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

Metabolic Mechanism of Delamanid, a New Anti-Tuberculosis Drug, in Human Plasma

Yoshihiko Shimokawa, Katsunori Sasahara, Noriyuki Koyama, Kazuyoshi Kitano, Masakazu Shibata, Noriaki Yoda and Ken Umehara
Drug Metabolism and Disposition August 2015, 43 (8) 1277-1283; DOI: https://doi.org/10.1124/dmd.115.064550
Yoshihiko Shimokawa
Tokushima Research Institute (Y.S., K.S., N.K., M.S., N.Y., K.U.) and Medicinal Chemistry Research Institute (K.K.), Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Katsunori Sasahara
Tokushima Research Institute (Y.S., K.S., N.K., M.S., N.Y., K.U.) and Medicinal Chemistry Research Institute (K.K.), Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Noriyuki Koyama
Tokushima Research Institute (Y.S., K.S., N.K., M.S., N.Y., K.U.) and Medicinal Chemistry Research Institute (K.K.), Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kazuyoshi Kitano
Tokushima Research Institute (Y.S., K.S., N.K., M.S., N.Y., K.U.) and Medicinal Chemistry Research Institute (K.K.), Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Masakazu Shibata
Tokushima Research Institute (Y.S., K.S., N.K., M.S., N.Y., K.U.) and Medicinal Chemistry Research Institute (K.K.), Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Noriaki Yoda
Tokushima Research Institute (Y.S., K.S., N.K., M.S., N.Y., K.U.) and Medicinal Chemistry Research Institute (K.K.), Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ken Umehara
Tokushima Research Institute (Y.S., K.S., N.K., M.S., N.Y., K.U.) and Medicinal Chemistry Research Institute (K.K.), Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
  • 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 + SI
  • PDF
Loading

Abstract

The metabolism of delamanid (OPC-67683, Deltyba), a novel treatment of multidrug-resistant tuberculosis, was investigated in vitro using plasma and purified protein preparations from humans and animals. Delamanid was rapidly degraded by incubation in the plasma of all species tested at 37°C, with half-life values (hours) of 0.64 (human), 0.84 (dog), 0.87 (rabbit), 1.90 (mouse), and 3.54 (rat). A major metabolite, (R)-2-amino-4,5-dihydrooxazole derivative (M1), was formed in the plasma by cleavage of the 6-nitro-2,3-dihydroimidazo(2,1-b)oxazole moiety of delamanid. The rate of M1 formation increased with temperature (0−37°C) and pH (6.0−8.0). Delamanid was not converted to M1 in plasma filtrate, with a molecular mass cutoff of 30 kDa, suggesting that bioconversion is mediated by plasma proteins of higher molecular weight. When delamanid was incubated in plasma protein fractions separated by gel filtration chromatography, M1 was observed in the fraction consisting of albumin, γ-globulin, and α1-acid glycoprotein. In pure preparations of these proteins, only human serum albumin (HSA) metabolized delamanid to M1. The formation of M1 followed Michaelis-Menten kinetics in both human plasma and the HSA solution, with similar Km values: 67.8 µM in plasma and 51.5 µM in HSA. The maximum velocity and intrinsic clearance values for M1 were also comparable in plasma and HSA. These results strongly suggest that albumin is predominantly responsible for metabolizing delamanid to M1. We propose that delamanid degradation by albumin begins with a nucleophilic attack of amino acid residues on the electron-poor carbon at the 5 position of nitro-dihydro-imidazooxazole, followed by cleavage of the imidazooxazole moiety to form M1.

Footnotes

    • Received March 27, 2015.
    • Accepted June 8, 2015.
  • dx.doi.org/10.1124/dmd.115.064550.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by 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: 43 (8)
Drug Metabolism and Disposition
Vol. 43, Issue 8
1 Aug 2015
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • 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.
Metabolic Mechanism of Delamanid, a New Anti-Tuberculosis Drug, in Human Plasma
(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

Metabolism of Delamanid by Albumin

Yoshihiko Shimokawa, Katsunori Sasahara, Noriyuki Koyama, Kazuyoshi Kitano, Masakazu Shibata, Noriaki Yoda and Ken Umehara
Drug Metabolism and Disposition August 1, 2015, 43 (8) 1277-1283; DOI: https://doi.org/10.1124/dmd.115.064550

Citation Manager Formats

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

Share
Research ArticleArticle

Metabolism of Delamanid by Albumin

Yoshihiko Shimokawa, Katsunori Sasahara, Noriyuki Koyama, Kazuyoshi Kitano, Masakazu Shibata, Noriaki Yoda and Ken Umehara
Drug Metabolism and Disposition August 1, 2015, 43 (8) 1277-1283; DOI: https://doi.org/10.1124/dmd.115.064550
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Sex- and lifestyle-related factors affect hepatic CYP levels
  • Adipocyte PXR does not play an essential role in obesity.
  • CYP3A-mediated oxidation of DABE and BIBR0951
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