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

In Vitro Characterization and Pharmacokinetics of Dapagliflozin (BMS-512148), a Potent Sodium-Glucose Cotransporter Type II Inhibitor, in Animals and Humans

M. Obermeier, M. Yao, A. Khanna, B. Koplowitz, M. Zhu, W. Li, B. Komoroski, S. Kasichayanula, L. Discenza, W. Washburn, W. Meng, B. A. Ellsworth, J. M. Whaley and W. G. Humphreys
Drug Metabolism and Disposition March 2010, 38 (3) 405-414; DOI: https://doi.org/10.1124/dmd.109.029165
M. Obermeier
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M. Yao
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
A. Khanna
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
B. Koplowitz
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M. Zhu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
W. Li
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
B. Komoroski
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. Kasichayanula
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
L. Discenza
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
W. Washburn
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
W. Meng
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
B. A. Ellsworth
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. M. Whaley
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
W. G. Humphreys
  • 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

(2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol (dapagliflozin; BMS-512148) is a potent sodium-glucose cotransporter type II inhibitor in animals and humans and is currently under development for the treatment of type 2 diabetes. The preclinical characterization of dapagliflozin, to allow compound selection and prediction of pharmacological and dispositional behavior in the clinic, involved Caco-2 cell permeability studies, cytochrome P450 (P450) inhibition and induction studies, P450 reaction phenotyping, metabolite identification in hepatocytes, and pharmacokinetics in rats, dogs, and monkeys. Dapagliflozin was found to have good permeability across Caco-2 cell membranes. It was found to be a substrate for P-glycoprotein (P-gp) but not a significant P-gp inhibitor. Dapagliflozin was not found to be an inhibitor or an inducer of human P450 enzymes. The in vitro metabolic profiles of dapagliflozin after incubation with hepatocytes from mice, rats, dogs, monkeys, and humans were qualitatively similar. Rat hepatocyte incubations showed the highest turnover, and dapagliflozin was most stable in human hepatocytes. Prominent in vitro metabolic pathways observed were glucuronidation, hydroxylation, and O-deethylation. Pharmacokinetic parameters for dapagliflozin in preclinical species revealed a compound with adequate oral exposure, clearance, and elimination half-life, consistent with the potential for single daily dosing in humans. The pharmacokinetics in humans after a single dose of 50 mg of [14C]dapagliflozin showed good exposure, low clearance, adequate half-life, and no metabolites with significant pharmacological activity or toxicological concern.

Footnotes

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

    doi:10.1124/dmd.109.029165.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • SGLT
    sodium-glucose cotransporter
    ADME
    absorption, distribution, metabolism, and excretion
    dapagliflozin/BMS-512148
    (2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol
    HPLC
    high-performance liquid chromatography
    P450
    cytochrome P450
    HLM
    human liver microsome
    ACN
    acetonitrile
    LC/MS/MS
    liquid chromatography/tandem mass spectroscopy
    TRA
    total radioactivity
    P-gp
    P-glycoprotein
    GF120918
    N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide
    fu
    fraction unbound
    DMSO
    dimethyl sulfoxide
    LC/MS
    liquid chromatography/mass spectrometry
    ODS
    octyl dodecyl sulfate, C18
    CPM
    counts per minute
    BQL
    below quantifiable limit
    AUC
    area under the concentration/time curve
    CL
    total body clearance
    MRT
    mean residence time
    Vss
    volume of distribution at steady state
    CLR
    renal clearance
    GFR
    glomerular filtration rate
    F
    oral bioavailability
    A
    apical
    B
    basolateral
    Tmax
    time that peak concentrations are reached
    BMS-511926
    2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
    BMS-639432
    2S,3R,4R,5S,6R)-2-(4-chloro-3-((4-ethoxyphenyl) (hydroxy)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

    • Received July 1, 2009.
    • Accepted December 7, 2009.
  • Copyright © 2010 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: 38 (3)
Drug Metabolism and Disposition
Vol. 38, Issue 3
1 Mar 2010
  • 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.
In Vitro Characterization and Pharmacokinetics of Dapagliflozin (BMS-512148), a Potent Sodium-Glucose Cotransporter Type II Inhibitor, in Animals and Humans
(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

In Vitro Characterization and Pharmacokinetics of Dapagliflozin (BMS-512148), a Potent Sodium-Glucose Cotransporter Type II Inhibitor, in Animals and Humans

M. Obermeier, M. Yao, A. Khanna, B. Koplowitz, M. Zhu, W. Li, B. Komoroski, S. Kasichayanula, L. Discenza, W. Washburn, W. Meng, B. A. Ellsworth, J. M. Whaley and W. G. Humphreys
Drug Metabolism and Disposition March 1, 2010, 38 (3) 405-414; DOI: https://doi.org/10.1124/dmd.109.029165

Citation Manager Formats

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

Share
Research ArticleArticle

In Vitro Characterization and Pharmacokinetics of Dapagliflozin (BMS-512148), a Potent Sodium-Glucose Cotransporter Type II Inhibitor, in Animals and Humans

M. Obermeier, M. Yao, A. Khanna, B. Koplowitz, M. Zhu, W. Li, B. Komoroski, S. Kasichayanula, L. Discenza, W. Washburn, W. Meng, B. A. Ellsworth, J. M. Whaley and W. G. Humphreys
Drug Metabolism and Disposition March 1, 2010, 38 (3) 405-414; DOI: https://doi.org/10.1124/dmd.109.029165
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

  • Identification of payload-containing catabolites of ADCs
  • PK Interactions of Licorice with Cytochrome P450s
  • Biotransformation of Trastuzumab and Pertuzumab
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