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
Journal of Pharmacology and Experimental Therapeutics
  • 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
Journal of Pharmacology and Experimental Therapeutics

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 jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Evaluation of the Use of Accelerated Infusions for the Determination of Pharmacokinetic Linearity

Keith W. Ward, Robin Griffiths, Mark A. Levy and Brian R. Smith
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 468-479;
Keith W. Ward
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robin Griffiths
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark A. Levy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brian R. Smith
  • 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

Accelerated infusions are potentially useful in the investigation of pharmacokinetic linearity. However, little information exists to validate this technique or to demonstrate its limitations. This investigation was performed to determine whether accelerated infusion regimens reliably estimate the range of pharmacokinetic linearity for molecules of varying pharmacokinetic properties, to evaluate the ability of accelerated infusions to identify pharmacokinetic nonlinearity, and to validate the accelerated infusion technique using compounds with known pharmacokinetic parameters. Simulations incorporating accelerated infusion as the input function resulted in the anticipated concentration-time profiles that contained an initial lag phase before reaching a linear slope. This lag phase increased with increasing distributional volume and in some instances was sufficiently great to obscure or prevent the linear portion of the profile. These simulations also revealed that clearance estimated from the apparently linear portion of the concentration-time profile can be erroneous under some conditions, as for large-volume compounds. Simulations of structured nonlinearity produced the predicted profiles for compounds with low to moderate volumes of distribution while demonstrating that modeling of data derived from compounds with large volumes of distribution may be inaccurate. Finally, experiments using accelerated infusions with various test compounds further demonstrated the usefulness of this technique while presenting limits imposed on the interpretation of the data. The results of this investigation indicate that the accelerated infusion may be used to determine pharmacokinetic linearity for compounds within certain pharmacokinetic boundaries, but that appropriate caution should be exercised in the extent of interpretation that should be extracted from such studies.

Footnotes

  • Send reprint requests to: Keith W. Ward, Ph.D., Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals R&D, UW 2720, 709 Swedeland Rd., King of Prussia, PA 19406. E-mail:Keith_W_Ward{at}SBPHRD.com

  • Abbreviations:
    CL
    clearance
    k
    slope
    K
    elimination rate constant
    Kacc
    acceleration rate constant
    k0
    target infusion rate
    MS
    mass spectrometry
    • Received September 23, 1999.
    • Accepted January 13, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET 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

Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
  • 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 Journal of Pharmacology and Experimental Therapeutics 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.
Evaluation of the Use of Accelerated Infusions for the Determination of Pharmacokinetic Linearity
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Evaluation of the Use of Accelerated Infusions for the Determination of Pharmacokinetic Linearity

Keith W. Ward, Robin Griffiths, Mark A. Levy and Brian R. Smith
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 468-479;

Citation Manager Formats

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

Share
Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Evaluation of the Use of Accelerated Infusions for the Determination of Pharmacokinetic Linearity

Keith W. Ward, Robin Griffiths, Mark A. Levy and Brian R. Smith
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 468-479;
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

  • Transport Is Not Rate-Limiting in Morphine Glucuronidation in the Single-Pass Perfused Rat Liver Preparation
  • Enhanced Hepatic Uptake and Bioactivity of Type α1(I) Collagen Gene Promoter-Specific Triplex-Forming Oligonucleotides after Conjugation with Cholesterol
  • Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana
Show more ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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 JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics