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

Effect of Multiple Dosing of Ketoconazole on Pharmacokinetics of Midazolam, a Cytochrome P-450 3A Substrate in Beagle Dogs

Masanori Kuroha, Akinori Azumano, Yoji Kuze, Minoru Shimoda and Eiichi Kokue
Drug Metabolism and Disposition January 2002, 30 (1) 63-68; DOI: https://doi.org/10.1124/dmd.30.1.63
Masanori Kuroha
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Akinori Azumano
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yoji Kuze
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Minoru Shimoda
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eiichi Kokue
  • 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

To evaluate effects of multiple dosing of ketoconazole (KTZ) on hepatic CYP3A, the pharmacokinetics of intravenous midazolam (MDZ, 0.5 mg/kg) before and during multiple dosing of KTZ were investigated in beagle dogs. KTZ tablets were given orally to dogs (n = 4) for 30 days (200 mg b.i.d.). With coadministration of KTZ, t1/2β of MDZ were significantly increased both on day 1 (2-fold) and on day 30 (3-fold). Total body clearance (CLtot) of MDZ declined gradually during the first 5 days after the start of KTZ treatment, and thereafter CLtot appeared to reach a plateau phase (one-fourth), depending on plasma KTZ concentrations. The effects of KTZ on the biotransformation of MDZ were also investigated using dog liver microsomes (n = 5). TheKi values of KTZ for MDZ 1′-hydroxylation and 4-hydroxylation were 0.0237 and 0.111 μM, respectively, indicating that KTZ extensively inhibits hepatic CYP3A activity in dogs. CLtot values estimated from in vitroKi values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma were consistent with in vivo CLtot of MDZ. The results in this study suggest that KTZ treatment is necessary until plasma concentrations of the drug reach a steady state to evaluate the effect of multiple dosing of the drug on hepatic CYP3A in vivo. In addition, it is suggested thatKi values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma enable precise in vitro-in vivo scaling.

Footnotes

  • Abbreviations used are::
    KTZ
    ketoconazole
    CLtot
    total body clearance
    MDZ
    midazolam
    1′-OH MDZ
    1′-hydroxymidazolam
    4-OH MDZ
    4-hydroxymidazolam
    Vdss
    volume of distribution at steady state
    t1/2β
    half-life in the β-phase
    • Received February 7, 2001.
    • Accepted July 18, 2001.
  • 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: 30 (1)
Drug Metabolism and Disposition
Vol. 30, Issue 1
1 Jan 2002
  • 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.
Effect of Multiple Dosing of Ketoconazole on Pharmacokinetics of Midazolam, a Cytochrome P-450 3A Substrate in Beagle Dogs
(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

Effect of Multiple Dosing of Ketoconazole on Pharmacokinetics of Midazolam, a Cytochrome P-450 3A Substrate in Beagle Dogs

Masanori Kuroha, Akinori Azumano, Yoji Kuze, Minoru Shimoda and Eiichi Kokue
Drug Metabolism and Disposition January 1, 2002, 30 (1) 63-68; DOI: https://doi.org/10.1124/dmd.30.1.63

Citation Manager Formats

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

Share
Research ArticleArticle

Effect of Multiple Dosing of Ketoconazole on Pharmacokinetics of Midazolam, a Cytochrome P-450 3A Substrate in Beagle Dogs

Masanori Kuroha, Akinori Azumano, Yoji Kuze, Minoru Shimoda and Eiichi Kokue
Drug Metabolism and Disposition January 1, 2002, 30 (1) 63-68; DOI: https://doi.org/10.1124/dmd.30.1.63
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Experimental Procedures
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Ontogeny of CPPGL
  • Expression of AKR and SDR Isoforms in the Human Intestine
  • Metabolism of Lufotrelvir in Humans
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