Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • For Subscribers
    • For Advertisers
    • 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

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
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • For Subscribers
    • For Advertisers
    • 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

In Silico Modeling of Nonspecific Binding to Human Liver Microsomes

Hua Gao, Lili Yao, Heather W. Mathieu, Ying Zhang, Tristan S. Maurer, Matthew D. Troutman, Dennis O. Scott, Roger B. Ruggeri and Jing Lin
Drug Metabolism and Disposition October 2008, 36 (10) 2130-2135; DOI: https://doi.org/10.1124/dmd.107.020131
Hua Gao
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lili Yao
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heather W. Mathieu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ying Zhang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tristan S. Maurer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew D. Troutman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dennis O. Scott
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Roger B. Ruggeri
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jing Lin
  • 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

Estimation of unbound fraction of substrate in microsomal incubation media is important in accurately predicting hepatic intrinsic clearance and drug-drug interactions. In this study, the unbound fraction of 1223 drug-like molecules in human liver microsomal incubation media has been determined using equilibrium dialysis. These compounds, which include 27 marketed drug molecules, cover a much broader range of physiochemical properties such as hydrophobicity, molecular weight, ionization state, and degree of binding than those examined in previous work. In developing the in silico model, we have used two-dimensional molecular descriptors including cLogP, Kier connectivity, shape, and E-state indices, a subset of MOE descriptors, and a set of absorption, disposition, metabolism, and excretion structural keys used for our in-house absorption, disposition, metabolism, excretion, and toxicity modeling. Hydrophobicity is the most important molecular property contributing to the nonspecific binding of substrate to microsomes. The prediction accuracy of the model is validated using a subset of 100 compounds, and 92% of the variance is accounted for by the model with a root mean square error (RMSE) of 0.10. For the training set of compounds, 99% of variance is accounted for by the model with a RMSE of 0.02. The performance of the developed model has been further tested using the 27 marketed drug molecules with a RMSE of 0.10 between the observed and the predicted unbound fraction values.

Footnotes

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

  • doi:10.1124/dmd.107.020131.

  • ABBREVIATIONS: P450, cytochrome P450; LC, liquid chromatography; MS/MS, tandem mass spectroscopy; ADME, absorption, disposition, metabolism, and excretion; ADMET, absorption, disposition, metabolism, excretion, and toxicity; NN, nearest neighbor.

    • Received December 13, 2007.
    • Accepted July 3, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

Log in using your username and password

Forgot your user name or password?

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00

Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.

PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 36 (10)
Drug Metabolism and Disposition
Vol. 36, Issue 10
1 Oct 2008
  • 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 Silico Modeling of Nonspecific Binding to Human Liver Microsomes
(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.
Citation Tools
Research ArticleArticle

In Silico Modeling of Nonspecific Binding to Human Liver Microsomes

Hua Gao, Lili Yao, Heather W. Mathieu, Ying Zhang, Tristan S. Maurer, Matthew D. Troutman, Dennis O. Scott, Roger B. Ruggeri and Jing Lin
Drug Metabolism and Disposition October 1, 2008, 36 (10) 2130-2135; DOI: https://doi.org/10.1124/dmd.107.020131

Citation Manager Formats

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

In Silico Modeling of Nonspecific Binding to Human Liver Microsomes

Hua Gao, Lili Yao, Heather W. Mathieu, Ying Zhang, Tristan S. Maurer, Matthew D. Troutman, Dennis O. Scott, Roger B. Ruggeri and Jing Lin
Drug Metabolism and Disposition October 1, 2008, 36 (10) 2130-2135; DOI: https://doi.org/10.1124/dmd.107.020131
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
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • UDP-glycosyltransferase 3A (UGT3A) metabolism of polycyclic aromatic hydrocarbons: potential importance in aerodigestive tract tissues
  • Identification and characterization of a new carboxylesterase 2 isozyme, mfCES2C, in the small intestine of cynomolgus monkeys
  • Nonlinear PBPK Modeling of Atipamezole
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 © 2019 by the American Society for Pharmacology and Experimental Therapeutics