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

Chemoenzymatic Synthesis, Characterization, and Scale-Up of Milk Thistle Flavonolignan Glucuronides

Brandon T. Gufford, Tyler N. Graf, Noemi D. Paguigan, Nicholas H. Oberlies and Mary F. Paine
Drug Metabolism and Disposition November 2015, 43 (11) 1734-1743; DOI: https://doi.org/10.1124/dmd.115.066076
Brandon T. Gufford
Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (B.T.G., M.F.P.); and Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.D.P., N.H.O.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tyler N. Graf
Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (B.T.G., M.F.P.); and Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.D.P., N.H.O.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Noemi D. Paguigan
Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (B.T.G., M.F.P.); and Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.D.P., N.H.O.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nicholas H. Oberlies
Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (B.T.G., M.F.P.); and Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.D.P., N.H.O.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mary F. Paine
Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington (B.T.G., M.F.P.); and Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.D.P., N.H.O.)
  • 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

Plant-based therapeutics, including herbal products, continue to represent a growing facet of the contemporary health care market. Mechanistic descriptions of the pharmacokinetics and pharmacodynamics of constituents composing these products remain nascent, particularly for metabolites produced following herbal product ingestion. Generation and characterization of authentic metabolite standards are essential to improve the quantitative mechanistic understanding of herbal product disposition in both in vitro and in vivo systems. Using the model herbal product, milk thistle, the objective of this work was to biosynthesize multimilligram quantities of glucuronides of select constituents (flavonolignans) to fill multiple knowledge gaps in the understanding of herbal product disposition and action. A partnership between clinical pharmacology and natural products chemistry expertise was leveraged to optimize reaction conditions for efficient glucuronide formation and evaluate alternate enzyme and reagent sources to improve cost effectiveness. Optimized reaction conditions used at least one-fourth the amount of microsomal protein (from bovine liver) and cofactor (UDP glucuronic acid) compared with typical conditions using human-derived subcellular fractions, providing substantial cost savings. Glucuronidation was flavonolignan-dependent. Silybin A, silybin B, isosilybin A, and isosilybin B generated five, four, four, and three monoglucuronides, respectively. Large-scale synthesis (40 mg of starting material) generated three glucuronides of silybin A: silybin A-7-O-β-d-glucuronide (15.7 mg), silybin A-5-O-β-d-glucuronide (1.6 mg), and silybin A-4´´-O-β-d-glucuronide (11.1 mg). This optimized, cost-efficient method lays the foundation for a systematic approach to synthesize and characterize herbal product constituent glucuronides, enabling an improved understanding of mechanisms underlying herbal product disposition and action.

Footnotes

    • Received June 26, 2015.
    • Accepted August 26, 2015.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM077482-S1]. B.T.G. was supported by fellowships awarded by the American Foundation for Pharmaceutical Education and the James and Diann Robbers Student Research Fund. B.T.G. is currently supported by the National Institute of General Medical Sciences [Grant T32-GM008425]. Alamethicin F50 was isolated as part of Program Project Grant P01-CA125066 from the National Institutes of Health National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health.

  • dx.doi.org/10.1124/dmd.115.066076.

  • ↵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 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 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.
Chemoenzymatic Synthesis, Characterization, and Scale-Up of Milk Thistle Flavonolignan Glucuronides
(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

Synthesis and Characterization of Milk Thistle Glucuronides

Brandon T. Gufford, Tyler N. Graf, Noemi D. Paguigan, Nicholas H. Oberlies and Mary F. Paine
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1734-1743; DOI: https://doi.org/10.1124/dmd.115.066076

Citation Manager Formats

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

Share
Research ArticleArticle

Synthesis and Characterization of Milk Thistle Glucuronides

Brandon T. Gufford, Tyler N. Graf, Noemi D. Paguigan, Nicholas H. Oberlies and Mary F. Paine
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1734-1743; DOI: https://doi.org/10.1124/dmd.115.066076
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

  • A PBPK model for CBD in adults and children
  • Mass Balance Recovery and Disposition of AZD4831 in Humans
  • Biotransformation of AZD4831 in Animals and Humans
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