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

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 (C_max, 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.

Fig. 1

Mean plasma concentration-time profile of 7-hydroxymitragynine after single oral dose in female beagle dogs (N = 3). Error represent SEM