Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • 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
  • 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
    • 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
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Gene Variants in CYP2C19 Are Associated with Altered In Vivo Bupropion Pharmacokinetics but Not Bupropion-Assisted Smoking Cessation Outcomes

Andy Z. X. Zhu, Qian Zhou, Lisa Sanderson Cox, Jasjit S. Ahluwalia, Neal L. Benowitz and Rachel F. Tyndale
Drug Metabolism and Disposition November 2014, 42 (11) 1971-1977; DOI: https://doi.org/10.1124/dmd.114.060285
Andy Z. X. Zhu
Departments of Pharmacology and Toxicology (A.Z.X.Z., Q.Z., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Ontario, Canada; Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas (L.S.C.); Department of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota (J.S.A.); Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California (N.L.B.); and Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada (R.F.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Qian Zhou
Departments of Pharmacology and Toxicology (A.Z.X.Z., Q.Z., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Ontario, Canada; Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas (L.S.C.); Department of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota (J.S.A.); Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California (N.L.B.); and Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada (R.F.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisa Sanderson Cox
Departments of Pharmacology and Toxicology (A.Z.X.Z., Q.Z., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Ontario, Canada; Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas (L.S.C.); Department of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota (J.S.A.); Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California (N.L.B.); and Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada (R.F.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jasjit S. Ahluwalia
Departments of Pharmacology and Toxicology (A.Z.X.Z., Q.Z., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Ontario, Canada; Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas (L.S.C.); Department of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota (J.S.A.); Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California (N.L.B.); and Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada (R.F.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Neal L. Benowitz
Departments of Pharmacology and Toxicology (A.Z.X.Z., Q.Z., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Ontario, Canada; Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas (L.S.C.); Department of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota (J.S.A.); Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California (N.L.B.); and Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada (R.F.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rachel F. Tyndale
Departments of Pharmacology and Toxicology (A.Z.X.Z., Q.Z., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Ontario, Canada; Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas (L.S.C.); Department of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota (J.S.A.); Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California (N.L.B.); and Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada (R.F.T.)
  • 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

Bupropion is used clinically to treat depression and to promote smoking cessation. It is metabolized by CYP2B6 to its active metabolite hydroxybupropion, yet alterations in CYP2B6 activity have little impact on bupropion plasma levels. Furthermore, less than 10% of a bupropion dose is excreted as urinary bupropion and its characterized metabolites hydroxybupropion, threohydrobupropion, and erythrohydrobupropion, suggesting that alternative metabolic pathways may exist. In vitro data suggested CYP2C19 could metabolize bupropion. The current study investigated the impact of functional CYP2C19 genetic variants on bupropion pharmacokinetics and treatment outcomes. In 42 healthy volunteers, CYP2C19*2 (a reduced activity allele) was associated with higher bupropion area under the plasma concentration–time curve (AUC), but similar hydroxybupropion AUC. The mean bupropion AUC was 771 versus 670 hours⋅ng/ml in individuals with and without CYP2C19*2, respectively (P = 0.017). CYP2C19*2 was also associated with higher threohydrobupropion and erythrohydrobupropion AUC (P < 0.005). Adjusting for CYP2B6 genotype did not alter these associations, and CYP2C19 variants did not alter the utility of the hydroxybupropion/bupropion ratio as a measure of CYP2B6 activity. Finally, in a clinical trial of 540 smokers, CYP2C19 genotype was not associated with smoking cessation outcomes, supporting the hypothesis that bupropion response is mediated by hydroxybupropion, which is not altered by CYP2C19. In conclusion, our study reports the first in vivo evidence that reduced CYP2C19 activity significantly increases the steady-state exposure to bupropion and its reductive metabolites threohydrobupropion and erythrohydrobupropion. These pharmacokinetic changes were not associated with differences in bupropion’s ability to promote smoking cessation in smokers, but may influence the side effects and toxicity associated with bupropion.

Footnotes

    • Received July 25, 2014.
    • Accepted September 3, 2014.
  • This work was supported by the National Institutes of Health [Grants DA020830, CA78603, CA091912, DA12393], and National Institutes of Health grants through University of California, San Francisco Clinical and Translational Science Institute Grant Number UL1 RR024131, Canadian Institutes of Health Research [Grant MOP86471], the Endowed Chair in Addiction for the Department of Psychiatry University of Toronto, grants from the Centre for Addiction and Mental Health (CAMH) and the CAMH Foundation, grants from the Canada Foundation for Innovation [Grants 20289 and 16014], and a grant from the Ontario Ministry of Research and Innovation.

  • N.L.B. serves as a consultant to several pharmaceutical companies that market smoking cessation medications, and has been a paid expert witness in litigation against tobacco companies. R.F.T. has participated in one-day advisory meetings for Novartis and McNeil.

  • dx.doi.org/10.1124/dmd.114.060285.

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

  • Copyright © 2014 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: 42 (11)
Drug Metabolism and Disposition
Vol. 42, Issue 11
1 Nov 2014
  • 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.
Gene Variants in CYP2C19 Are Associated with Altered In Vivo Bupropion Pharmacokinetics but Not Bupropion-Assisted Smoking Cessation Outcomes
(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

Gene Variants in CYP2C19 Alter Bupropion Pharmacokinetics

Andy Z. X. Zhu, Qian Zhou, Lisa Sanderson Cox, Jasjit S. Ahluwalia, Neal L. Benowitz and Rachel F. Tyndale
Drug Metabolism and Disposition November 1, 2014, 42 (11) 1971-1977; DOI: https://doi.org/10.1124/dmd.114.060285

Citation Manager Formats

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

Gene Variants in CYP2C19 Alter Bupropion Pharmacokinetics

Andy Z. X. Zhu, Qian Zhou, Lisa Sanderson Cox, Jasjit S. Ahluwalia, Neal L. Benowitz and Rachel F. Tyndale
Drug Metabolism and Disposition November 1, 2014, 42 (11) 1971-1977; DOI: https://doi.org/10.1124/dmd.114.060285
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

  • BSEP Function in Suspension Hepatocytes
  • Candesartan glucuronide serves as a CYP2C8 inhibitor
  • Role of AADAC on eslicarbazepine acetate hydrolysis
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 © 2021 by the American Society for Pharmacology and Experimental Therapeutics