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
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
    • 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 jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
OtherLETTERS TO THE EDITOR

Response to Comments on “Multiple Transporters Affect the Disposition of Atorvastatin and Its Two Active Hydroxy Metabolites: Application of in Vitro and ex Situ Systems”

Yvonne Y. Lau, Hideaki Okochi, Yong Huang and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics March 2006, 316 (3) 1387; DOI: https://doi.org/10.1124/jpet.105.099473
Yvonne Y. Lau
Department of Biopharmaceutical Sciences, University of California, San Francisco, CA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hideaki Okochi
Department of Biopharmaceutical Sciences, University of California, San Francisco, CA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yong Huang
Department of Biopharmaceutical Sciences, University of California, San Francisco, CA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Leslie Z. Benet
Department of Biopharmaceutical Sciences, University of California, San Francisco, CA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • eLetters
  • PDF
Loading

We thank Dr. Kivistö for his comments related to our recent study (Lau et al., 2006) and for giving us a further opportunity to emphasize the importance of understanding transporter-enzyme interplay. Our study and our prior work referenced therein are directed at pointing out that drug-drug interactions resulting in inhibition or induction of both uptake and efflux transporters can result in changes in drug metabolism, even when enzyme levels and activity are unchanged by the interacting drug. We use rifampicin as a general inhibitor of hepatic OATP uptake transporters because it is a drug that we can dose to humans both via the intravenous and oral route and because it differentiates drug interactions related to uptake transporters in the liver and gut from interactions related to enzymatic processes and efflux transporters. Thus, it is a model OATP inhibitor, but we must also quantitate its inhibitory effects on enzyme levels and efflux transporters as we did in the study in question.

Dr. Kivistö's comments relate not to the model compound aspects of rifampicin but rather to its effects when dosed to patients. Upon continuing dosing, its up-regulation of enzyme levels, P-glycoprotein, and MRP2 are well known. In fact, our early studies investigating the effects of multipledose rifampicin on cyclosporine (Hebert et al., 1992; Wu et al., 1995) could not be explained only by hepatic metabolism of cyclosporine and led us to our initial hypothesis concerning the importance of CYP3A4 and P-glycoprotein interplay in the intestine in explaining the marked decrease in cyclosporine blood levels with concomitant, multiple dosing of rifampicin. Future publications from our laboratory will demonstrate that our in vitro and isolated perfused rat liver studies with rifampicin and atorvastatin are relevant to dosing of these two drugs in whole animal studies and in humans. We have recently completed single-dose pharmacokinetic studies of this interaction in rats and humans, where atorvastatin is dosed orally and rifampicin intravenously, showing that the effects noted in the acute studies here are also significant in animals and humans (unpublished data).

Even though we use rifampicin as a model transporter inhibitor, we believe that Dr. Kivistö will recognize that his statement that “such findings are not relevant to continuous drug treatment in clinical practice” may not necessarily be true. A relevant example is the clinical study of Bidstrup et al. (2004), which evaluates the effects of rifampicin on the metabolism of repaglinide. When rifampicin was dosed for 7 days and repaglinide was dosed concomitantly on day 7, a 50% reduction of median repaglinide area under the curve (AUC) was observed compared with a single dose of repaglinide in the absence of rifampicin. However, when repaglinide was dosed on day 8, following 7 days of dosing of rifampicin (when rifampicin was no longer present in the plasma), the authors found “an almost 80% reduction of median repaglinide AUC.” The authors suggest that this may be related to rifampin as both an inducer and inhibitor of the metabolism of repaglinide. Most recently, Kajosaari et al. (2005) confirmed this enzyme inhibitory effect of rifampicin in hepatic microsome studies. With such microsomal studies, no potential transporter effects would be evaluated, as we have demonstrated (Lam and Benet, 2004). We hypothesize that a further potential reason that the effect observed on day 7 dosing of repaglinide with rifampicin was significantly less than observed on day 8 dosing of repaglinide (when rifampicin was not present) may be due to rifampicin's ability to inhibit the hepatic uptake of repaglinide during the day 7 studies. We suspect that a number of rifampicin interaction studies may be compromised by concomitant dosing of rifampicin on the day of study of the interacting drug. Thus, it is clinically important to understand all of the potential inductive and inhibitory effects that an interactive drug may have on both enzymatic and transporter processes if one is to correctly characterize and understand the potential for and extent of drug-drug interactions.

Footnotes

    • Received December 5, 2005.
    • Accepted December 14, 2005.
  • doi:10.1124/jpet.105.099473.

  • ABBREVIATIONS: OATP, organic anion-transporting polypeptide; AUC, area under the curve.

  • The American Society for Pharmacology and Experimental Therapeutics

References

  1. ↵
    Bidstrup TB, Stilling N, Damkier P, Scharling B, Thomsen MS, and Brøsen K (2004) Rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide. Eur J Clin Pharmacol 60: 109–114.
    OpenUrlCrossRefPubMed
  2. ↵
    Hebert MF, Roberts JP, Prueksaritanont T, and Benet LZ (1992) Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 52: 453–457.
    OpenUrlCrossRefPubMed
  3. ↵
    Kajosaari LI, Laitila J, Neuvonen PJ, and Backman JT (2005) Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. Basic Clin Pharmacol Toxicol 97: 249–256.
    OpenUrlCrossRefPubMed
  4. ↵
    Lam JL and Benet LZ (2004) Hepatic microsome studies are insufficient to characterize in vivo metabolic clearance and metabolic drug-drug interactions: studies of digoxin metabolism in primary rat hepatocytes versus microsomes. Drug Metab Dispos 32: 1311–1316.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Lau YY, Okochi H, Huang Y, and Benet LZ (2006) Multiple transporters affect the disposition of atorvastatin and its two active hydroxy metabolites: application of in vitro and ex situ systems. J Pharmacol Exp Ther 316: 762–771.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    Wu C-Y, Benet LZ, Hebert MF, Gupta SK, Rowland M, Gomez DY, and Wacher VJ (1995) Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine. Clin Pharmacol Ther 58: 492–497.
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 316 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 316, Issue 3
1 Mar 2006
  • 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 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.
Response to Comments on “Multiple Transporters Affect the Disposition of Atorvastatin and Its Two Active Hydroxy Metabolites: Application of in Vitro and ex Situ Systems”
(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
OtherLETTERS TO THE EDITOR

Response to Comments on “Multiple Transporters Affect the Disposition of Atorvastatin and Its Two Active Hydroxy Metabolites: Application of in Vitro and ex Situ Systems”

Yvonne Y. Lau, Hideaki Okochi, Yong Huang and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics March 1, 2006, 316 (3) 1387; DOI: https://doi.org/10.1124/jpet.105.099473

Citation Manager Formats

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

Share
OtherLETTERS TO THE EDITOR

Response to Comments on “Multiple Transporters Affect the Disposition of Atorvastatin and Its Two Active Hydroxy Metabolites: Application of in Vitro and ex Situ Systems”

Yvonne Y. Lau, Hideaki Okochi, Yong Huang and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics March 1, 2006, 316 (3) 1387; DOI: https://doi.org/10.1124/jpet.105.099473
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
    • Footnotes
    • References
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Letters to the Editor
  • Letters to the Editor
  • TDF is not an Inhibitor of OCT1
Show more LETTERS TO THE EDITOR

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 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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics