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 ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics of Novel Dipeptide Ester Prodrugs of Acyclovir after Oral Administration: Intestinal Absorption and Liver Metabolism

Banmeet S. Anand, Suresh Katragadda and Ashim K. Mitra
Journal of Pharmacology and Experimental Therapeutics November 2004, 311 (2) 659-667; DOI: https://doi.org/10.1124/jpet.104.069997
Banmeet S. Anand
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Suresh Katragadda
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ashim K. Mitra
  • 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

The amino acid prodrug of acyclovir (ACV), valacyclovir (VACV), is an effective antiherpetic drug. Systemic availability of ACV in humans is 3 to 5 times higher after oral administration of VACV. Enhanced bioavailability of VACV has been attributed to its carrier-mediated intestinal absorption via hPEPT1 peptide transporter followed by rapid and complete conversion to ACV. An earlier report suggested that the dipeptide ester prodrugs of ACV possess high affinity toward the intestinal oligopeptide transporter hPEPT1 and therefore seem to be promising candidates in the treatment of oral herpes virus infections. In the present study, we have examined the bioavailability of a series of dipeptide prodrugs of ACV after oral administration in Sprague-Dawley rats with cannulated jugular and portal veins. The area under plasma-concentration time curves expressed as minutes microgram milliliter-1 for total concentration of VACV (208.4 ± 41.2), and the dipeptide prodrugs Gly-Val-ACV (GVACV) (416.1 ± 140.9), Val-Val-ACV (VVACV) (147.7 ± 89.3), and Val-Tyr-ACV (VYACV) (180.7 ± 81.2) were significantly higher than that of ACV (21.2 ± 5.2) upon intestinal absorption. Interestingly, the bioavailability of ACV after administration of GVACV was approximately 2-fold higher than VACV. There was significant metabolism by hepatic first pass effect of the dipeptide prodrugs as evident by the higher levels of ACV obtained after systemic absorption compared with intestinal absorption of GVACV and VVACV. The dipeptide prodrugs of ACV exhibited higher systemic availability of regenerated ACV upon oral administration and thus seem to be promising drug candidates in treatment of genital herpes infections.

Footnotes

  • ↵1 Current address: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080.

  • ABBREVIATIONS: hPEPT1, human intestinal peptide transporter; ACV, acyclovir; BPHL, biphenyl hydrolase-like; FBS, fetal bovine serum; VACV, valacyclovir; VVACV, valine-valine acyclovir; GVACV, glycine-valine acyclovir; GYACV, glycine-tyrosine acyclovir; VYACV, valine-tyrosine acyclovir; DPBS, Dulbecco's phosphate-buffered saline; HPLC, high-performance liquid chromatography; AUC, area under the curve; CL/F, clearance; MRT, mean residence time; Papp, apparent permeability; HSV, herpes simplex virus.

  • This work was supported by National Institutes of Health Grants R01 EY09171 and R01 EY10659.

  • doi:10.1124/jpet.104.069997.

    • Received April 14, 2004.
    • Accepted June 14, 2004.
  • 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: 311 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 2
1 Nov 2004
  • Table of Contents
  • About the Cover
  • Index by author
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.
Pharmacokinetics of Novel Dipeptide Ester Prodrugs of Acyclovir after Oral Administration: Intestinal Absorption and Liver Metabolism
(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 ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics of Novel Dipeptide Ester Prodrugs of Acyclovir after Oral Administration: Intestinal Absorption and Liver Metabolism

Banmeet S. Anand, Suresh Katragadda and Ashim K. Mitra
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 659-667; DOI: https://doi.org/10.1124/jpet.104.069997

Citation Manager Formats

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

Share
Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics of Novel Dipeptide Ester Prodrugs of Acyclovir after Oral Administration: Intestinal Absorption and Liver Metabolism

Banmeet S. Anand, Suresh Katragadda and Ashim K. Mitra
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 659-667; DOI: https://doi.org/10.1124/jpet.104.069997
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

  • Transport Is Not Rate-Limiting in Morphine Glucuronidation in the Single-Pass Perfused Rat Liver Preparation
  • Enhanced Hepatic Uptake and Bioactivity of Type α1(I) Collagen Gene Promoter-Specific Triplex-Forming Oligonucleotides after Conjugation with Cholesterol
  • Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana
Show more ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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