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 ArticleToxicology

BTK small molecule inhibitors induce a distinct pancreatic toxicity in rats

Rebecca I Erickson, Leah K. Schutt, Jacqueline Tarrant, Michelle McDowell, Lichuan Liu, Adam R Johnson, Sock-Cheng Lewin-Koh, Maj Hedehus, Jed Ross, Richard A.D. Carano, Karin Staflin, Fiona Zhong, James Crawford, Shelly Zhong, Karin Reif, Arna Katewa, Harvey Wong, Wendy Young, Donna Dambach and Dinah Misner
Journal of Pharmacology and Experimental Therapeutics November 7, 2016, jpet.116.236224; DOI: https://doi.org/10.1124/jpet.116.236224
Rebecca I Erickson
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Leah K. Schutt
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jacqueline Tarrant
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michelle McDowell
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lichuan Liu
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adam R Johnson
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sock-Cheng Lewin-Koh
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maj Hedehus
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jed Ross
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard A.D. Carano
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karin Staflin
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Fiona Zhong
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James Crawford
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shelly Zhong
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Karin Reif
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Arna Katewa
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Harvey Wong
2 University of British Columbia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wendy Young
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Donna Dambach
1 Genentech, Inc.;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dinah Misner
1 Genentech, Inc.;
  • 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

Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematological cancers and autoimmune diseases. GDC-0853 is a selective and reversible oral small molecule BTK inhibitor in development for the treatment of rheumatoid arthritis and systemic lupus erythematosus. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer caused pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation. Similar findings were not observed in mice or dogs at much higher exposures. Hemorrhage in the peri-islet vasculature emerged between 4 and 7 daily doses of GDC-0853 and was histologically similar to spontaneously occurring changes in aging SD rats. This suggests that GDC-0853 could be exacerbating a background finding in younger animals. Glucose homeostasis was dysregulated following a glucose challenge; however, this occurred only after 28 days of administration and was not directly associated with onset or severity of pancreatic lesions. There were no changes in other common serum biomarkers assessing endocrine and exocrine pancreatic function. Additionally, these lesions were not readily detectable via Doppler ultrasound, computed tomography, or magnetic resonance imaging. Our results indicate that pancreatic lesions in rats are likely a class effect of BTK inhibitors, which may exacerbate an islet-centered pathology that is unlikely to be relevant to humans.

  • autoimmune disorders
  • toxicity
  • toxicity testing
  • toxicology
  • The American Society for Pharmacology and Experimental Therapeutics
Next
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
  • 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 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.
BTK small molecule inhibitors induce a distinct pancreatic toxicity in rats
(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 ArticleToxicology

BTK small molecule inhibitors induce a distinct pancreatic toxicity in rats

Rebecca I Erickson, Leah K. Schutt, Jacqueline Tarrant, Michelle McDowell, Lichuan Liu, Adam R Johnson, Sock-Cheng Lewin-Koh, Maj Hedehus, Jed Ross, Richard A.D. Carano, Karin Staflin, Fiona Zhong, James Crawford, Shelly Zhong, Karin Reif, Arna Katewa, Harvey Wong, Wendy Young, Donna Dambach and Dinah Misner
Journal of Pharmacology and Experimental Therapeutics November 7, 2016, jpet.116.236224; DOI: https://doi.org/10.1124/jpet.116.236224

Citation Manager Formats

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

Share
Research ArticleToxicology

BTK small molecule inhibitors induce a distinct pancreatic toxicity in rats

Rebecca I Erickson, Leah K. Schutt, Jacqueline Tarrant, Michelle McDowell, Lichuan Liu, Adam R Johnson, Sock-Cheng Lewin-Koh, Maj Hedehus, Jed Ross, Richard A.D. Carano, Karin Staflin, Fiona Zhong, James Crawford, Shelly Zhong, Karin Reif, Arna Katewa, Harvey Wong, Wendy Young, Donna Dambach and Dinah Misner
Journal of Pharmacology and Experimental Therapeutics November 7, 2016, jpet.116.236224; DOI: https://doi.org/10.1124/jpet.116.236224
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
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Nafamostat is a Potent Human Diamine Oxidase Inhibitor
  • Chemoproteomics Investigation of Testicular Toxicity with BTK Inhibitor
  • Bosentan Alters Bile Salt Disposition
Show more Toxicology

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