Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • 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
  • 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
    • 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
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Characterization of the Inhibitory Effects of N-Butylpyridinium Chloride and Structurally Related Ionic Liquids on Organic Cation Transporters 1/2 and Human Toxic Extrusion Transporters 1/2-K In Vitro and In Vivo

Yaofeng Cheng, Lucy J. Martinez-Guerrero, Stephen H. Wright, Robert K. Kuester, Michelle J. Hooth and I. Glenn Sipes
Drug Metabolism and Disposition September 2011, 39 (9) 1755-1761; DOI: https://doi.org/10.1124/dmd.110.035865
Yaofeng Cheng
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lucy J. Martinez-Guerrero
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen H. Wright
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert K. Kuester
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michelle J. Hooth
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
I. Glenn Sipes
  • 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

Ionic liquids (ILs) are a class of salts that are expected to be used as a new source of solvents and for many other applications. Our previous studies revealed that selected ILs, structurally related organic cations, are eliminated exclusively in urine as the parent compound, partially mediated by renal transporters. This study investigated the inhibitory effects of N-butylpyridinium chloride (NBuPy-Cl) and structurally related ILs on organic cation transporters (OCTs) and multidrug and toxic extrusion transporters (MATEs) in vitro and in vivo. After Chinese hamster ovary cells expressing rat (r) OCT1, rOCT2, human (h) OCT2, hMATE1, or hMATE2-K were constructed, the ability of NBuPy-Cl, 1-methyl-3-butylimidazolium chloride (Bmim-Cl), N-butyl-N-methylpyrrolidinium chloride (BmPy-Cl), and alkyl substituted pyridinium ILs to inhibit these transporters was determined in vitro. NBuPy-Cl (0, 0.5, or 2 mg/kg per hour) was also infused into rats to assess its effect on the pharmacokinetics of metformin, a substrate of OCTs and MATEs. NBuPy-Cl, Bmim-Cl, and BmPy-Cl displayed strong inhibitory effects on these transporters (IC50 = 0.2–8.5 μM). In addition, the inhibitory effects of alkyl-substituted pyridinium ILs on OCTs increased dramatically as the length of the alkyl chain increased. The IC50 values were 0.1, 3.8, 14, and 671 μM (hexyl-, butyl-, and ethyl-pyridinium and pyridinium chloride) for rOCT2-mediated metformin transport. Similar structurally related inhibitory kinetics were also observed for rOCT1 and hOCT2. The in vivo coadministration study revealed that NBuPy-Cl reduced the renal clearance of metformin in rats. These results demonstrate that ILs compete with other substrates of OCTs and MATEs and could alter the in vivo pharmacokinetics of such substrates.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Contract N01-ES45529] (National Toxicology Program); the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK58251]; and the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES06694].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.035865.

  • ABBREVIATIONS:

    IL
    ionic liquid
    SAR
    structure-activity relationship
    NBuPy-Cl
    N-butylpyridinium chloride
    Bmim-Cl
    1-butyl-3-methylimidazolium chloride
    BmPy-Cl
    N-butyl-N-methylpyrrolidinium chloride
    OCT
    organic cation transporter
    MATE
    multidrug and toxic extrusion transporter
    Py-Cl
    pyridine hydrochloride
    EtPy-Cl
    1-ethylpyridinium chloride
    HePy-Cl
    1-hexylpyridinium chloride
    TEA
    tetraethylammonium trifluoroacetate
    MPP
    1-methyl-4-phenylpyridinium
    CHO
    Chinese hamster ovary
    r
    rat
    h
    human
    LSC
    liquid scintillation counter
    GFR
    glomerular filtration rate
    Kt
    concentration of substrate that results in half-maximal transport.

  • Received August 13, 2010.
  • Accepted June 1, 2011.
  • U.S. Government work not protected by U.S. copyright
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: 39 (9)
Drug Metabolism and Disposition
Vol. 39, Issue 9
1 Sep 2011
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • 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.
Characterization of the Inhibitory Effects of N-Butylpyridinium Chloride and Structurally Related Ionic Liquids on Organic Cation Transporters 1/2 and Human Toxic Extrusion Transporters 1/2-K In Vitro and In Vivo
(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

Characterization of the Inhibitory Effects of N-Butylpyridinium Chloride and Structurally Related Ionic Liquids on Organic Cation Transporters 1/2 and Human Toxic Extrusion Transporters 1/2-K In Vitro and In Vivo

Yaofeng Cheng, Lucy J. Martinez-Guerrero, Stephen H. Wright, Robert K. Kuester, Michelle J. Hooth and I. Glenn Sipes
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1755-1761; DOI: https://doi.org/10.1124/dmd.110.035865

Citation Manager Formats

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

Characterization of the Inhibitory Effects of N-Butylpyridinium Chloride and Structurally Related Ionic Liquids on Organic Cation Transporters 1/2 and Human Toxic Extrusion Transporters 1/2-K In Vitro and In Vivo

Yaofeng Cheng, Lucy J. Martinez-Guerrero, Stephen H. Wright, Robert K. Kuester, Michelle J. Hooth and I. Glenn Sipes
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1755-1761; DOI: https://doi.org/10.1124/dmd.110.035865
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Results
    • Discussion
    • Authorship Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Candesartan glucuronide serves as a CYP2C8 inhibitor
  • Role of AADAC on eslicarbazepine acetate hydrolysis
  • Gene expression profile of human intestinal epithelial cells
Show more Articles

Similar Articles

  • 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 © 2021 by the American Society for Pharmacology and Experimental Therapeutics