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

Interaction of Cisapride with the Human Cytochrome P450 System: Metabolism and Inhibition Studies

Zeruesenay Desta, Nadia Soukhova, Subena K. Mahal and David A. Flockhart
Drug Metabolism and Disposition July 2000, 28 (7) 789-800;
Zeruesenay Desta
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nadia Soukhova
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Subena K. Mahal
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David A. Flockhart
  • 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

Using human liver microsomes (HLMs) and recombinant cytochrome P450s (CYP450s), we characterized the CYP450 isoforms involved in the primary metabolic pathways of cisapride and documented the ability of cisapride to inhibit the CYP450 system. In HLMs, cisapride was N-dealkylated to norcisapride (NORCIS) and hydroxylated to 3-fluoro-4-hydroxycisapride (3-F-4-OHCIS) and to 4-fluoro-2-hydroxycisapride (4-F-2-OHCIS). Formation of NORCIS, 3-F-4-OHCIS, and 4-F-2-OHCIS in HLMs exhibited Michaelis-Menten kinetics (Km: 23.4 ± 8.6, 32 ± 11, and 31 ± 23 μM; Vmax: 155 ± 91, 52 ± 23, and 31 ± 23 pmol/min/mg of protein, respectively). The average in vitro intrinsic clearance (Vmax/Km) revealed that the formation of NORCIS was 3.9- to 5.9-fold higher than that of the two hydroxylated metabolites. Formation rate of NORCIS from 10 μM cisapride in 14 HLMs was highly variable (range, 4.9–133.6 pmol/min/mg of protein) and significantly correlated with the activities of CYP3A (r = 0.86,P = .0001), CYP2C19, and 1A2. Of isoform-specific inhibitors, 1 μM ketoconazole and 50 μM troleandomycin were potent inhibitors of NORCIS formation from 10 μM cisapride (by 51 ± 9 and 44 ± 17%, respectively), whereas the effect of other inhibitors was minimal. Of 10 recombinant human CYP450s tested, CYP3A4 formed NORCIS from 10 μM cisapride at the highest rate (V = 0.56 ± 0.13 pmol/min/pmol of P450) followed by CYP2C8 (V = 0.29 ± 0.08 pmol/min/pmol of P450) and CYP2B6 (0.15 ± 0.04 pmol/min/pmol of P450). The formation of 3-F-4-OHCIS was mainly catalyzed by CYP2C8 (V = 0.71 ± 0.24 pmol/min/pmol of P450) and that of 4-F-2-OHCIS by CYP3A4 (0.16 ± 0.03 pmol/min/pmol of P450). Clearly, recombinant CYP2C8 participates in cisapride metabolism, but when the in vitro intrinsic clearances obtained were corrected for abundance of each CYP450 in the liver, CYP3A4 is the dominant isoform. Cisapride was a relatively potent inhibitor of CYP2D6, with no significant effect on other isoforms tested, but theKi value derived (14 ± 16 μM) was much higher than the clinically expected concentration of cisapride (<1 μM). Our data suggest that CYP3A is the main isoform involved in the overall metabolic clearance of cisapride. Cisapride metabolism is likely to be subject to interindividual variability in CYP3A expression and to drug interactions involving this isoform.

Footnotes

  • Send reprint requests to: Zeruesenay Desta, Ph.D., Division of Clinical Pharmacology, Georgetown University Medical Center, 3900 Reservoir Rd. NW, Med-Dent Bldg. Room SE408, Washington, DC 20007. E-mail: gebreegz{at}gusun.georgetown.edu

  • This work was funded in part by Grant T32-GM08386 from the National Institute of General Medical Sciences, Bethesda, MD.

  • Abbreviations used are::
    CYP450
    cytochrome P450
    NORCIS
    norcisapride
    3-F-4-OHCIS
    3-fluoro-4-hydroxycisapride
    4-F-2-OHCIS
    4-fluoro-2-hydroxycisapride
    HLMs
    human liver microsomes
    Clint
    intrinsic clearance
    • Received November 4, 1999.
    • Accepted April 10, 2000.
  • 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: 28 (7)
Drug Metabolism and Disposition
Vol. 28, Issue 7
1 Jul 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 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.
Interaction of Cisapride with the Human Cytochrome P450 System: Metabolism and Inhibition Studies
(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

Interaction of Cisapride with the Human Cytochrome P450 System: Metabolism and Inhibition Studies

Zeruesenay Desta, Nadia Soukhova, Subena K. Mahal and David A. Flockhart
Drug Metabolism and Disposition July 1, 2000, 28 (7) 789-800;

Citation Manager Formats

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

Share
Research ArticleArticle

Interaction of Cisapride with the Human Cytochrome P450 System: Metabolism and Inhibition Studies

Zeruesenay Desta, Nadia Soukhova, Subena K. Mahal and David A. Flockhart
Drug Metabolism and Disposition July 1, 2000, 28 (7) 789-800;
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
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Determination of Acyl-, O-, and N-Glucuronide
  • TMDD Affects PK of IL-10 Fc-fusion Proteins
  • Uptake as the RDS in Pevonedistat Hepatic Clearance
Show more Article

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