Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • For Subscribers
    • For Advertisers
    • 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

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
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • For Subscribers
    • For Advertisers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Metabolism and Pharmacokinetics of Novel Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitor Apatinib in Humans

Juefang Ding, Xiaoyan Chen, Zhiwei Gao, Xiaojian Dai, Liang Li, Cen Xie, Haoyuan Jiang, Lijia Zhang and Dafang Zhong
Drug Metabolism and Disposition June 2013, 41 (6) 1195-1210; DOI: https://doi.org/10.1124/dmd.112.050310
Juefang Ding
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.D., X.C., Z.G., X.D., L.L., C.X., D.Z.); and Jiangsu Hengrui Medicine Co. Ltd., Lianyungang, China (H.J., L.Z.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiaoyan Chen
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.D., X.C., Z.G., X.D., L.L., C.X., D.Z.); and Jiangsu Hengrui Medicine Co. Ltd., Lianyungang, China (H.J., L.Z.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zhiwei Gao
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.D., X.C., Z.G., X.D., L.L., C.X., D.Z.); and Jiangsu Hengrui Medicine Co. Ltd., Lianyungang, China (H.J., L.Z.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiaojian Dai
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.D., X.C., Z.G., X.D., L.L., C.X., D.Z.); and Jiangsu Hengrui Medicine Co. Ltd., Lianyungang, China (H.J., L.Z.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Liang Li
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.D., X.C., Z.G., X.D., L.L., C.X., D.Z.); and Jiangsu Hengrui Medicine Co. Ltd., Lianyungang, China (H.J., L.Z.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cen Xie
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.D., X.C., Z.G., X.D., L.L., C.X., D.Z.); and Jiangsu Hengrui Medicine Co. Ltd., Lianyungang, China (H.J., L.Z.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Haoyuan Jiang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.D., X.C., Z.G., X.D., L.L., C.X., D.Z.); and Jiangsu Hengrui Medicine Co. Ltd., Lianyungang, China (H.J., L.Z.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lijia Zhang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.D., X.C., Z.G., X.D., L.L., C.X., D.Z.); and Jiangsu Hengrui Medicine Co. Ltd., Lianyungang, China (H.J., L.Z.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dafang Zhong
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (J.D., X.C., Z.G., X.D., L.L., C.X., D.Z.); and Jiangsu Hengrui Medicine Co. Ltd., Lianyungang, China (H.J., L.Z.)
  • 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

Apatinib is a new oral antiangiogenic molecule that inhibits vascular endothelial growth factor receptor-2. The present study aimed to determine the metabolism, pharmacokinetics, and excretion of apatinib in humans and to identify the enzymes responsible for its metabolism. The primary routes of apatinib biotransformation included E- and Z-cyclopentyl-3-hydroxylation, N-dealkylation, pyridyl-25-N-oxidation, 16-hydroxylation, dioxygenation, and O-glucuronidation after 3-hydroxylation. Nine major metabolites were confirmed by comparison with reference standards. The total recovery of the administered dose was 76.8% within 96 hours postdose, with 69.8 and 7.02% of the administered dose excreted in feces and urine, respectively. About 59.0% of the administered dose was excreted unchanged via feces. Unchanged apatinib was detected in negligible quantities in urine, indicating that systemically available apatinib was extensively metabolized. The major circulating metabolite was the pharmacologically inactive E-3-hydroxy-apatinib-O-glucuronide (M9-2), the steady-state exposure of which was 125% that of the apatinib. The steady-state exposures of E-3-hydroxy-apatinib (M1-1), Z-3-hydroxy-apatinib (M1-2), and apatinib-25-N-oxide (M1-6) were 56, 22, and 32% of parent drug exposure, respectively. Calculated as pharmacological activity index values, the contribution of M1-1 to the pharmacology of the drug was 5.42 to 19.3% that of the parent drug. The contribution of M1-2 and M1-6 to the pharmacology of the drug was less than 1%. Therefore, apatinib was a major contributor to the overall pharmacological activity in humans. Apatinib was metabolized primarily by CYP3A4/5 and, to a lesser extent, by CYP2D6, CYP2C9, and CYP2E1. UGT2B7 was the main enzyme responsible for M9-2 formation. Both UGT1A4 and UGT2B7 were responsible for Z-3-hydroxy-apatinib-O-glucuronide (M9-1) formation.

Footnotes

    • Received November 26, 2012.
    • Accepted March 18, 2013.
  • ↵dx.doi.org/10.1124/dmd.112.050310.

  • Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

Log in using your username and password

Forgot your user name or password?

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00

Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.

PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 41 (6)
Drug Metabolism and Disposition
Vol. 41, Issue 6
1 Jun 2013
  • 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.
Metabolism and Pharmacokinetics of Novel Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitor Apatinib in Humans
(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.
Citation Tools
Research ArticleArticle

Metabolism and Pharmacokinetics of Apatinib in Humans

Juefang Ding, Xiaoyan Chen, Zhiwei Gao, Xiaojian Dai, Liang Li, Cen Xie, Haoyuan Jiang, Lijia Zhang and Dafang Zhong
Drug Metabolism and Disposition June 1, 2013, 41 (6) 1195-1210; DOI: https://doi.org/10.1124/dmd.112.050310

Citation Manager Formats

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

Metabolism and Pharmacokinetics of Apatinib in Humans

Juefang Ding, Xiaoyan Chen, Zhiwei Gao, Xiaojian Dai, Liang Li, Cen Xie, Haoyuan Jiang, Lijia Zhang and Dafang Zhong
Drug Metabolism and Disposition June 1, 2013, 41 (6) 1195-1210; DOI: https://doi.org/10.1124/dmd.112.050310
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
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • UDP-glycosyltransferase 3A (UGT3A) metabolism of polycyclic aromatic hydrocarbons: potential importance in aerodigestive tract tissues
  • Identification and characterization of a new carboxylesterase 2 isozyme, mfCES2C, in the small intestine of cynomolgus monkeys
  • Comparative Proteomics of Human Liver Microsomes and S9
Show more Articles

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 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 © 2019 by the American Society for Pharmacology and Experimental Therapeutics