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

Differences in Metformin and Thiamine Uptake between Human and Mouse Organic Cation Transporter 1: Structural Determinants and Potential Consequences for Intrahepatic Concentrations

Marleen J. Meyer, Alzbeta Tuerkova, Sarah Römer, Christoph Wenzel, Tina Seitz, Jochen Gaedcke, Stefan Oswald, Jürgen Brockmöller, Barbara Zdrazil and Mladen V. Tzvetkov
Drug Metabolism and Disposition December 2020, 48 (12) 1380-1392; DOI: https://doi.org/10.1124/dmd.120.000170
Marleen J. Meyer
Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany (M.J.M., S.R., C.W., S.O., M.V.T.); Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Vienna, Austria (A.T., B.Z.); and Department of General, Visceral, and Pediatric Surgery (J.G.) and Institute of Clinical Pharmacology (T.S., J.B.), University Medical Center Göttingen, Göttingen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alzbeta Tuerkova
Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany (M.J.M., S.R., C.W., S.O., M.V.T.); Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Vienna, Austria (A.T., B.Z.); and Department of General, Visceral, and Pediatric Surgery (J.G.) and Institute of Clinical Pharmacology (T.S., J.B.), University Medical Center Göttingen, Göttingen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sarah Römer
Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany (M.J.M., S.R., C.W., S.O., M.V.T.); Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Vienna, Austria (A.T., B.Z.); and Department of General, Visceral, and Pediatric Surgery (J.G.) and Institute of Clinical Pharmacology (T.S., J.B.), University Medical Center Göttingen, Göttingen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christoph Wenzel
Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany (M.J.M., S.R., C.W., S.O., M.V.T.); Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Vienna, Austria (A.T., B.Z.); and Department of General, Visceral, and Pediatric Surgery (J.G.) and Institute of Clinical Pharmacology (T.S., J.B.), University Medical Center Göttingen, Göttingen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tina Seitz
Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany (M.J.M., S.R., C.W., S.O., M.V.T.); Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Vienna, Austria (A.T., B.Z.); and Department of General, Visceral, and Pediatric Surgery (J.G.) and Institute of Clinical Pharmacology (T.S., J.B.), University Medical Center Göttingen, Göttingen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jochen Gaedcke
Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany (M.J.M., S.R., C.W., S.O., M.V.T.); Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Vienna, Austria (A.T., B.Z.); and Department of General, Visceral, and Pediatric Surgery (J.G.) and Institute of Clinical Pharmacology (T.S., J.B.), University Medical Center Göttingen, Göttingen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefan Oswald
Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany (M.J.M., S.R., C.W., S.O., M.V.T.); Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Vienna, Austria (A.T., B.Z.); and Department of General, Visceral, and Pediatric Surgery (J.G.) and Institute of Clinical Pharmacology (T.S., J.B.), University Medical Center Göttingen, Göttingen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jürgen Brockmöller
Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany (M.J.M., S.R., C.W., S.O., M.V.T.); Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Vienna, Austria (A.T., B.Z.); and Department of General, Visceral, and Pediatric Surgery (J.G.) and Institute of Clinical Pharmacology (T.S., J.B.), University Medical Center Göttingen, Göttingen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Barbara Zdrazil
Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany (M.J.M., S.R., C.W., S.O., M.V.T.); Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Vienna, Austria (A.T., B.Z.); and Department of General, Visceral, and Pediatric Surgery (J.G.) and Institute of Clinical Pharmacology (T.S., J.B.), University Medical Center Göttingen, Göttingen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Barbara Zdrazil
Mladen V. Tzvetkov
Institute of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany (M.J.M., S.R., C.W., S.O., M.V.T.); Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Vienna, Austria (A.T., B.Z.); and Department of General, Visceral, and Pediatric Surgery (J.G.) and Institute of Clinical Pharmacology (T.S., J.B.), University Medical Center Göttingen, Göttingen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Mladen V. Tzvetkov
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

The most commonly used oral antidiabetic drug, metformin, is a substrate of the hepatic uptake transporter OCT1 (gene name SLC22A1). However, OCT1 deficiency leads to more pronounced reductions of metformin concentrations in mouse than in human liver. Similarly, the effects of OCT1 deficiency on the pharmacokinetics of thiamine were reported to differ between human and mouse. Here, we compared the uptake characteristics of metformin and thiamine between human and mouse OCT1 using stably transfected human embryonic kidney 293 cells. The affinity for metformin was 4.9-fold lower in human than in mouse OCT1, resulting in a 6.5-fold lower intrinsic clearance. Therefore, the estimated liver-to-blood partition coefficient is only 3.34 in human compared with 14.4 in mouse and may contribute to higher intrahepatic concentrations in mice. Similarly, the affinity for thiamine was 9.5-fold lower in human than in mouse OCT1. Using human-mouse chimeric OCT1, we showed that simultaneous substitution of transmembrane helices TMH2 and TMH3 resulted in the reversal of affinity for metformin. Using homology modeling, we suggest several explanations, of which a different interaction of Leu155 (human TMH2) compared with Val156 (mouse TMH2) with residues in TMH3 had the strongest experimental support. In conclusion, the contribution of human OCT1 to the cellular uptake of thiamine and especially of metformin may be much lower than that of mouse OCT1. This may lead to an overestimation of the effects of OCT1 on hepatic concentrations in humans when using mouse as a model. In addition, comparative analyses of human and mouse orthologs may help reveal mechanisms of OCT1 transport.

SIGNIFICANCE STATEMENT OCT1 is a major hepatic uptake transporter of metformin and thiamine, but this study reports strong differences in the affinity for both compounds between human and mouse OCT1. Consequently, intrahepatic metformin concentrations could be much higher in mice than in humans, impacting metformin actions and representing a strong limitation of using rodent animal models for predictions of OCT1-related pharmacokinetics and efficacy in humans. Furthermore, OCT1 transmembrane helices TMH2 and TMH3 were identified to confer the observed species-specific differences in metformin affinity.

Footnotes

    • Received July 6, 2020.
    • Accepted September 28, 2020.
  • This work was supported in part by European Regional Development Fund (ERDF) [Grant GHS-18-0021] to M.V.T.

  • Part of this work has been presented in the poster “OCT1 of mice and men – species-specific differences in the function of OCT1” by Meyer, MJ; Bolesta, M; Schreier, P; Krätzner, R; Seitz, T; Brockmöller, J; Tzvetkov, MV at the 11th International BioMedical Transporters Conference, Aug. 4-8, 2019 in Lucerne, Switzerland. This work is part of the Ph.D. thesis of M.J.M.

  • https://doi.org/10.1124/dmd.120.000170.

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

  • Copyright © 2020 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: 48 (12)
Drug Metabolism and Disposition
Vol. 48, Issue 12
1 Dec 2020
  • 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.
Differences in Metformin and Thiamine Uptake between Human and Mouse Organic Cation Transporter 1: Structural Determinants and Potential Consequences for Intrahepatic Concentrations
(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

Human and Mouse OCT1 Differ in Metformin and Thiamine Uptake

Marleen J. Meyer, Alzbeta Tuerkova, Sarah Römer, Christoph Wenzel, Tina Seitz, Jochen Gaedcke, Stefan Oswald, Jürgen Brockmöller, Barbara Zdrazil and Mladen V. Tzvetkov
Drug Metabolism and Disposition December 1, 2020, 48 (12) 1380-1392; DOI: https://doi.org/10.1124/dmd.120.000170

Citation Manager Formats

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

Human and Mouse OCT1 Differ in Metformin and Thiamine Uptake

Marleen J. Meyer, Alzbeta Tuerkova, Sarah Römer, Christoph Wenzel, Tina Seitz, Jochen Gaedcke, Stefan Oswald, Jürgen Brockmöller, Barbara Zdrazil and Mladen V. Tzvetkov
Drug Metabolism and Disposition December 1, 2020, 48 (12) 1380-1392; DOI: https://doi.org/10.1124/dmd.120.000170
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
    • 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

  • 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