Potential Contribution of 7‐Hydroxymitragynine, a Metabolite of the Primary Kratom (Mitragyna Speciosa) Alkaloid Mitragynine, to the μ‐Opioid Activity of Mitragynine in Rats
Authors: Hiranita Takato , Sharma Abhisheak , Oyola Francisco Leon , Obeng Samuel , Reeves Morgan E. , Restrepo Luis F. , Patel Avi , Behnke Mira , Ho Nicholas P. , Williamson Morgan R. , Gamez Jimenez Lea R. , McCurdy Christopher R. , McMahon Lance R. 
Published: April 2020

Mitragyna speciosa (kratom) has been used as a treatment for opioid use disorder in Southeast Asia. The primary kratom alkaloid mitragynine has received much attention due to its opioid pharmacology. One of the in vivo metabolites of mitragynine, 7‐hydroxymitragynine, is a more potent μ‐opioid receptor agonist than mitragynine; this has led to the hypothesis that mitragynine is a prodrug that exerts opioid agonist activity, in part, through metabolic conversion to 7‐hydroxymitragynine. Here, we investigated this hypothesis by comparing mitragynine and 7‐hydroxymitragynine for 1) in vitro binding affinity ([3H]DAMGO) and efficacy (GTPgS) at the μ‐opioid receptor, 2) plasma levels following p.o. mitragynine using a UPLC‐MS/MS method, and 3) potency and effectiveness to produce acute antinociception in the hotplate assay at 52° C. In the hotplate assay, the i.v. route of administration was used to minimize the conversion of mitragynine to 7‐hydroxymitragynine in order to directly compare the pharmacology of the two alkaloids. The binding affinity of 7‐hydroxymitragynine at the human μ‐opioid receptor (Ki=78 nM) was 22‐fold lower than morphine and 9.0‐fold higher than mitragynine. The % maximum GTPgS stimulations of 7‐hydroxymitragynine and morphine at the μ‐opioid receptor were 45% (up to 30 μM) and 90% (up to 30 μM), respectively. In contrast, mitragynine (up to 100 μM) did not significantly stimulate GTPgS. Following p.o. administration of mitragynine (HCl salt, 55 mg/kg), the Cmax value of 7‐hydroxymitragynine (85 ng/mL) was 14‐fold less than that of mitragynine. The Tmax values of 7‐hydroxymitragynine and mitragynine were 30 and 84 minutes, respectively. The % metabolite ratio [(AUC7‐hydroxymitragynine/AUCmitragynine)*100] was 8%. The % maximum possible effects (MPE, ED50 values in mg/kg, i.v.) of 7‐hydroxymitragynine (up to 0.1 mg/kg), morphine (up to 1.0 mg/kg) and mitragynine (up to 17.8 mg/kg) were 100% (1.9), 100% (5.1) and 34% (>17.8). In addition, 32 mg/kg mitragynine was lethal. Finally, drug discrimination was used as a pharmacologically selective measure of μ‐opioid receptor agonism in vivo. In rats discriminating morphine (3.2 mg/kg, i.p.) from vehicle, the discriminative stimulus effects of mitragynine were assessed 90 minutes after p.o. administration to correspond to its Tmax. Mitragynine (up to 178 mg/kg) produced 76% morphine‐lever responding (ED50=51 mg/kg). Though the conversion rate of 7‐hydroxymitragynine from p.o. mitragynine is low, 7‐hydroxymitragynine is a more potent and efficacious μ‐opioid receptor agonist than mitragynine, suggesting that conversion to this metabolite may contribute to the in vivo μ‐opioid activity of mitragynine.

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Supported by NIDA grants DA23205 and DA48353.