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
  • Log out
  • 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
  • Log out
  • 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

Metabolism And Disposition of the HIV-1 Protease Inhibitor Ritonavir (ABT-538) in Rats, Dogs, and Humans

Jon F. Denissen, Brian A. Grabowski, Marianne K. Johnson, Alex M. Buko, Dale J. Kempf, Samuel B. Thomas and Bruce W. Surber
Drug Metabolism and Disposition April 1997, 25 (4) 489;
Jon F. Denissen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brian A. Grabowski
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marianne K. Johnson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alex M. Buko
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dale J. Kempf
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Samuel B. Thomas
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bruce W. Surber
  • 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 metabolism and disposition of [14C]ritonavir (ABT-538, NORVIR), a potent, orally active HIV-1 protease inhibitor, were investigated in male and female Sprague-Dawley rats, beagle dogs, and HIV-negative male human volunteers. Rats and dogs received a 5 mg/kg iv, 20 mg/kg oral or 20 mg/kg intraduodenal dose, whereas humans received a single 600-mg liquid oral dose. Ritonavir was cleared primarily viahepatobiliary elimination in all three species. After iv or oral dosing in either rats or dogs, >92% of the dose was recovered in rat and dog feces and ≤4% was recovered in the urine. Humans excreted 86.3% of the oral dose in feces and 11.3% in urine over 6 days. Bile-exteriorized rats and dogs excreted 85.5% and 39.8%, respectively, of the iv dose in bile, with <3% recovered in urine. Radio-HPLC analysis of bile, feces, and urine from all three species indicated extensive metabolism of ritonavir to a number of oxidative metabolites, some being species-specific, and all involving metabolism at the terminal functional groups of the molecule. Glucuronide metabolites were observed in dog only. Plasma radioactivity consisted predominantly of unchanged parent drug in all three species. M-2, the product of hydroxylation at the methine carbon of the terminal isopropyl moiety of ritonavir, was the only metabolite present in human plasma and made up 30.4% of the total dose recovered in human excreta over 6 days. Tissue distribution of ritonavir in rat was widespread, with good distribution into lymphatic tissue but low CNS penetration. Plasma protein binding of ritonavir was high (96–99.5%) in all species and was nonsaturable in humans at concentrations up to 30 μg/ml. Partitioning into the formed elements of whole blood was minimal.

Footnotes

  • Send reprint requests to: Dr. Jon F. Denissen, Biotransformation Department, D46V, Bldg AP9, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064.

  • Abbreviations used are::
    ritonavir
    10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic-acid, 5-thiazolylmethyl ester, [5S -(5R*,8R*,10R*11R*)]
    HIV
    human immunodeficiency virus type-1
    AIDS
    acquired immune deficiency syndrome
    • Received October 3, 1996.
    • Accepted December 18, 1996.
  • 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
Vol. 25, Issue 4
1 Apr 1997
  • Table of Contents
  • 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.
Metabolism And Disposition of the HIV-1 Protease Inhibitor Ritonavir (ABT-538) in Rats, Dogs, and Humans
(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 And Disposition of the HIV-1 Protease Inhibitor Ritonavir (ABT-538) in Rats, Dogs, and Humans

Jon F. Denissen, Brian A. Grabowski, Marianne K. Johnson, Alex M. Buko, Dale J. Kempf, Samuel B. Thomas and Bruce W. Surber
Drug Metabolism and Disposition April 1, 1997, 25 (4) 489;

Citation Manager Formats

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

Share
Research ArticleArticle

Metabolism And Disposition of the HIV-1 Protease Inhibitor Ritonavir (ABT-538) in Rats, Dogs, and Humans

Jon F. Denissen, Brian A. Grabowski, Marianne K. Johnson, Alex M. Buko, Dale J. Kempf, Samuel B. Thomas and Bruce W. Surber
Drug Metabolism and Disposition April 1, 1997, 25 (4) 489;
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
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Series-Compartment Models of Hepatic Elimination
  • Warfarin PBPK Model with TMDD Mechanism
  • Identification of payload-containing catabolites of ADCs
Show more Article

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