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Oral Pharmacokinetics in Beagle Dogs of the Mitragynine Metabolite, 7-Hydroxymitragynine

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Abstract

Background and Objectives

7-Hydroxymitragynine (7-HMG) is an oxidative metabolite of mitragynine, the most abundant alkaloid in the leaves of Mitragyna speciosa (otherwise known as kratom). While mitragynine is a weak partial µ-opioid receptor (MOR) agonist, 7-HMG is a potent and full MOR agonist. It is produced from mitragynine by cytochrome P450 (CYP) 3A, a drug-metabolizing CYP isoform predominate in the liver that is also highly expressed in the intestine. Given the opioidergic potency of 7-HMG, a single oral dose pharmacokinetic and safety study of 7-HMG was performed in beagle dogs.

Methods

Following a single oral dose (1 mg/kg) of 7-HMG, plasma samples were obtained from healthy female beagle dogs. Concentrations of 7-HMG were determined using ultra-performance liquid chromatography coupled with a tandem mass spectrometer (UPLC-MS/MS). Pharmacokinetic parameters were calculated using a model-independent non-compartmental analysis of plasma concentration-time data.

Results

Absorption of 7-HMG was rapid, with a peak plasma concentration (Cmax, 56.4 ± 1.6 ng/ml) observed within 15 min post-dose. In contrast, 7-HMG elimination was slow, exhibiting a mono-exponential distribution and mean elimination half-life of 3.6 ± 0.5 h. Oral dosing of 1 mg/kg 7-HMG was well tolerated with no observed adverse events or significant changes to clinical laboratory tests.

Conclusions

These results provide the first pharmacokinetic and safety data for 7-HMG in the dog and therefore contribute to the understanding of the putative pharmacologic role of 7-HMG resulting from an oral delivery of mitragynine from kratom.

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Acknowledgement

Authors thank Ms. Paige Maxwell for providing technical support.

Author information

Authors and Affiliations

  1. Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA

    Elizabeth A. Maxwell

  2. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA

    Tamara I. King, Shyam H. Kamble, Kanumuri Siva Rama Raju, Erin C. Berthold, Christopher R. McCurdy & Abhisheak Sharma

  3. Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA

    Shyam H. Kamble, Kanumuri Siva Rama Raju, Christopher R. McCurdy & Abhisheak Sharma

  4. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA

    Francisco León & Christopher R. McCurdy

  5. Division of Therapeutics and Medical Consequences, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA

    Aidan Hampson

  6. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA

    Lance R. McMahon

Authors
  1. Elizabeth A. Maxwell
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  2. Tamara I. King
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  3. Shyam H. Kamble
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  4. Kanumuri Siva Rama Raju
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  5. Erin C. Berthold
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  6. Francisco León
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  7. Aidan Hampson
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  8. Lance R. McMahon
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  9. Christopher R. McCurdy
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  10. Abhisheak Sharma
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Corresponding authors

Correspondence to Christopher R. McCurdy or Abhisheak Sharma.

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Author contributions

Conception and design of the work were performed by Elizabeth A. Maxwell, Franscisco Leon, Aidan Hampson, Lance R. McMahon, Christopher R. McCurdy, Abhisheak Sharma. Material preparation, data collection and analysis were performed by Elizabeth A. Maxwell, Tamara King, Shyam H. Kamble, Kanumuri S. R. Raju, Franscisco Leon, Lance R. McMahon, Christopher R. McCurdy, Abhisheak Sharma. The first draft of the manuscript was written by Elizabeth A. Maxwell, Abhisheak Sharma and all authors edited or commented on versions of the manuscript. All authors read and approved the final manuscript.

Funding

This study was financially supported by UG3 DA048353 and R01 DA047855 grants from the National Institute on Drug Abuse and the University of Florida Clinical and Translational Science Institute, which is supported in part by the NIH National Center for Advancing Translational Sciences under award number UL1TR001427. Dr. Hampson was substantially involved in UG3 DA048353, consistent with his role as Scientific Officer. He had no substantial involvement in the other cited grants.

Disclaimer

The views and opinions expressed in this manuscript are those of the authors only and do not necessarily represent the views, official policy or position of the U.S. Department of Health and Human Services or any of its affiliated institutions or agencies.

Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

The study was approved and performed in accordance with the guidelines of the Institutional Animal Care and Use Committee (protocol number: 201910731, dated July 11, 2019) at the University of Florida.

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Maxwell, E.A., King, T.I., Kamble, S.H. et al. Oral Pharmacokinetics in Beagle Dogs of the Mitragynine Metabolite, 7-Hydroxymitragynine. Eur J Drug Metab Pharmacokinet 46, 459–463 (2021). https://doi.org/10.1007/s13318-021-00684-2

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  • DOI: https://doi.org/10.1007/s13318-021-00684-2

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