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

Enhanced Methamphetamine Metabolism in Rhesus Macaque as Compared with Human: An Analysis Using a Novel Method of Liquid Chromatography with Tandem Mass Spectrometry, Kinetic Study, and Substrate Docking

Ravinder Earla, Santosh Kumar, Lei Wang, Steven Bosinger, Junhao Li, Ankit Shah, Mohitkumar Gangwani, Anantha Nookala, Xun Liu, Lu Cao, Austin Jackson, Peter S. Silverstein, Howard S. Fox, Weihua Li and Anil Kumar
Drug Metabolism and Disposition December 2014, 42 (12) 2097-2108; DOI: https://doi.org/10.1124/dmd.114.059378
Ravinder Earla
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Santosh Kumar
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lei Wang
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven Bosinger
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Junhao Li
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ankit Shah
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mohitkumar Gangwani
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anantha Nookala
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xun Liu
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lu Cao
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Austin Jackson
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter S. Silverstein
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Howard S. Fox
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Weihua Li
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.F.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anil Kumar
Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri–Kansas City, Kansas City, Missouri (R.E., A.S., M.K.G., A.N., X.L., L.C., A.J., P.S.S., A.K.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences, Memphis, Tennessee (S.K.); Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China (L.W., J.L., W.L.); Yerkes National Primate Research Center, Emory University, Atlanta, Georgia (S.B.); University of Nebraska Medical Center, Omaha, Nebraska (H.S.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 + SI
  • PDF
Loading

Abstract

Methamphetamine (MA), which remains one of the widely used drugs of abuse, is metabolized by the cytochrome P450 (P450) family of enzymes in humans. However, metabolism of methamphetamine in macaques is poorly understood. Therefore, we first developed and validated a very sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) method using solid phase extraction of rhesus plasma with a lower limit of quantitation at 1.09 ng/ml for MA and its metabolites, 4-hydroxy methamphetamine (4-OH MA), amphetamine (AM), 4-OH amphetamine (4-OH AM), and norephedrine. We then analyzed plasma samples of MA-treated rhesus, which showed >10-fold higher concentrations of AM (∼29 ng/ml) and 4-OH AM (∼28 ng/ml) than MA (∼2 ng/ml). Because the plasma levels of MA metabolites in rhesus were much higher than in human samples, we examined MA metabolism in human and rhesus microsomes. Interestingly, the results showed that AM and 4-OH AM were formed more rapidly and that the catalytic efficiency (Vmax/Km) for the formation of AM was ∼8-fold higher in rhesus than in human microsomes. We further examined the differences in these kinetic characteristics using three selective inhibitors of each human CYP2D6 and CYP3A4 enzymes. The results showed that each of these inhibitors inhibited both d- and l-MA metabolism by 20%–60% in human microsomes but not in rhesus microsomes. The differences between human and rhesus CYP2D6 and CYP3A4 enzymes were further assessed by docking studies for both d and l-MA. In conclusion, our results demonstrated an enhanced MA metabolism in rhesus compared with humans, which is likely to be caused by differences in MA-metabolizing P450 enzymes between these species.

Footnotes

    • Received June 3, 2014.
    • Accepted October 8, 2014.
  • The work was funded by the National Institutes of Health National Institute on Drug Abuse [Grant DA025528 and DA025011] (to A.K.); and the National Natural Science Foundation of China [Grant 81373328] (to W.L.).

  • dx.doi.org/10.1124/dmd.114.059378.

  • ↵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 (12)
Drug Metabolism and Disposition
Vol. 42, Issue 12
1 Dec 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.
Enhanced Methamphetamine Metabolism in Rhesus Macaque as Compared with Human: An Analysis Using a Novel Method of Liquid Chromatography with Tandem Mass Spectrometry, Kinetic Study, and Substrate Docking
(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

P450-Mediated Methamphetamine Metabolism in Rhesus and Human

Ravinder Earla, Santosh Kumar, Lei Wang, Steven Bosinger, Junhao Li, Ankit Shah, Mohitkumar Gangwani, Anantha Nookala, Xun Liu, Lu Cao, Austin Jackson, Peter S. Silverstein, Howard S. Fox, Weihua Li and Anil Kumar
Drug Metabolism and Disposition December 1, 2014, 42 (12) 2097-2108; DOI: https://doi.org/10.1124/dmd.114.059378

Citation Manager Formats

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

Share
Research ArticleArticle

P450-Mediated Methamphetamine Metabolism in Rhesus and Human

Ravinder Earla, Santosh Kumar, Lei Wang, Steven Bosinger, Junhao Li, Ankit Shah, Mohitkumar Gangwani, Anantha Nookala, Xun Liu, Lu Cao, Austin Jackson, Peter S. Silverstein, Howard S. Fox, Weihua Li and Anil Kumar
Drug Metabolism and Disposition December 1, 2014, 42 (12) 2097-2108; DOI: https://doi.org/10.1124/dmd.114.059378
Reddit logo Twitter logo Facebook 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

  • Olanzapine Glucuronidation in Humanized Mice
  • rs2242480 Regulates the Expression of CYP3A4 and CYP3A5
  • Absorption, Metabolism, and Excretion of Taselisib
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