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

Rosuvastatin Liver Partitioning in Cynomolgus Monkeys: Measurement In Vivo and Prediction Using In Vitro Monkey Hepatocyte Uptake

Bridget L. Morse, Hong Cai, Jamus G. MacGuire, Maxine Fox, Lisa Zhang, Yueping Zhang, Xiaomei Gu, Hong Shen, Elizabeth A. Dierks, Hong Su, Chiuwa E. Luk, Punit Marathe, Yue-Zhong Shu, W. Griffith Humphreys and Yurong Lai
Drug Metabolism and Disposition November 2015, 43 (11) 1788-1794; DOI: https://doi.org/10.1124/dmd.115.065946
Bridget L. Morse
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hong Cai
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jamus G. MacGuire
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maxine Fox
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisa Zhang
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yueping Zhang
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiaomei Gu
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hong Shen
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elizabeth A. Dierks
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hong Su
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chiuwa E. Luk
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Punit Marathe
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yue-Zhong Shu
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
W. Griffith Humphreys
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yurong Lai
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.)
  • 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

Unbound plasma concentrations may not reflect those in target tissues, and there is a need for methods to predict tissue partitioning. Here, we investigate the unbound liver partitioning (Kpu,u) of rosuvastatin, a substrate of hepatic organic anion transporting peptides, in cynomolgus monkeys and compare it with that determined using hepatocytes in vitro. Rosuvastatin (3 mg/kg) was administered orally to monkeys and plasma and liver (by ultrasound-guided biopsy) collected over time. Uptake into monkey hepatocytes was evaluated up to steady state. Binding in monkey plasma, liver, and hepatocytes was determined using equilibrium dialysis. Mean in vivo Kpu,u was 118 after correcting total liver partitioning by plasma and liver binding. In vitro uptake data were analyzed by compartmental modeling to determine active uptake clearance, passive diffusion, the intracellular unbound fraction, and Kpu,u. In vitro Kpu,u underpredicted that in vivo, resulting in the need for an empirical in vitro to in vivo scaling factor of 10. Adjusting model parameters using hypothetical scaling factors for transporter expression and surface area or assuming no effect of protein binding on active transport increased partitioning values by 1.1-, 6-, and 9-fold, respectively. In conclusion, in vivo rosuvastatin unbound liver partitioning in monkeys was underpredicted using hepatocytes in vitro. Modeling approaches that allow integrating corrections from passive diffusion or protein binding on active uptake could improve the estimation of in vivo intracellular partitioning of this organic anion transporting peptide substrate. A similar assessment of other active hepatic transport mechanisms could confirm and determine the extent to which limited accumulation in isolated hepatocytes needs to be considered in drug development.

Footnotes

    • Received June 11, 2015.
    • Accepted September 3, 2015.
  • ↵1 Current affiliation: Analytical Sciences, GlaxoSmithKline, King of Prussia, Pennsylvania.

  • This research was supported by Bristol-Myers Squibb, Co.

  • This research was previously presented as an abstract: Morse BL, Cai H, MacGuire JG, Fox M, Zhang L, Zhang Y, Gu X, Shen H, Dierks EA, Su H, et al. (2015) Prediction of in vivo rosuvastatin liver partitioning in cynomolgus monkeys using in vitro hepatocyte uptake. American Association of Pharmaceutical Scientists/International Transporter Consortium Joint Workshop on Drug Transporters; 2015 Apr 20–22; Baltimore, MD. American Association of Pharmaceutical Scientists, Arlington, VA.

  • dx.doi.org/10.1124/dmd.115.065946.

  • Copyright © 2015 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: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
  • 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.
Rosuvastatin Liver Partitioning in Cynomolgus Monkeys: Measurement In Vivo and Prediction Using In Vitro Monkey Hepatocyte Uptake
(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

Prediction of Rosuvastatin Liver Partitioning in Monkeys

Bridget L. Morse, Hong Cai, Jamus G. MacGuire, Maxine Fox, Lisa Zhang, Yueping Zhang, Xiaomei Gu, Hong Shen, Elizabeth A. Dierks, Hong Su, Chiuwa E. Luk, Punit Marathe, Yue-Zhong Shu, W. Griffith Humphreys and Yurong Lai
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1788-1794; DOI: https://doi.org/10.1124/dmd.115.065946

Citation Manager Formats

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

Share
Research ArticleArticle

Prediction of Rosuvastatin Liver Partitioning in Monkeys

Bridget L. Morse, Hong Cai, Jamus G. MacGuire, Maxine Fox, Lisa Zhang, Yueping Zhang, Xiaomei Gu, Hong Shen, Elizabeth A. Dierks, Hong Su, Chiuwa E. Luk, Punit Marathe, Yue-Zhong Shu, W. Griffith Humphreys and Yurong Lai
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1788-1794; DOI: https://doi.org/10.1124/dmd.115.065946
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
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Series-Compartment Models of Hepatic Elimination
  • Warfarin PBPK Model with TMDD Mechanism
  • Identification of payload-containing catabolites of ADCs
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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics