Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • For Subscribers
    • For Advertisers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • 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

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
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • For Subscribers
    • For Advertisers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

KIIV, AN IN VIVO PARAMETER FOR PREDICTING THE MAGNITUDE OF A DRUG INTERACTION ARISING FROM COMPETITIVE ENZYME INHIBITION

John M. Neal, Kent L. Kunze, René H. Levy, Robert A. O'Reilly and William F. Trager
Drug Metabolism and Disposition August 2003, 31 (8) 1043-1048; DOI: https://doi.org/10.1124/dmd.31.8.1043
John M. Neal
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kent L. Kunze
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
René H. Levy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert A. O'Reilly
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William F. Trager
  • 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 goal of the study was to test the assumption that a competitive inhibition constant determined in vivo, Kiiv, like its corresponding in vitro counterpart, Ki, is independent of inhibitor concentration. Inhibition of the CYP2C9-dependent formation of (S)-7-hydroxywarfarin from (S)-warfarin was measured in seven healthy subjects at three different doses of fluconazole. Prothrombin time measurements showed increasing anticoagulant activity with increasing fluconazole dose. The pharmacokinetic parameters calculated from the (S)- and (R)-warfarin plasma levels were consistent with previous studies. Fluconazole reduced the clearance of (S)-warfarin to a greater extent than that of (R)-warfarin. The decrease in clearance of both warfarin enantiomers was fluconazole dose-dependent. The formation of (S)-7-hydroxywarfarin was inhibited by 31, 55, and 77% at the 100, 200, and 300 mg daily doses of fluconazole, respectively. Kiiv, values calculated from these data based on plasma fluconazole levels at each dose and data from earlier work at 400-mg daily doses of fluconazole were 30.7 ± 23.7, 19.6 ± 3.8, 17.9 ± 7.5, and 19.8 ± 3.5 μM, respectively. These results confirm the hypothesis that Kiiv is independent of inhibitor concentration.

Footnotes

  • ↵1 Abbreviations used are: P450, cytochrome P450; Kiiv, in vivo constant for competitive inhibition of an enzyme; Ki, in vitro constant for competitive inhibition of an enzyme; AUC, area under the curve; PT, the response of the prothrombin time; CL, clearance limits; F, bioavailability; Vss, apparent volume of distribution.

  • ↵2 The classic expression for competitive enzyme inhibition is Math where i = fraction of inhibition, [I] = inhibitor concentration, [S] = substrate concentration, Km is the Michaelis-Menten constant for the substrate, and Ki is the inhibition constant.

  • ↵3 The difference between the mean fluconazole concentration over 24 h and the 24-h fluconazole concentration, ranges between 10 and 20% with the mean value being higher (Kunze and Trager, 1996). Thus, use of the 24-h value in eq. 2 would be expected to lead to a slightly lower value for Kiiv than would be obtained using the mean value. This is exactly what is found. Using the data from the earlier paper by Kunze and Trager (1996), the mean fluconazole concentrations over 24 h yielded a Kiiv of 22.5 ± 3.5 μM whereas the fluconazole concentrations from the same study at 24-h postdose yielded a Kiiv of 19.8 ± 3.5 μM.

  • This study was supported in part by Grant 32165 from the National Institutes of Health (Bethesda, MD).

    • Received January 7, 2003.
    • Accepted April 22, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

Log in using your username and password

Forgot your user name or password?

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00

Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.

PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 31 (8)
Drug Metabolism and Disposition
Vol. 31, Issue 8
1 Aug 2003
  • 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.
KIIV, AN IN VIVO PARAMETER FOR PREDICTING THE MAGNITUDE OF A DRUG INTERACTION ARISING FROM COMPETITIVE ENZYME INHIBITION
(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.
Citation Tools
Research ArticleArticle

KIIV, AN IN VIVO PARAMETER FOR PREDICTING THE MAGNITUDE OF A DRUG INTERACTION ARISING FROM COMPETITIVE ENZYME INHIBITION

John M. Neal, Kent L. Kunze, René H. Levy, Robert A. O'Reilly and William F. Trager
Drug Metabolism and Disposition August 1, 2003, 31 (8) 1043-1048; DOI: https://doi.org/10.1124/dmd.31.8.1043

Citation Manager Formats

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

KIIV, AN IN VIVO PARAMETER FOR PREDICTING THE MAGNITUDE OF A DRUG INTERACTION ARISING FROM COMPETITIVE ENZYME INHIBITION

John M. Neal, Kent L. Kunze, René H. Levy, Robert A. O'Reilly and William F. Trager
Drug Metabolism and Disposition August 1, 2003, 31 (8) 1043-1048; DOI: https://doi.org/10.1124/dmd.31.8.1043
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

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

Related Articles

Cited By...

More in this TOC Section

  • UDP-glycosyltransferase 3A (UGT3A) metabolism of polycyclic aromatic hydrocarbons: potential importance in aerodigestive tract tissues
  • Identification and characterization of a new carboxylesterase 2 isozyme, mfCES2C, in the small intestine of cynomolgus monkeys
  • Comparative Proteomics of Human Liver Microsomes and S9
Show more Articles

Similar Articles

  • 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 © 2019 by the American Society for Pharmacology and Experimental Therapeutics