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

Identification of Bioactivating Enzymes Involved in the Hydrolysis of Laninamivir Octanoate, a Long-Acting Neuraminidase Inhibitor, in Human Pulmonary Tissue

Kumiko Koyama, Yuji Ogura, Daisuke Nakai, Mihoko Watanabe, Toshiko Munemasa, Yuka Oofune, Kazuishi Kubota, Akira Shinagawa and Takashi Izumi
Drug Metabolism and Disposition June 2014, 42 (6) 1031-1038; DOI: https://doi.org/10.1124/dmd.114.057620
Kumiko Koyama
Drug Metabolism & Pharmacokinetics Research Laboratories (K.Ko., D.N., T.I.), and Translational Medicine and Clinical Pharmacology Department (T.M.), Daiichi Sankyo Co., Ltd.; Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd. (Y.Og., M.W., Y.Of., K.Ku., A.S.), Tokyo, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuji Ogura
Drug Metabolism & Pharmacokinetics Research Laboratories (K.Ko., D.N., T.I.), and Translational Medicine and Clinical Pharmacology Department (T.M.), Daiichi Sankyo Co., Ltd.; Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd. (Y.Og., M.W., Y.Of., K.Ku., A.S.), Tokyo, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daisuke Nakai
Drug Metabolism & Pharmacokinetics Research Laboratories (K.Ko., D.N., T.I.), and Translational Medicine and Clinical Pharmacology Department (T.M.), Daiichi Sankyo Co., Ltd.; Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd. (Y.Og., M.W., Y.Of., K.Ku., A.S.), Tokyo, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mihoko Watanabe
Drug Metabolism & Pharmacokinetics Research Laboratories (K.Ko., D.N., T.I.), and Translational Medicine and Clinical Pharmacology Department (T.M.), Daiichi Sankyo Co., Ltd.; Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd. (Y.Og., M.W., Y.Of., K.Ku., A.S.), Tokyo, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Toshiko Munemasa
Drug Metabolism & Pharmacokinetics Research Laboratories (K.Ko., D.N., T.I.), and Translational Medicine and Clinical Pharmacology Department (T.M.), Daiichi Sankyo Co., Ltd.; Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd. (Y.Og., M.W., Y.Of., K.Ku., A.S.), Tokyo, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuka Oofune
Drug Metabolism & Pharmacokinetics Research Laboratories (K.Ko., D.N., T.I.), and Translational Medicine and Clinical Pharmacology Department (T.M.), Daiichi Sankyo Co., Ltd.; Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd. (Y.Og., M.W., Y.Of., K.Ku., A.S.), Tokyo, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kazuishi Kubota
Drug Metabolism & Pharmacokinetics Research Laboratories (K.Ko., D.N., T.I.), and Translational Medicine and Clinical Pharmacology Department (T.M.), Daiichi Sankyo Co., Ltd.; Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd. (Y.Og., M.W., Y.Of., K.Ku., A.S.), Tokyo, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Akira Shinagawa
Drug Metabolism & Pharmacokinetics Research Laboratories (K.Ko., D.N., T.I.), and Translational Medicine and Clinical Pharmacology Department (T.M.), Daiichi Sankyo Co., Ltd.; Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd. (Y.Og., M.W., Y.Of., K.Ku., A.S.), Tokyo, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Takashi Izumi
Drug Metabolism & Pharmacokinetics Research Laboratories (K.Ko., D.N., T.I.), and Translational Medicine and Clinical Pharmacology Department (T.M.), Daiichi Sankyo Co., Ltd.; Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd. (Y.Og., M.W., Y.Of., K.Ku., A.S.), Tokyo, 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

Laninamivir octanoate (LO) is an octanoyl ester prodrug of the neuraminidase inhibitor laninamivir. After inhaled administration, LO exhibits clinical efficacy for both treatment and prophylaxis of influenza virus infection, resulting from hydrolytic bioactivation into its pharmacologically active metabolite laninamivir in the pulmonary tissue. In this study, we focused on the identification of LO-hydrolyzing enzymes from human pulmonary tissue extract using proteomic correlation profiling—a technology integration of traditional biochemistry and proteomics. In a single elution step by gel-filtration chromatography, LO-hydrolyzing activity was separated into two distinct peaks, designated as peak I and peak II. By mass spectrometry, 1160 and 1003 proteins were identified and quantitated for peak I and peak II, respectively, and enzyme candidates were ranked based on the correlation coefficient between the enzyme activity and the proteomic profiles. Among proteins with a high correlation value, S-formylglutathione hydrolase (esterase D; ESD) and acyl-protein thioesterase 1 (APT1) were selected as the most likely candidates for peak I and peak II, respectively, which was confirmed by LO-hydrolyzing activity of recombinant proteins. In the case of peak II, LO-hydrolyzing activity was completely inhibited by treatment with a specific APT1 inhibitor, palmostatin B. Moreover, immunohistochemical analysis revealed that both enzymes were mainly localized in the pulmonary epithelia, a primary site of influenza virus infection. These findings demonstrate that ESD and APT1 are key enzymes responsible for the bioactivation of LO in human pulmonary tissue.

Footnotes

    • Received February 25, 2014.
    • Accepted March 28, 2014.
  • K.Ko. and Y.O. contributed equally to this work.

  • dx.doi.org/10.1124/dmd.114.057620.

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

  • Copyright © 2014 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: 42 (6)
Drug Metabolism and Disposition
Vol. 42, Issue 6
1 Jun 2014
  • 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.
Identification of Bioactivating Enzymes Involved in the Hydrolysis of Laninamivir Octanoate, a Long-Acting Neuraminidase Inhibitor, in Human Pulmonary Tissue
(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

Identification of Laninamivir Octanoate Hydrolases

Kumiko Koyama, Yuji Ogura, Daisuke Nakai, Mihoko Watanabe, Toshiko Munemasa, Yuka Oofune, Kazuishi Kubota, Akira Shinagawa and Takashi Izumi
Drug Metabolism and Disposition June 1, 2014, 42 (6) 1031-1038; DOI: https://doi.org/10.1124/dmd.114.057620

Citation Manager Formats

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

Share
Research ArticleArticle

Identification of Laninamivir Octanoate Hydrolases

Kumiko Koyama, Yuji Ogura, Daisuke Nakai, Mihoko Watanabe, Toshiko Munemasa, Yuka Oofune, Kazuishi Kubota, Akira Shinagawa and Takashi Izumi
Drug Metabolism and Disposition June 1, 2014, 42 (6) 1031-1038; DOI: https://doi.org/10.1124/dmd.114.057620
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

  • Gadoxetate-enhanced MRI and FXR in benign tumours
  • In vitro DDI assessment of peptide analogues
  • Endogenous substrates of rat organic cation transporters
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