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

Metabolism of the Human Immunodeficiency Virus Protease Inhibitors Indinavir and Ritonavir by Human Intestinal Microsomes and Expressed Cytochrome P4503A4/3A5: Mechanism-Based Inactivation of Cytochrome P4503A by Ritonavir

Tatiana Koudriakova, Eugenia Iatsimirskaia, Ilya Utkin, Eric Gangl, Paul Vouros, Elena Storozhuk, Daniela Orza, Julia Marinina and Nicholas Gerber
Drug Metabolism and Disposition June 1998, 26 (6) 552-561;
Tatiana Koudriakova
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eugenia Iatsimirskaia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ilya Utkin
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eric Gangl
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul Vouros
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elena Storozhuk
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniela Orza
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Julia Marinina
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nicholas Gerber
  • 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

Both ritonavir and indinavir were readily metabolized by human intestinal microsomes. Comparison of the patterns of metabolites in incubations with enterocyte microsomes and expressed cytochrome P450 (CYP) isozymes and immunoinhibition and chemical inhibition studies showed the essential role of the CYP3A subfamily in the metabolism of both protease inhibitors by the small intestine. Ritonavir was similarly biotransformed by microsomes containing expressed CYP3A4 or CYP3A5 isozymes (KM = 0.05–0.07 μM,Vmax = 1–1.4 nmol/min/nmol CYP). In contrast, both the patterns of metabolites and the enzyme kinetic parameters for the metabolism of indinavir by expressed CYP3A5 (KM = 0.21 μM,Vmax = 0.24 nmol/min/nmol CYP) and CYP3A4 (KM = 0.04 μM,Vmax = 0.68 nmol/min/nmol CYP) were different. The biotransformation of both indinavir and ritonavir in human enterocyte microsomes was characterized by very lowKM values (0.2–0.4 μM for indinavir and <0.1 μM for ritonavir). The Vmaxfor indinavir metabolism was greater in enterocyte (163 ± 35 pmol/min/mg protein) than in liver (68 ± 44 pmol/min/mg protein) microsomes. The metabolism of ritonavir in liver and enterocyte microsomes was associated with inactivation of CYP3A. The initialVmax for ritonavir metabolism by enterocyte microsomes was 89 ± 59 pmol/min/mg protein. The apparent inactivation rate constants for intestinal CYP3A and expressed CYP3A4 were 0.078 and 0.135 min−1, respectively. Metabolic inactivation of CYP3A by ritonavir explains the improved bioavailability and pharmacokinetics of ritonavir and the sustained elevation of blood levels of other, concomitantly administered, substrates of CYP3A.

Footnotes

  • Send reprint requests to: Tatiana Koudriakova, Department of Pharmacology, The Ohio State University, 5084 Graves Hall, 333 W. 10th Ave., Columbus, OH 43210.

  • Abbreviations used are::
    HIV
    human immunodeficiency virus
    CYP
    cytochrome P450
    ACN
    acetonitrile
    TEA
    triethylamine
    TFA
    trifluoroacetic acid
    MAB3A4
    monoclonal antibody to cytochrome P4503A4
    kin
    inactivation rate constant
    ESI
    electrospray ionization
    CID
    collision-induced dissociation
    • Received October 31, 1997.
    • Accepted February 26, 1998.
  • 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. 26, Issue 6
1 Jun 1998
  • 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 of the Human Immunodeficiency Virus Protease Inhibitors Indinavir and Ritonavir by Human Intestinal Microsomes and Expressed Cytochrome P4503A4/3A5: Mechanism-Based Inactivation of Cytochrome P4503A by Ritonavir
(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 of the Human Immunodeficiency Virus Protease Inhibitors Indinavir and Ritonavir by Human Intestinal Microsomes and Expressed Cytochrome P4503A4/3A5: Mechanism-Based Inactivation of Cytochrome P4503A by Ritonavir

Tatiana Koudriakova, Eugenia Iatsimirskaia, Ilya Utkin, Eric Gangl, Paul Vouros, Elena Storozhuk, Daniela Orza, Julia Marinina and Nicholas Gerber
Drug Metabolism and Disposition June 1, 1998, 26 (6) 552-561;

Citation Manager Formats

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

Share
Research ArticleArticle

Metabolism of the Human Immunodeficiency Virus Protease Inhibitors Indinavir and Ritonavir by Human Intestinal Microsomes and Expressed Cytochrome P4503A4/3A5: Mechanism-Based Inactivation of Cytochrome P4503A by Ritonavir

Tatiana Koudriakova, Eugenia Iatsimirskaia, Ilya Utkin, Eric Gangl, Paul Vouros, Elena Storozhuk, Daniela Orza, Julia Marinina and Nicholas Gerber
Drug Metabolism and Disposition June 1, 1998, 26 (6) 552-561;
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
    • Materials and Methods
    • 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