Rate and extent of mitragynine and 7‐hydroxymitragynine blood–brain barrier transport and their intra‐brain distribution: the missing link in pharmacodynamic studies

Abstract

Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood-brain barrier (BBB) transport of mitragynine and 7-hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7-hydroxymitragynine transport across the BBB, with an investigation of their post-BBB intra-brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P-glycoprotein (P-gp). Mitragynine showed higher apical-to-basolateral (A-B, i.e. blood-to-brain side) permeability than 7-hydroxymitragynine. 7-Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B-A/A-B) of 1.39. Both were found to inhibit the P-gp and are also subject to efflux by the P-gp. Assessment of the extent of BBB transport in vivo in rats from unbound brain to plasma concentration ratios (K ) revealed extensive efflux of both compounds, with less than 10 percent of unbound mitragynine and 7-hydroxymitragynine in plasma crossing the BBB. By contrast, the extent of intra-brain distribution was significantly different, with mitragynine having 18-fold higher brain tissue uptake in brain slice assay compared with 7-hydroxymitragynine. Mitragynine showed a moderate capacity to accumulate inside brain parenchymal cells, while 7-hydroxymitragynine showed restricted cellular barrier transport. The presented findings from this systematic investigation of brain pharmacokinetics of mitragynine and 7-hydroxymitragynine are essential for design and interpretation of in vivo experiments aiming to establish exposure-response relationship.

7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects

“…It should be mentioned that during the preparation of this manuscript, other groups separately reported the formation of 7-OH as a metabolite of mitragynine in vitro and in rats, but the mechanistic significance of this finding was not established through pharmacological studies. 38,39 Here we confirmed these concurrent research findings and provided the essential in vivo link demonstrating the pharmacological relevance of 7-OH.…”

Acute mitragynine administration suppresses cortical oscillatory power and systems theta coherence in rats

“…In addition, brain concentrations of 7-HMG appear to be sufficient in mediating the opioid receptor–mediated analgesic activity of mitragynine, leading the authors to postulate that mitragynine actually has little effect at MORs (Kruegel et al, 2019). This is especially important, when considering the fact that mitragynine crosses the blood–brain barrier preferentially compared with 7-HMG (18-fold higher uptake) (Yusof et al, 2019). While the specific kinetic parameters associated with intraperitoneal administration have not been assessed, mitragynine is rapidly absorbed via oral and intravenous delivery and undergoes fast distribution from the central compartment to peripheral compartments (Avery et al, 2019).…”

Assessing the therapeutic potential and toxicity of Mitragyna speciosa in opioid use disorder

“…In addition, 7-hydroxymitragynine is an active metabolite of mitragynine and it shows a 22.5-fold increased binding affinity (K i , 7.2 ± 0.9 nM) over mitragynine at the mu-opioid receptor [5,6]. Due to the higher polar surface area of the molecule, 7-hydroxymitragynine has a more limited ability to cross the blood-brain barrier when compared to mitragynine, and it is further converted to even more potent and efficacious metabolite, mitragynine pseudoindoxyl specifically in human plasma [8,9]. Levels of 7-hydroxymitragynine in Malaysian street samples and other freshly prepared extracts are below the lower limit of quantification (0.01 %w/w) of analytical methods, but in commercial kratom products in the United States was present up to 2 %w/w [1,10].…”