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

High Daily Dose and Being a Substrate of Cytochrome P450 Enzymes Are Two Important Predictors of Drug-Induced Liver Injury

Ke Yu, Xingchao Geng, Minjun Chen, Jie Zhang, Bingshun Wang, Katarina Ilic and Weida Tong
Drug Metabolism and Disposition April 2014, 42 (4) 744-750; DOI: https://doi.org/10.1124/dmd.113.056267
Ke Yu
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas (K.Y., M.C., J.Z., W.T.); National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, China's State Food and Drug Administration, Beijing, China (X.G.); Department of Biostatistics, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.W.); and Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (K.I.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xingchao Geng
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas (K.Y., M.C., J.Z., W.T.); National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, China's State Food and Drug Administration, Beijing, China (X.G.); Department of Biostatistics, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.W.); and Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (K.I.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Minjun Chen
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas (K.Y., M.C., J.Z., W.T.); National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, China's State Food and Drug Administration, Beijing, China (X.G.); Department of Biostatistics, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.W.); and Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (K.I.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jie Zhang
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas (K.Y., M.C., J.Z., W.T.); National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, China's State Food and Drug Administration, Beijing, China (X.G.); Department of Biostatistics, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.W.); and Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (K.I.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bingshun Wang
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas (K.Y., M.C., J.Z., W.T.); National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, China's State Food and Drug Administration, Beijing, China (X.G.); Department of Biostatistics, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.W.); and Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (K.I.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Katarina Ilic
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas (K.Y., M.C., J.Z., W.T.); National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, China's State Food and Drug Administration, Beijing, China (X.G.); Department of Biostatistics, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.W.); and Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (K.I.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Weida Tong
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas (K.Y., M.C., J.Z., W.T.); National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, China's State Food and Drug Administration, Beijing, China (X.G.); Department of Biostatistics, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.W.); and Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (K.I.)
  • 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

Drug-induced liver injury (DILI) is complicated and difficult to predict. It has been observed that drugs with extensive hepatic metabolism have a higher likelihood of causing DILI. Cytochrome P450 (P450) enzymes are primarily involved in hepatic metabolism. Identifying the associations of DILI with drugs that are P450 substrates, inhibitors, or inducers will be extremely helpful to clinicians during the decision-making process of caring for a patient suspected of having DILI. We collected metabolism data on P450 enzymes for 254 orally administered drugs in the Liver Toxicity Knowledge Base Benchmark Dataset with a known daily dose, and applied logistic regression to identify these associations. We revealed that drugs that are substrates of P450 enzymes have a higher likelihood of causing DILI [odds ratio (OR), 3.99; 95% confidence interval (95% CI), 2.07–7.67; P < 0.0001], which is dose-independent, and drugs that are P450 inhibitors have a higher likelihood of generating DILI only when they are administered at high daily doses (OR, 6.03; 95% CI, 1.32–27.5; P = 0.0098). However, drugs that are P450 inducers are not observed to be associated with DILI (OR, 1.55; 95% CI, 0.65–3.68; P = 0.3246). Our findings will be useful in identifying the suspected medication as a cause of liver injury in clinical settings.

Footnotes

    • Received December 2, 2013.
    • Accepted January 23, 2014.
  • K.Y. is supported by the Research Participation Program at the National Center for Toxicological Research (NCTR) administrated by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration (FDA). B.W. is supported by the FDA/NCTR Division of Bioinformatics and Biostatistics, ORISE, Chinese Ministry of Science and Technology [National Science and Technology Mega Project Grant 2012ZX09301001-006(003)], and Shanghai Jiao Tong University [K.C. Wong Medical Fellowship Fund]. K.I. worked at NCTR during her summer sabbatical and was supported by ORISE and the Republic of Serbia Ministry of Education and Science (Project 175064, 2011–2014). The views presented in this article do not reflect those of the FDA. Any mention of commercial products is for clarification and is not intended to constitute endorsement or recommendation for use.

  • K.Y. and X.G. contributed equally to this work.

  • ↵dx.doi.org/10.1124/dmd.113.056267.

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

  • 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: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
  • 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.
High Daily Dose and Being a Substrate of Cytochrome P450 Enzymes Are Two Important Predictors of Drug-Induced Liver Injury
(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

Two Important Predictors for Drug-Induced Liver Injury

Ke Yu, Xingchao Geng, Minjun Chen, Jie Zhang, Bingshun Wang, Katarina Ilic and Weida Tong
Drug Metabolism and Disposition April 1, 2014, 42 (4) 744-750; DOI: https://doi.org/10.1124/dmd.113.056267

Citation Manager Formats

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

Share
Research ArticleArticle

Two Important Predictors for Drug-Induced Liver Injury

Ke Yu, Xingchao Geng, Minjun Chen, Jie Zhang, Bingshun Wang, Katarina Ilic and Weida Tong
Drug Metabolism and Disposition April 1, 2014, 42 (4) 744-750; DOI: https://doi.org/10.1124/dmd.113.056267
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
  • Olanzapine Glucuronidation in Humanized Mice
  • rs2242480 Regulates the Expression of CYP3A4 and CYP3A5
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