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
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
    • 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 jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleMetabolism, Transport, and Pharmacogenomics

Simultaneous Assessment of Hepatic Transport and Metabolism Pathways with a Single Probe Using Individualized PBPK Modeling of 14CO2 Production Rate Data

Yoko Franchetti and Thomas D. Nolin
Journal of Pharmacology and Experimental Therapeutics October 2019, 371 (1) 151-161; DOI: https://doi.org/10.1124/jpet.119.257212
Yoko Franchetti
Departments of Pharmaceutical Sciences (Y.F.) and Pharmacy and Therapeutics (T.D.N.), Center of Clinical Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas D. Nolin
Departments of Pharmaceutical Sciences (Y.F.) and Pharmacy and Therapeutics (T.D.N.), Center of Clinical Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Thomas D. Nolin
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

Erythromycin is a substrate of cytochrome P4503A4 (CYP3A4) and multiple drug transporters. Although clinical evidence suggests that uptake transport is likely to play a dominant role in erythromycin’s disposition, the relative contributions of individual pathways are unclear. Phenotypic evaluation of multiple pathways generally requires a probe drug cocktail. This approach can result in ambiguous conclusions due to imprecision stemming from overlapping specificity of multiple drugs. We hypothesized that an individualized physiologically based pharmacokinetic modeling approach incorporating 14CO2 production rates (iPBPK-R) of the erythromycin breath test (ERMBT) would enable us to differentiate the contribution of metabolic and transporter pathways to erythromycin disposition. A seven-compartmental physiologically based pharmacokinetic (PBPK) model was built for 14C-erythromycin administered intravenously. Transporter clearance and CYP3A4 clearance were embedded in hepatic compartments. 14CO2 production rates were simulated taking the first derivative of by-product 14CO2 concentrations. Parameters related to nonrenal elimination pathways were estimated by model fitting the ERMBT data of 12 healthy subjects individually. Optimized iPBPK-R models fit the individual rate data well. Using one probe, nine PBPK parameters were simultaneously estimated per individual. Maximum velocity of uptake transport, CYP3A4 clearance, total passive diffusion, and others were found to collectively control 14CO2 production rates. The median CYP3A4 clearance was 12.2% of the input clearance. Male subjects had lower CYP3A4 activity than female subjects by 11.3%. We applied iPBPK-R to ERMBT data to distinguish and simultaneously estimate the activity of multiple nonrenal elimination pathways in healthy subjects. The iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate-limiting elimination pathways using a single probe.

SIGNIFICANCE STATEMENT Our developed individualized physiologically based pharmacokinetic modeling approach incorporating rate data (iPBPK-R) enabled us to distinguish and simultaneously estimate the activity of multiple nonrenal elimination pathways of erythromycin in healthy subjects. A new interpretation of erythromycin breath test (ERMBT) data was also obtained via iPBPK-R. We found that rate data have rich information allowing estimation of per-person PBPK parameters. This study serves as proof of principle that the iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate-limiting elimination pathways using a single probe. iPBPK-R can be applied to other rate-derived data beyond ERMBT. Potential areas of application include drug–drug interaction, pathophysiological effects on drug disposition, and the role of biomarkers on hemodialysis efficiency utilizing estimated adjustment factors with correlation analysis.

Footnotes

    • Received February 21, 2019.
    • Accepted July 31, 2019.
  • This work is an extension of a study previously funded by the Satellite Healthcare Research Foundation. Y.F. is supported by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. T.D.N. is supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM107122]. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1548562, and XSEDE Bridges at the Pittsburgh Supercomputing Center through allocation BIO180015.

  • https://doi.org/10.1124/jpet.119.257212.

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

  • Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 371 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 371, Issue 1
1 Oct 2019
  • 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.
Simultaneous Assessment of Hepatic Transport and Metabolism Pathways with a Single Probe Using Individualized PBPK Modeling of 14CO2 Production Rate Data
(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 ArticleMetabolism, Transport, and Pharmacogenomics

PBPK Modeling to Assess Hepatic Pathways with a Single Probe

Yoko Franchetti and Thomas D. Nolin
Journal of Pharmacology and Experimental Therapeutics October 1, 2019, 371 (1) 151-161; DOI: https://doi.org/10.1124/jpet.119.257212

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleMetabolism, Transport, and Pharmacogenomics

PBPK Modeling to Assess Hepatic Pathways with a Single Probe

Yoko Franchetti and Thomas D. Nolin
Journal of Pharmacology and Experimental Therapeutics October 1, 2019, 371 (1) 151-161; DOI: https://doi.org/10.1124/jpet.119.257212
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
    • Conclusion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • HDL Mimetic 4F Modulates Aβ Distribution in Brain and Plasma
  • AOX1 Inhibition by Gefitinib, Erlotinib, and Metabolites
  • Catalytic Activity of CYP2C9 Variants
Show more Metabolism, Transport, and Pharmacogenomics

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 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 © 2021 by the American Society for Pharmacology and Experimental Therapeutics