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 ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Scaling Drug Biotransformation Data from cDNA-Expressed Cytochrome P-450 to Human Liver: A Comparison of Relative Activity Factors and Human Liver Abundance in Studies of Mirtazapine Metabolism

Elke Störmer, Lisa L. von Moltke and David J. Greenblatt
Journal of Pharmacology and Experimental Therapeutics November 2000, 295 (2) 793-801;
Elke Störmer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisa L. von Moltke
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David J. Greenblatt
  • 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

The present study represents a comparison of three approaches to transform recombinant cytochrome P-450 (rCYP) enzyme kinetic data to human liver activity using mirtazapine (MIR) biotransformation as a model. MIR metabolite rCYP formation rates were corrected using I) relative activity factors (RAFs) determined on site, II) RAFs based on activity data provided by the rCYP manufacturer, and III) immunologically determined human liver abundance of CYP isoforms reported in the literature. For 2.5, 25, and 250 μM MIR, predictions of 1) the relative contribution of CYP isoforms to a particular reaction, 2) absolute metabolite formation rates, 3) the relative contribution of each pathway to net MIR biotransformation, and 4) the relative contribution of CYP isoforms to net MIR biotransformation were generated, and the results were compared with data obtained with human liver microsomes (HLM). We found that RAFs determined on site most accurately predict the results observed in HLM. Estimations based on liver abundance systematically underestimated CYP1A2 and overestimated CYP3A and CYP2C9 contributions to MIR metabolism and, therefore, seem less suitable to predict CYP isoform involvement in a particular reaction. Normalized RAFs calculated from the manufacturer activity data fell within the range of RAFs determined on site and lead to similar results for CYP isoform contribution to metabolic reactions and to net MIR biotransformation. Considering the time and resource-intensive step of RAF determination, manufacturer RAFs are an alternative to RAFs determined on site for the transformation of rCYP enzyme kinetic data; both of them provide more accurate estimations than immunologically determined human liver CYP isoform content.

Footnotes

  • Send reprint requests to: David J. Greenblatt, M.D., Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. E-mail: dj.greenblatt{at}tufts.edu

  • ↵1 This work was supported by Grants MH-34223, MH-01237, and DA-05258 from the U.S. Department of Health and Human Services.

  • ↵2 Recipient of an HSP III doctoral grant by the German Academic Exchange Service (DAAD).

  • Abbreviations:
    rCYP
    recombinant cytochrome P-450
    CYP
    cytochrome P-450
    MIR
    mirtazapine
    OHM
    8-hydroxymirtazapine
    DMM
    N-desmethylmirtazapine
    MNO
    mirtazapine-N-oxide
    HLM
    human liver microsomes
    RAF
    relative activity factor
    • Received April 4, 2000.
    • Accepted July 19, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET 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

Journal of Pharmacology and Experimental Therapeutics: 295 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 2
1 Nov 2000
  • Table of Contents
  • About the Cover
  • Index by author
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.
Scaling Drug Biotransformation Data from cDNA-Expressed Cytochrome P-450 to Human Liver: A Comparison of Relative Activity Factors and Human Liver Abundance in Studies of Mirtazapine Metabolism
(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 ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Scaling Drug Biotransformation Data from cDNA-Expressed Cytochrome P-450 to Human Liver: A Comparison of Relative Activity Factors and Human Liver Abundance in Studies of Mirtazapine Metabolism

Elke Störmer, Lisa L. von Moltke and David J. Greenblatt
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 793-801;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Scaling Drug Biotransformation Data from cDNA-Expressed Cytochrome P-450 to Human Liver: A Comparison of Relative Activity Factors and Human Liver Abundance in Studies of Mirtazapine Metabolism

Elke Störmer, Lisa L. von Moltke and David J. Greenblatt
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 793-801;
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

  • Transport Is Not Rate-Limiting in Morphine Glucuronidation in the Single-Pass Perfused Rat Liver Preparation
  • Enhanced Hepatic Uptake and Bioactivity of Type α1(I) Collagen Gene Promoter-Specific Triplex-Forming Oligonucleotides after Conjugation with Cholesterol
  • Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana
Show more ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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