Dataset Information

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 (V_d, 6.3 ± 0.6 L/kg) and high clearance (Cl, 1.8 ± 0.4 L/h/kg). Following oral mitragynine dosing, first peak plasma (C_max, 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 C_max of 31.5 ± 3.3 ng/mL and a T_max 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.

SUBMITTER: Maxwell EA

PROVIDER: S-EPMC7907416 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Pharmacokinetics and Safety of Mitragynine in Beagle Dogs.

Maxwell Elizabeth A EA King Tamara I TI Kamble Shyam H SH Raju Kanumuri Siva Rama KSR Berthold Erin C EC León Francisco F Avery Bonnie A BA McMahon Lance R LR McCurdy Christopher R CR Sharma Abhisheak A

Planta medica 20200721 17

Mitragynine is the most abundant psychoactive alkaloid derived from the leaves of <i>Mitragyna speciosa</i> (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 st ...[more]

PMID: 32693425

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Project description:A single-oral-dose, two-period cross-over study with a 5-day washout period under fed condition was conducted in six beagle dogs to explore the pharmacokinetic characteristics and relative bioavailability between sustained-release (SR) tablets and enteric-coated (EC) tablets of pentoxifylline (PTX) and its metabolite. The results showed that M5 exhibited the highest exposure level, while M1 demonstrated the lowest in both the SR and EC tablet groups. For PTX and M1, T1/2 were 0.42 and 0.55 h, with tmax of 1.83 and 1.83 h, respectively, in the SR tablet group; in the EC tablet group, T1/2 were 0.38 and 0.47 h, respectively. However, a significantly prolonged absorption process was noted, with tmax values of 5.06 and 5.78 h. In contrast, M5 exhibited distinct pharmacokinetic differences compared to PTX and M1. For the SR tablet group, T1/2 and tmax were recorded at 2.03 and 3.08 h, respectively. In the EC tablet group, T1/2 and tmax were 1.67 and 5.78 h, respectively. With regard to the geometric least squares mean (LSM) of AUC and Cmax for SR tablets and EC tablets, the ratios of SR/EC of PTX, M1 and M5 were 67.62% (90% CI, 50.49%-90.55%), 78.18% (90% CI, 54.15%-112.88%), and 119.11% (90% CI, 99.62%-142.41%), respectively, for AUC(0-t). The ratios were 67.62% (90% CI, 50.50%-90.55%), 78.36% (90% CI, 54.48%-112.72%), and 119.39% (90% CI, 100.03%-142.50%) for AUC(0-∞) and 54.36% (90% CI, 36.63%-80.67%), 58.80% (90% CI, 40.84%-84.66%), and 100.51% (90% CI, 89.50%-112.88%) for Cmax, respectively. The AUC ratio predictions of bioconversion results indicated that there was no significant difference in the bioconversion of M1 between the SR tablets and EC tablets, with conversion rates of 0.37 and 0.36, respectively. In contrast, the conversion rate of M5 demonstrated a significant difference (p < 0.05) between the SR tablets and EC tablets, with the ratio of 3.09 and 1.91, respectively. Furthermore, the EC tablet group demonstrated notable inter-individual differences and irregular drug absorption, following meals. Consequently, the SR tablets appeared to provide a more stable and controllable therapeutic effect in beagle dogs.

Dataset Information

Pharmacokinetics and Safety of Mitragynine in Beagle Dogs.

Publications

Pharmacokinetics and Safety of Mitragynine in Beagle Dogs.

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