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

Hepatic Scaling Factors for In Vitro–In Vivo Extrapolation of Metabolic Drug Clearance in Patients with Colorectal Cancer with Liver Metastasis

Areti-Maria Vasilogianni, Brahim Achour, Daniel Scotcher, Sheila Annie Peters, Zubida M. Al-Majdoub, Jill Barber and Amin Rostami-Hodjegan
Drug Metabolism and Disposition July 2021, 49 (7) 563-571; DOI: https://doi.org/10.1124/dmd.121.000359
Areti-Maria Vasilogianni
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, United Kingdom (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom (A.R.-H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brahim Achour
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, United Kingdom (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom (A.R.-H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel Scotcher
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, United Kingdom (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom (A.R.-H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sheila Annie Peters
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, United Kingdom (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom (A.R.-H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zubida M. Al-Majdoub
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, United Kingdom (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom (A.R.-H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jill Barber
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, United Kingdom (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom (A.R.-H.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Amin Rostami-Hodjegan
Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, United Kingdom (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom (A.R.-H.)
  • 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

In vitro–in vivo extrapolation (IVIVE) linked with physiologically based pharmacokinetics (PBPK) modeling is used to predict the fates of drugs in patients. Ideally, the IVIVE-PBPK models should incorporate systems information accounting for characteristics of the specific target population. There is a paucity of such scaling factors in cancer, particularly microsomal protein per gram of liver (MPPGL) and cytosolic protein per gram of liver (CPPGL). In this study, cancerous and histologically normal liver tissue from 16 patients with colorectal liver metastasis were fractionated to microsomes and cytosol. Protein content was measured in homogenates, microsomes, and cytosol. The loss of microsomal protein during fractionation was accounted for using corrections based on NADPH cytochrome P450 reductase activity in different matrices. MPPGL was significantly lower in cancerous tissue (24.8 ± 9.8 mg/g) than histologically normal tissue (39.0 ± 13.8 mg/g). CPPGL in cancerous tissue was 42.1 ± 12.9 mg/g compared with 56.2 ± 16.9 mg/g in normal tissue. No correlations between demographics (sex, age, and body mass index) and MPPGL or CPPGL were apparent in the data. The generated scaling factors together with assumptions regarding the relative volumes of cancerous versus noncancerous tissue were used to simulate plasma exposure of drugs with different extraction ratios. The PBPK simulations revealed a substantial difference in drug exposure (area under the curve), up to 3.3-fold, when using typical scaling factors (healthy population) instead of disease-related parameters in cancer population. These indicate the importance of using population-specific scalars in IVIVE-PBPK for different disease states.

SIGNIFICANCE STATEMENT Accuracy in predicting the fate of drugs from in vitro data using IVIVE-PBPK depends on using correct scaling factors. The values for two of such scalars, namely microsomal and cytosolic protein per gram of liver, is not known in patients with cancer. This study presents, for the first time, scaling factors from cancerous and matched histologically normal livers. PBPK simulations of various metabolically cleared drugs demonstrate the necessity of population-specific scaling for model-informed precision dosing in oncology.

Footnotes

    • Received January 5, 2021.
    • Accepted April 5, 2021.
  • This work was supported by Merck KGaA, Frankfurter St. 250, F130/005, 64293 Darmstadt, Germany.

  • A.R.-H. holds shares in Certara, a company focusing on Model‐Informed Drug Development, and declares no support from any organization for the submitted work. All other authors declare that they have no conflicts of interest.

  • https://dx.doi.org/10.1124/dmd.121.000359.

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

  • Copyright © 2021 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: 49 (7)
Drug Metabolism and Disposition
Vol. 49, Issue 7
1 Jul 2021
  • 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.
Hepatic Scaling Factors for In Vitro–In Vivo Extrapolation of Metabolic Drug Clearance in Patients with Colorectal Cancer with Liver Metastasis
(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

Hepatic Scaling Factors for CL in Colorectal Cancer

Areti-Maria Vasilogianni, Brahim Achour, Daniel Scotcher, Sheila Annie Peters, Zubida M. Al-Majdoub, Jill Barber and Amin Rostami-Hodjegan
Drug Metabolism and Disposition July 1, 2021, 49 (7) 563-571; DOI: https://doi.org/10.1124/dmd.121.000359

Citation Manager Formats

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

Share
Research ArticleArticle

Hepatic Scaling Factors for CL in Colorectal Cancer

Areti-Maria Vasilogianni, Brahim Achour, Daniel Scotcher, Sheila Annie Peters, Zubida M. Al-Majdoub, Jill Barber and Amin Rostami-Hodjegan
Drug Metabolism and Disposition July 1, 2021, 49 (7) 563-571; DOI: https://doi.org/10.1124/dmd.121.000359
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
    • 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

  • Role of Human MSRA on Sulindac Activation
  • Determination of Acyl-, O-, and N-Glucuronide
  • Uptake as the RDS in Pevonedistat Hepatic Clearance
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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics