Planta Med 2020; 86(17): 1278-1285
DOI: 10.1055/a-1212-5475
Pharmacokinetic Investigations
Original Papers

Pharmacokinetics and Safety of Mitragynine in Beagle Dogs

Elizabeth A. Maxwell
1  Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
,
Tamara I. King
2  Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
,
Shyam H. Kamble
2  Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
3  Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA
,
Kanumuri Siva Rama Raju
2  Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
3  Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA
,
Erin C. Berthold
2  Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
,
Francisco León
4  Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA
,
Bonnie A. Avery
2  Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
3  Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA
,
Lance R. McMahon
5  Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA
,
Christopher R. McCurdy
3  Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA
4  Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA
,
2  Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
3  Translational Drug Development Core, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA
› Author Affiliations
Supported by: National Institute on Drug Abuse R01 DA047855
Supported by: National Institute on Drug Abuse UG3 DA048353
Supported by: National Center for Advancing Translational Sciences UL1TR001427

Abstract

Mitragynine is the most abundant psychoactive alkaloid derived from the leaves of Mitragyna speciosa (kratom), a tropical plant indigenous to regions of Southeast Asia. Mitragynine displays a moderate affinity to opioid receptors, and kratom is often self-prescribed to treat pain and/or opioid addiction. The purpose of this study was to investigate the safety and pharmacokinetic properties of mitragynine in the dog. Single dose oral (5 mg/kg) and intravenous (0.1 mg/kg) pharmacokinetic studies of mitragynine were performed in female beagle dogs. The plasma concentrations of mitragynine were measured using ultra-performance liquid chromatography coupled with a tandem mass spectrometer, and the pharmacokinetic properties were analyzed using non-compartmental analysis. Following intravenous administration, mitragynine showed a large volume of distribution (Vd, 6.3 ± 0.6 L/kg) and high clearance (Cl, 1.8 ± 0.4 L/h/kg). Following oral mitragynine dosing, first peak plasma (Cmax, 278.0 ± 47.4 ng/mL) concentrations were observed within 0.5 h. A potent mu-opioid receptor agonist and active metabolite of mitragynine, 7-hydroxymitragynine, was also observed with a Cmax of 31.5 ± 3.3 ng/mL and a Tmax of 1.7 ± 0.6 h in orally dosed dogs while its plasma concentrations were below the lower limit of quantification (1 ng/mL) for the intravenous study. The absolute oral bioavailability of mitragynine was 69.6%. Administration of mitragynine was well tolerated, although mild sedation and anxiolytic effects were observed. These results provide the first detailed pharmacokinetic information for mitragynine in a non-rodent species (the dog) and therefore also provide significant information for allometric scaling and dose predictions when designing clinical studies.

Supporting Information



Publication History

Received: 31 March 2020

Accepted after revision: 29 June 2020

Publication Date:
21 July 2020 (online)

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