Pharmacokinetics and Safety of Mitragynine in Beagle Dogs

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.

A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

“…17,18,20,22 We also reported oxidative metabolism of mitragynine to 7OH mitragynine using a CYP3A-mediated pathway following oral administration of mitragynine in mice. 19 Metabolism of mitragynine to 7OH in vitro 24 and in dogs 25 has been reported by other groups too. More recently, we also reported an atomic-level description of how kratom alkaloids may bind and allosterically modulate MOR 21 .…”

The Lack of Contribution of 7-Hydroxymitragynine to the Antinociceptive Effects of Mitragynine in Mice: A Pharmacokinetic and Pharmacodynamic Study

“…Though these results provide valuable information about a preclinical rodent model, species differences in the fraction of MTG metabolized to 7HMG have been reported. In female beagle dogs, the AUC ratio of 7HMG to MTG was 13%, 1.4-fold greater than that found in female mice indicating that concentrations of free 7HMG may be greater in dogs and have more potential to influence the overall pharmacology of MTG (Maxwell et al, 2020). Combining the population PK/PD approach with physiologically based pharmacokinetic modeling that considers the aforementioned species and sex differences uncovered in this study will be helpful in translating preclinical results into first in human dose recommendations while also contributing to the continued evaluation of MTG.…”

“…MTG was isolated and purified from a kratom alkaloid enriched extract (OPMS, Choice Organics, Los Angeles, CA, USA) as described in previous literature (Avery et al, 2019;Sharma et al, 2019) and was used as the hydrochloride (HCl) salt with a purity ≥ 98%. 7HMG (purity ≥ 98%) was obtained through semi-synthesis from MTG as previously reported (Maxwell et al, 2020) and used as the freebase. Purity and structural characterization of MTG and 7HMG were established using 1 H proton and 13 C carbon nuclear magnetic resonance spectroscopy (NMR), ultra-high-performance liquid chromatography-photodiode array detection (UHPLC-PDA), and liquid chromatography high-resolution quadrupole time of flight mass spectrometry (LC-Q-TOF-MS).…”

“…1 H and 13 C NMR spectra were obtained using Bruker Avance NEO 600 NMR and Bruker Avance II 600 MHz NMR spectrometers operating at 600 MHz in 1 H and 151 MHz in 13 C (Bruker Co., Billerica, MA, USA). A previously reported ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method validated for the quantification of MTG and 7HMG was used to analyze study samples (Maxwell, 2020). The UPLC-MS/MS was a Waters Acquity Class-I chromatograph coupled with a Xevo TQ-S Micro triple quadrupole mass spectrometer (Waters, Milford, MA, USA).…”

“…The method was updated to a quantitation range of 2-800 ng/mL with a 0.4 µL injection volume. In addition, the method was previously validated in dog plasma (Maxwell et al, 2020) so partial validations were performed for each of the additional matrices (mouse plasma, brain, lung, liver, kidney, and spleen).…”