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

Nutritional Status Affects Fluvastatin-Induced Hepatotoxicity and Myopathy in Rats

Junko Sugatani, Satoshi Sadamitsu, Masatoshi Kurosawa, Shin-ichi Ikushiro, Toshiyuki Sakaki, Akira Ikari and Masao Miwa
Drug Metabolism and Disposition October 2010, 38 (10) 1655-1664; DOI: https://doi.org/10.1124/dmd.110.034090
Junko Sugatani
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Satoshi Sadamitsu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Masatoshi Kurosawa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shin-ichi Ikushiro
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Toshiyuki Sakaki
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Akira Ikari
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Masao Miwa
  • 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

Rats that consumed a high-fat and high-sucrose diet (HF diet) developed hepatic steatosis. Treatment of HF diet-fed rats with fluvastatin (8 mg/kg) was lethal, followed by an elevation in levels of plasma aspartate aminotransferase and creatine kinase activities and skeletal muscle toxicity. This study was conducted to determine whether nutritional status affects statin-induced adverse effects in rats. Fluvastatin treatment of rats fed the HF diet led to an increase in systemic exposure, suggesting altered metabolism and elimination. In fact, although hepatic multidrug resistance-associated protein (Mrp) 2 and multidrug resistance (Mdr) 1b protein levels were not significantly changed by fluvastatin treatment for 8 days of rats fed a HF diet, the organic anion-transporting protein (Oatp) 1, Mrp3, CYP1A, CYP2C, UDP-glucuronosyltransferase (UGT) 1A1, and UGT1A5 protein levels were moderately decreased and the Oatp2, CYP3A, and UGT2B1 protein levels were markedly suppressed. No significant difference in the baseline level of Oatp1, Oatp2, Mrp2, Mrp3, Mdr1b, CYP1A, CYP2C, CYP3A, UGT1A1, UGT1A5, or UGT2B1 protein was found between the standard diet- and HF diet-fed groups. In addition, the mRNA levels of Oatp2, CYP2C11, and CYP3A1/2 were markedly decreased in HF diet-fed and fluvastatin-treated rats. There was no significant difference in the glucuronidation activities against fluvastatin among the four groups. In liver cell nuclei, levels of constitutive androstane receptor, pregnane X receptor, and hepatocyte nuclear factor 4α proteins were decreased in fluvastatin-treated HF diet-fed rats, which correlated with the decrease in Oatp2, CYP2C, and CYP3A. Taken together, these results indicate that nutritional status may influence adverse effects of fluvastatin by increasing systemic exposure through modulation of hepatic uptake and elimination.

Footnotes

  • This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology, Japan [Global Center of Excellence for Innovation in Human Health Sciences Program and Grant-in-Aid for Scientific Research 21590170, 22590068].

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

    doi:10.1124/dmd.110.034090.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    OATP/Oatp
    organic anion-transporting polypeptide
    P450
    cytochrome P450
    UGT
    UDP-glucuronosyltransferase
    HF diet
    high-fat and high-sucrose diet
    SD diet
    standard diet
    AST
    aspartate aminotransferase
    CK
    creatine kinase
    ALT
    alanine aminotransferase
    γ-GTP
    γ-glutamyltranspeptidase
    MRP/Mrp
    multidrug resistance-associated protein
    CAR
    constitutive androstane receptor
    PXR
    pregnane X receptor
    RXR
    retinoid X receptor
    HNF
    hepatocyte nuclear factor
    PPARα
    peroxisome proliferator-activated receptor
    Mdr
    multidrug resistance
    HPLC
    high-performance liquid chromatography
    Ct
    cycle threshold.

  • Received April 24, 2010.
  • Accepted June 29, 2010.
  • Copyright © 2010 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: 38 (10)
Drug Metabolism and Disposition
Vol. 38, Issue 10
1 Oct 2010
  • 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.
Nutritional Status Affects Fluvastatin-Induced Hepatotoxicity and Myopathy in Rats
(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

Nutritional Status Affects Fluvastatin-Induced Hepatotoxicity and Myopathy in Rats

Junko Sugatani, Satoshi Sadamitsu, Masatoshi Kurosawa, Shin-ichi Ikushiro, Toshiyuki Sakaki, Akira Ikari and Masao Miwa
Drug Metabolism and Disposition October 1, 2010, 38 (10) 1655-1664; DOI: https://doi.org/10.1124/dmd.110.034090

Citation Manager Formats

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

Share
Research ArticleArticle

Nutritional Status Affects Fluvastatin-Induced Hepatotoxicity and Myopathy in Rats

Junko Sugatani, Satoshi Sadamitsu, Masatoshi Kurosawa, Shin-ichi Ikushiro, Toshiyuki Sakaki, Akira Ikari and Masao Miwa
Drug Metabolism and Disposition October 1, 2010, 38 (10) 1655-1664; DOI: https://doi.org/10.1124/dmd.110.034090
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
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • 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 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