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
Rapid CommunicationShort Communication

The In Vitro Interaction of Dexmedetomidine with Human Liver Microsomal Cytochrome P4502D6 (CYP2D6)

A. David Rodrigues and Ellen M. Roberts
Drug Metabolism and Disposition May 1997, 25 (5) 651-655;
A. David Rodrigues
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ellen M. Roberts
  • 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 effect of dexmedetomidine (DEX) on cytochrome P4502D6 (CYP2D6)-dependent dextromethorphan O-demethylase (DEXTROase) activity was studied using native human liver microsomes. DEX (0.01–4.0 μM) inhibited DEXTROase activity (IC50 = 1.8 ± 0.25 μM; mean ± SD; N = 5 livers) and was less potent than quinidine (QND), a prototypical and clinically relevant CYP2D6 inhibitor (IC50 = 0.22 ± 0.02 μM; mean Ki = 0.07 μM). Similar results were obtained with human B-lymphoblast microsomes containing cDNA-expressed CYP2D6 (DEX, IC50 = 2.2 μM; QND, IC50 = 0.15 μM). Formal kinetic analyses indicated that DEX was a reversible mixed (competitive/noncompetitive) inhibitor of DEXTROase activity in human liver microsomes, where Kies >Ki and α > 1 (Ki = 0.4 ± 0.2 μM; Kies = 2.3 ± 0.9 μM; α = 8.1 ± 6.8; N = 3 livers). In addition, DEX elicited a Type llb difference spectrum (λmax ∼436 nm; λmin ∼414 nm) when added to cDNA-expressed CYP2D6 under aerobic (oxidized) conditions. These data indicated that DEX was able to bind reversibly to the heme (ferric) iron of CYP2D6. It is postulated that binding occursvia the 4(5)-substituted imidazole moiety. In this instance, binding was characterized by a spectral dissociation constant (Ks ) of 0.4 μM that was identical to theKi obtained with native human liver microsomes.

Footnotes

  • Send reprint requests to: Dr. A. David Rodrigues, Drug Metabolism I, Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, WP26-A 2044, West Point, PA 19486-0004.

  • ↵2 DEX (0.9–85 ng/ml) binding to human plasma protein in vitro is 93.7%; J. M. Machinist, Ph.D. (Abbott Laboratories), unpublished observations.

  • ↵3 Intersubject variability is low (coefficient of variation ≤ 22%) and the peak concentration of DEX in plasma, after a loading dose, is not more than 2-fold greater than that at steady state.

  • ↵4 M. Karol, Ph.D. (Abbott Laboratories), personal communication.

  • Abbreviations used are::
    DEX
    dexmedetomidine, (±)-4-[1-(2, 3-dimethylphenyl)ethyl]-1H-imidazole
    CYP
    cytochrome P450
    CYP2D6
    cytochrome P4502D6
    QND
    quinidine
    DEXTRO
    dextromethorphan
    DEXTROase
    [O-methyl-14C]DEXTRO O-demethylase
    Vmax
    apparent maximal initial reaction velocity
    KM
    apparent Michaelis constant
    [drug]plasma
    concentration of drug (free and protein bound) in plasma
    Ks
    apparent spectral dissociation constant
    ΔAmax
    apparent maximal absorbance difference elicited by DEX ([DEX]free) upon addition to CYP2D6
    ΔAmax′
    apparent maximal absorbance difference elicited by DEX ([DEX]total) upon addition to CYP2D6
    [CYP]
    cytochrome P450 concentration
    [DEX]free
    concentration of free DEX (drug nominally in equilibrium with enzyme)
    [DEX]total
    concentration of total DEX added to the cuvette
    IC50
    concentration of drug required to inhibit activity by 50%
    Ki
    apparent inhibition constant (dissociation constant of the enzyme inhibitor, or EI, complex)
    Kies
    apparent dissociation constant of the enyzyme-inhibitor-substrate, or EIS, complex
    SERT
    sertraline
    FLUV
    fluvoxamine
  • 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 5
1 May 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.
The In Vitro Interaction of Dexmedetomidine with Human Liver Microsomal Cytochrome P4502D6 (CYP2D6)
(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
Rapid CommunicationShort Communication

The In Vitro Interaction of Dexmedetomidine with Human Liver Microsomal Cytochrome P4502D6 (CYP2D6)

A. David Rodrigues and Ellen M. Roberts
Drug Metabolism and Disposition May 1, 1997, 25 (5) 651-655;

Citation Manager Formats

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

Share
Rapid CommunicationShort Communication

The In Vitro Interaction of Dexmedetomidine with Human Liver Microsomal Cytochrome P4502D6 (CYP2D6)

A. David Rodrigues and Ellen M. Roberts
Drug Metabolism and Disposition May 1, 1997, 25 (5) 651-655;
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 and Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Preincubation Effects on Inhibition of OCT1 by CsA
  • Carbamazepine Metabolite and Hypersensitivity Reactions
  • SULT4A1 Preserves Mitochondrial Function
Show more Short Communication

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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics