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

Novel Binding Mode of the Acidic CYP2D6 Substrates Pactimibe and Its Metabolite R-125528

Masakatsu Kotsuma, Hiroyuki Hanzawa, Yoriko Iwata, Kenji Takahashi and Taro Tokui
Drug Metabolism and Disposition September 2008, 36 (9) 1938-1943; DOI: https://doi.org/10.1124/dmd.108.020776
Masakatsu Kotsuma
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hiroyuki Hanzawa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yoriko Iwata
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kenji Takahashi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Taro Tokui
  • 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

Typical CYP2D6 substrates generally contain a basic nitrogen atom that interacts with Asp301 and/or Glu216 and an aromatic moiety adjacent to the site of metabolism. Recently, we found novel acidic substrates for CYP2D6, pactimibe, and its indole metabolite, R-125528, that are not protonated but are negatively charged at physiological pH. The Km value of R-125528 in CYP2D6-expressing microsomes was determined to be 1.74 μM, which was comparable with those of typical basic CYP2D6 substrates (1–10 μM). Pactimibe has lower affinity than R-125528; however, the Km value was comparable with that of metoprolol. Interestingly, their sites of metabolism, the ω-1 position of the N-octyl indoline/indole group, were relatively distant from the aromatic moiety. A pactimibe analog with an N-decyl chain was similarly labile against CYP2D6; however, analogs with N-hexyl or N-dodecyl chains were stable to CYP2D6. An induced fit docking of the ligands with an X-ray crystal structure of substrate-free CYP2D6 (Protein Data Bank code 2F9Q) indicated the involvement of an electrostatic interaction between the carboxyl group and Arg221 and hydrophobic interaction between the aromatic moiety and Phe483. The docking model correctly positioned the site of metabolism above the heme. The effect of the N-alkyl chain length of pactimibe analogs on their CYP2D6 metabolic stability was plausibly explained by the docking model. In conclusion, we report herein a novel CYP2D6 binding mode for the acidic substrates pactimibe and R-125528. Further investigation, such as a site-directed mutation, will be necessary to directly demonstrate the involvement of Arg221 in CYP2D6 binding.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.020776.

  • ABBREVIATIONS: P450, cytochrome P450; pdb, Protein Data Bank; M-2, ω-1 oxidized form of R-125528; LC/MS, liquid chromatography/mass spectrometry; IFD, induced fit docking.

    • Received March 5, 2008.
    • Accepted June 3, 2008.
  • 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: 36 (9)
Drug Metabolism and Disposition
Vol. 36, Issue 9
1 Sep 2008
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
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.
Novel Binding Mode of the Acidic CYP2D6 Substrates Pactimibe and Its Metabolite R-125528
(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

Novel Binding Mode of the Acidic CYP2D6 Substrates Pactimibe and Its Metabolite R-125528

Masakatsu Kotsuma, Hiroyuki Hanzawa, Yoriko Iwata, Kenji Takahashi and Taro Tokui
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1938-1943; DOI: https://doi.org/10.1124/dmd.108.020776

Citation Manager Formats

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

Share
Research ArticleArticle

Novel Binding Mode of the Acidic CYP2D6 Substrates Pactimibe and Its Metabolite R-125528

Masakatsu Kotsuma, Hiroyuki Hanzawa, Yoriko Iwata, Kenji Takahashi and Taro Tokui
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1938-1943; DOI: https://doi.org/10.1124/dmd.108.020776
Reddit logo Twitter logo Facebook 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

  • Metabolic enzymes in nintedanib metabolism
  • Mechanism of AO Inactivation by Hydralazine
  • Warfarin PBPK modeling with target binding
Show more Articles

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