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
OtherMetabolism, Transport, and Pharmacogenetics

Refined prediction of pharmacokinetic kratom-drug interactions: time-dependent inhibition considerations

Rakshit S. Tanna, Dan-Dan Tian, Nadja B. Cech, Nicholas H. Oberlies, Allan E. Rettie, Kenneth E. Thummel and Mary F. Paine
Journal of Pharmacology and Experimental Therapeutics October 22, 2020, JPET-AR-2020-000270; DOI: https://doi.org/10.1124/jpet.120.000270
Rakshit S. Tanna
1Pharmaceutical Sciences, Washington State University, United States of America
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dan-Dan Tian
2Washington State University, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nadja B. Cech
3United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nicholas H. Oberlies
4Chemistry and Biochemistry, University of North Carolina at Greensboro, United States of America
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Allan E. Rettie
5Dept. of Medicinal Chemistry, University of Washington, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kenneth E. Thummel
6Department of Pharmaceutics, University of Washington, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mary F. Paine
1Pharmaceutical Sciences, Washington State University, United States of America
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: mary.paine@wsu.edu
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

Preparations from the leaves of the kratom plant (Mitragyna speciosa) are consumed for their opioid-like effects. Several deaths have been associated with kratom used concomitantly with some drugs. Pharmacokinetic interactions are potential underlying mechanisms of these fatalities. Accumulating in vitro evidence has demonstrated select kratom alkaloids, including the abundant indole alkaloid mitragynine, as reversible inhibitors of several cytochromes P450 (CYPs). The objective of this work was to refine the mechanistic understanding of potential kratom-drug interactions by considering both reversible and time-dependent CYP inhibition (TDI) in the liver and intestine. Mitragynine was tested against CYP2C9 (diclofenac 4′-hydroxylation), CYP2D6 (dextromethorphan O-demethylation), and CYP3A (midazolam 1′-hydroxylation) activities in human liver microsomes (HLMs) and CYP3A activity in human intestinal microsomes (HIMs). Comparing the absence to presence of NADPH during pre-incubation of mitragynine with HLMs or HIMs, an ~7-fold leftward shift in IC50 (~20 to 3 μM) towards CYP3A resulted, prompting determination of TDI parameters (HLMs: KI, 4.1 {plus minus} 0.9 μM; kinact, 0.068 {plus minus} 0.01 min-1; HIMs: KI, 4.2 {plus minus} 2.5 μM; kinact, 0.079 {plus minus} 0.02 min-1). Mitragynine caused no leftward shift in IC50 towards CYP2C9 (~40 μM) and CYP2D6 (~1 μM) but was a strong competitive inhibitor of CYP2D6 (Ki, 1.17 {plus minus} 0.07 μM). Using a recommended mechanistic static model, mitragynine (2-g kratom dose) was predicted to increase dextromethorphan and midazolam area under the plasma concentration-time curve (AUC) by 1.06 and 5.69-fold, respectively. The predicted midazolam AUC ratio exceeded the recommended cut-off (1.25), which would have been missed if TDI was not considered.

Significance Statement Kratom, a botanical natural product increasingly consumed for its opioid-like effects, may precipitate potentially serious pharmacokinetic interactions with drugs. The abundant kratom indole alkaloid, mitragynine, was shown to be a time-dependent inhibitor of hepatic and intestinal cytochrome P450 3A activity. A mechanistic static model predicted mitragynine to increase systemic exposure to the probe drug substrate midazolam by 5.7-fold, necessitating further evaluation via dynamic models and clinical assessment to advance understanding of consumer safety associated with kratom use.

  • CYP inhibition
  • CYP2D6
  • CYP3A
  • Drug interactions
  • drug metabolism
  • gastrointestinal cytochrome P450
  • in vitro-in vivo prediction (IVIVE)
  • mechanism-based inhibition
  • natural products
  • pharmacokinetics
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
Next
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
  • 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 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.
Refined prediction of pharmacokinetic kratom-drug interactions: time-dependent inhibition considerations
(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
OtherMetabolism, Transport, and Pharmacogenetics

Refined prediction of potential kratom-drug interactions

Rakshit S. Tanna, Dan-Dan Tian, Nadja B. Cech, Nicholas H. Oberlies, Allan E. Rettie, Kenneth E. Thummel and Mary F. Paine
Journal of Pharmacology and Experimental Therapeutics October 22, 2020, JPET-AR-2020-000270; DOI: https://doi.org/10.1124/jpet.120.000270

Citation Manager Formats

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

Share
OtherMetabolism, Transport, and Pharmacogenetics

Refined prediction of potential kratom-drug interactions

Rakshit S. Tanna, Dan-Dan Tian, Nadja B. Cech, Nicholas H. Oberlies, Allan E. Rettie, Kenneth E. Thummel and Mary F. Paine
Journal of Pharmacology and Experimental Therapeutics October 22, 2020, JPET-AR-2020-000270; DOI: https://doi.org/10.1124/jpet.120.000270
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
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Indobufen on Inflammation and Peritoneal Transport Function
  • ACP-5862—Major Metabolite of BTK Inhibitor Acalabrutinib
  • CNS Distribution of the ATM Inhibitor AZD1390
Show more Article

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