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
Journal of Pharmacology and Experimental Therapeutics
  • 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
Journal of Pharmacology and Experimental Therapeutics

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 jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleDrug Discovery and Translational Medicine

Pegylation Improves the Pharmacokinetics and Bioavailability of Small-Molecule Drugs Hydrolyzable by Esterases: A Study of Phospho-Ibuprofen

George Mattheolabakis, Chi C. Wong, Yu Sun, Carol A. Amella, Robert Richards, Panayiotis P. Constantinides and Basil Rigas
Journal of Pharmacology and Experimental Therapeutics October 2014, 351 (1) 61-66; DOI: https://doi.org/10.1124/jpet.114.217208
George Mattheolabakis
Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chi C. Wong
Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yu Sun
Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carol A. Amella
Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert Richards
Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Panayiotis P. Constantinides
Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Basil Rigas
Department of Medicine, Stony Brook University, Stony Brook, New York (G.M., C.C.W., Y.S., C.A.A., R.R., B.R.); and Medicon Pharmaceuticals, Inc. (P.P.C., B.R.), Stony Brook, New York
  • 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

Esterase hydrolysis of drugs can accelerate their elimination, thereby limiting their efficacy. Polyethylene glycol (PEG) covalently attached to drugs (pegylation) is known to improve the efficiency of many drugs. Using as a test agent the novel phospho-ibuprofen (PI), we examined whether pegylation of PI could abrogate its hydrolytic degradation by esterases; PI, known to inhibit colon cancer growth, has a carboxylic ester hydrolyzable by carboxylesterases (CES). We covalently attached mPEG-2000 to PI (PI-PEG) and studied its stability by exposing it to cells overexpressing CES and by administering it to mice. We also evaluated PI-PEG’s anticancer efficacy in human colon cancer xenografts and in Apcmin/+ mice. PI-PEG was stable in the presence of cells overexpressing CES1 or CES2, whereas PI was extensively hydrolyzed (90.2 ± 0.7%, 14.3 ± 1.1%, mean ± S.E.M.). In mice, PI was nearly completely hydrolyzed. Intravenous administration of PI-PEG resulted in significant levels in blood and in colon cancer xenografts (xenograft values in parentheses): area under the curve for 0–24 hours = 2351 (2621) (nmol/g) × h; Cmax = 1965 (886) nmol/g; Tmax = 0.08 (2) hour. The blood levels of ibuprofen, its main hydrolytic product, were minimal. Compared with controls, PI-PEG inhibited the growth of the xenografts by 74.8% (P < 0.01) and reduced intestinal tumor multiplicity in Apcmin/+ mice by 73.1% (P < 0.01), prolonging their survival (100% versus 55.1% of controls; P = 0.013). Pegylation protects PI from esterase hydrolysis and improves its pharmacokinetics. In preclinical models of colon cancer, PI-PEG is a safe and efficacious agent that merits further evaluation.

Footnotes

    • Received June 2, 2014.
    • Accepted July 18, 2014.
  • This work was supported in part by an assistance award [W81XWH-10-1-0873] from the US Army Medical Research Acquisition Activity. B.R. has an equity position in Medicon Pharmaceuticals, Inc. P.P.C. is a consultant for Medicon Pharmaceuticals, Inc.

  • dx.doi.org/10.1124/jpet.114.217208.

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

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET 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

Journal of Pharmacology and Experimental Therapeutics: 351 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 1
1 Oct 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 Journal of Pharmacology and Experimental Therapeutics 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.
Pegylation Improves the Pharmacokinetics and Bioavailability of Small-Molecule Drugs Hydrolyzable by Esterases: A Study of Phospho-Ibuprofen
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleDrug Discovery and Translational Medicine

Pegylation Prevents Phospho-Ibuprofen Hydrolysis

George Mattheolabakis, Chi C. Wong, Yu Sun, Carol A. Amella, Robert Richards, Panayiotis P. Constantinides and Basil Rigas
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 61-66; DOI: https://doi.org/10.1124/jpet.114.217208

Citation Manager Formats

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

Share
Research ArticleDrug Discovery and Translational Medicine

Pegylation Prevents Phospho-Ibuprofen Hydrolysis

George Mattheolabakis, Chi C. Wong, Yu Sun, Carol A. Amella, Robert Richards, Panayiotis P. Constantinides and Basil Rigas
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 61-66; DOI: https://doi.org/10.1124/jpet.114.217208
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
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Glucose transport modulators and mouse behavioral testing
  • Translational PK/PD Modeling of M3258
  • Kidney protective effects of BI 685509
Show more Drug Discovery and Translational Medicine

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 JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics