration achieved after oral dosing; F, bioavailability; Fin vitro, predicted bioavailability based upon microsome data; t1/2, half-life; Vdss, steady-state volume of distribution; HPLC, high-performance liquid chromatography; LC/MS/MS, liquid chromatography-tandem mass spectrometry.

    • Received June 10, 2004.
    • Accepted August 26, 2004.
  • 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: 32 (12)
Drug Metabolism and Disposition
Vol. 32, Issue 12
1 Dec 2004
  • Table of Contents
  • About the Cover
  • Index by author
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.
THE CHIMPANZEE (PAN TROGLODYTES) AS A PHARMACOKINETIC MODEL FOR SELECTION OF DRUG CANDIDATES: MODEL CHARACTERIZATION AND APPLICATION
(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

THE CHIMPANZEE (PAN TROGLODYTES) AS A PHARMACOKINETIC MODEL FOR SELECTION OF DRUG CANDIDATES: MODEL CHARACTERIZATION AND APPLICATION

Harvey Wong, Scott J. Grossman, Stephen A. Bai, Sharon Diamond, Matthew R. Wright, James E. Grace, Mingxin Qian, Kan He, Krishnaswamy Yeleswaram and David D. Christ
Drug Metabolism and Disposition December 1, 2004, 32 (12) 1359-1369; DOI: https://doi.org/10.1124/dmd.104.000943

Citation Manager Formats

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

Share
Research ArticleArticle

THE CHIMPANZEE (PAN TROGLODYTES) AS A PHARMACOKINETIC MODEL FOR SELECTION OF DRUG CANDIDATES: MODEL CHARACTERIZATION AND APPLICATION

Harvey Wong, Scott J. Grossman, Stephen A. Bai, Sharon Diamond, Matthew R. Wright, James E. Grace, Mingxin Qian, Kan He, Krishnaswamy Yeleswaram and David D. Christ
Drug Metabolism and Disposition December 1, 2004, 32 (12) 1359-1369; DOI: https://doi.org/10.1124/dmd.104.000943
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

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

Related Articles

Cited By...

More in this TOC Section

  • Sex- and lifestyle-related factors affect hepatic CYP levels
  • Adipocyte PXR does not play an essential role in obesity.
  • CYP3A-mediated oxidation of DABE and BIBR0951
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