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

Reductive Isoxazole Ring Opening of the Anticoagulant Razaxaban Is the Major Metabolic Clearance Pathway in Rats and Dogs

Donglu Zhang, Nirmala Raghavan, Shiang-Yuan Chen, Haiying Zhang, Mimi Quan, Lloyd Lecureux, Laura M. Patrone, Patrick Y. S. Lam, Samuel J. Bonacorsi, Robert M. Knabb, Gary L. Skiles and Kan He
Drug Metabolism and Disposition February 2008, 36 (2) 303-315; DOI: https://doi.org/10.1124/dmd.107.018416
Donglu Zhang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nirmala Raghavan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shiang-Yuan Chen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Haiying Zhang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mimi Quan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lloyd Lecureux
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laura M. Patrone
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patrick Y. S. Lam
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Samuel J. Bonacorsi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert M. Knabb
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gary L. Skiles
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kan He
  • 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

Razaxaban is a selective, potent, and orally bioavailable inhibitor of coagulation factor Xa. The molecule contains a 1,2-benzisoxazole structure. After oral administration of [14C]razaxaban to intact and bile duct-cannulated rats (300 mg/kg) and dogs (20 mg/kg), metabolism followed by biliary excretion was the major elimination pathway in both species, accounting for 34 to 44% of the dose, whereas urinary excretion accounted for 3 to 13% of the dose. Chromatographic separation of radioactivity in urine, bile, and feces of rats and dogs showed that razaxaban was extensively metabolized in both species. Metabolites were identified on the basis of liquid chromatography/tandem mass spectrometry and comparison with synthetic standards. Among the 12 metabolites identified, formation of an isoxazole-ring opened benzamidine metabolite (M1) represented a major metabolic pathway of razaxaban in rats and dogs. However, razaxaban was the major circulating drug-related component (>70%) in both species, and M1, M4, and M7 were minor circulating components. In addition to the in vivo observations, M1 was formed as the primary metabolite in rat and dog hepatocytes and in the rat liver cytosolic fraction. The formation of M1 in the rat liver fraction required the presence of NADH. Theses results suggest that isoxazole ring reduction, forming a stable benzamidine metabolite (M1), represents the primary metabolic pathway of razaxaban in vivo and in vitro. The reduction reaction was catalyzed by NADH-dependent reductase(s) in the liver and possibly by intestinal microflora on the basis of the recovery of M1 in feces of bile duct-cannulated rats.

Footnotes

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

  • doi:10.1124/dmd.107.018416.

  • ABBREVIATIONS: razaxaban, BMS-561389, DPC906, 1-(3′-aminobenzisoxazol-5′-yl)-3-trifluoromethyl-N-[2-fluoro-4-(2′-dimethyl aminomethylimidazol-1-yl)phenyl]-1H-pyrazole-5-carboxyamide; HPLC, high performance liquid chromatography; NMR; nuclear magnetic resonance; MS, mass spectrometry; DMF, dimethylformamide; TFA, trifluoroacetic acid; ESI, electrospray ionization; BDC, bile duct cannulated; LC, liquid chromatography; MS/MS, tandem mass spectrometry; ABT-418, (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D2624, N-(2,6-dimethylphenyl)-5-methyl-3-isoxazolecarboxamide; AG7088, trans-(4S,2′R,5′S,3′′′S)-4-{2′-4-(4-fluorobenzyl)-6′-methyl-5′-[(5″-methylisoxazole-3′-carbonylamino]-4-oxoheptanoylamino}-5-(2′′′-oxopyrrolidin-3′′′-yl)pent-2-enoic acid ethyl ester.

  • ↵1 Current affiliation: Amgen, Department of Pharmacokinetics and Drug Metabolism, One Amgen Center Drive, Thousand Oaks, CA 91320.

    • Received August 21, 2007.
    • Accepted October 31, 2007.
  • 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 (2)
Drug Metabolism and Disposition
Vol. 36, Issue 2
1 Feb 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.
Reductive Isoxazole Ring Opening of the Anticoagulant Razaxaban Is the Major Metabolic Clearance Pathway in Rats and 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

Reductive Isoxazole Ring Opening of the Anticoagulant Razaxaban Is the Major Metabolic Clearance Pathway in Rats and Dogs

Donglu Zhang, Nirmala Raghavan, Shiang-Yuan Chen, Haiying Zhang, Mimi Quan, Lloyd Lecureux, Laura M. Patrone, Patrick Y. S. Lam, Samuel J. Bonacorsi, Robert M. Knabb, Gary L. Skiles and Kan He
Drug Metabolism and Disposition February 1, 2008, 36 (2) 303-315; DOI: https://doi.org/10.1124/dmd.107.018416

Citation Manager Formats

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

Share
Research ArticleArticle

Reductive Isoxazole Ring Opening of the Anticoagulant Razaxaban Is the Major Metabolic Clearance Pathway in Rats and Dogs

Donglu Zhang, Nirmala Raghavan, Shiang-Yuan Chen, Haiying Zhang, Mimi Quan, Lloyd Lecureux, Laura M. Patrone, Patrick Y. S. Lam, Samuel J. Bonacorsi, Robert M. Knabb, Gary L. Skiles and Kan He
Drug Metabolism and Disposition February 1, 2008, 36 (2) 303-315; DOI: https://doi.org/10.1124/dmd.107.018416
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 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