Pharmacokinetics and Safety of Mitragynine in Beagle Dogs

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 (5mg/kg) and intravenous (0.1mg/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 +/- 0.6L/kg) and high clearance (Cl, 1.8 +/- 0.4L/h/kg). Following oral mitragynine dosing, first peak plasma (C (max) , 278.0 +/- 47.4ng/mL) concentrations were observed within 0.5h. A potent mu-opioid receptor agonist and active metabolite of mitragynine, 7-hydroxymitragynine, was also observed with a C (max) of 31.5 +/- 3.3ng/mL and a T (max) of 1.7 +/- 0.6h in orally dosed dogs while its plasma concentrations were below the lower limit of quantification (1ng/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.