Evaluation of In Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Properties of Mitragynine, 7-Hydroxymitragynine, and Mitraphylline

Abstract

Mitragyna speciosa (kratom) is a popular herb in Southeast Asia, which is traditionally used to treat withdrawal symptoms associated with opiate addiction. Mitragynine, 7-hydroxymitragynine, and mitraphylline are reported to be the central nervous system active alkaloids which bind to the opiate receptors. Mitraphylline is also present in the bark of Uncaria tomentosa (cat's claw). Several therapeutic properties have been reported for these compounds but limited information is available on the absorption and distribution properties. This study focuses on evaluating the absorption, distribution, metabolism, and excretion (ADME) properties of these compounds and their effect on major efflux transporter P-glycoprotein, using in vitro methods. Quantitative analysis was performed by the Q-TOF LC-MS system. Mitragynine was unstable in simulated gastric fluid with 26 % degradation but stable in simulated intestinal fluid. 7-Hydroxymitragynine degraded up to 27 % in simulated gastric fluid, which could account for its conversion to mitragynine (23 %), while only 6 % degradation was seen in simulated intestinal fluid. Mitraphylline was stable in simulated gastric fluid but unstable in simulated intestinal fluid (13.6 % degradation). Mitragynine and 7-hydroxymitragynine showed moderate permeability across Caco-2 and MDR-MDCK monolayers with no significant efflux. However, mitraphylline was subjected to efflux mediated by P-glycoprotein in both Caco-2 and MDR-MDCK monolayers. Mitragynine was found to be metabolically stable in both human liver microsomes and S9 fractions. In contrast, both 7-hydroxymitragynine and mitraphylline were metabolized by human liver microsomes with half-lives of 24 and 50 min, respectively. All three compounds exhibited high plasma protein binding (> 90 %) determined by equilibrium dialysis. Mitragynine and 7-hydroxymitragynine inhibited P-glycoprotein with EC50 values of 18.2 ± 3.6 µM and 32.4 ± 1.9 µM, respectively, determined by the calcein-AM fluorescent assay, while no inhibition was seen with mitraphylline. These data indicate the possibility of a drug interaction if mitragynine and 7-hydroxymitragynine are coadministered with drugs that are P-glycoprotein substrates.

P-glycoprotein interactions of novel psychoactive substances – Stimulation of ATP consumption and transport across Caco-2 monolayers

“…Mitragynine seemed to be a weaker inhibitor than verapamil, although it is remarkable that both P app values, A to B and B to A, were reduced. These findings are in line with recent findings [14] that not only mitragynine, but also 7-hydroxymitragynine, a further alkaloid in Mitragyna speciosa (Kratom), were inhibitors of P-gp. Only diclofensine did not influence the apparent permeabilities and the ER of R123.…”

“…P-gp [11][12][13][14][15][16]. However, this is an issue of growing interest, particularly because appearance and abuse have increased dramatically over the last years [17][18][19][20].…”

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

“…We found that MG was two times more BBB permeable than 7‐OHMG, which is in agreement with previous study that reported MG permeability to be between 1.45 and 1.50 times higher than 7‐OHMG, measured in epithelial cell models (Manda et al . ). The higher rate of BBB permeation of MG could partly be related to its lipophilicity, estimated log P oct of 4.11 (ACD ChemSketch), higher than that estimated for 7‐OHMG, i.e.…”

PXR mediated induction of CYP3A4, CYP1A2, and P‐gp by Mitragyna speciosa and its alkaloids

“…In one report, mitragynine was shown to have CYP1A2 induction activity (Lim et al, ). In addition, P‐gp inhibitory activity of mitragynine and 7‐hydroxymitragynine was recently reported by us (Manda et al, ) and later by others (Meyer et al, ). To our knowledge, there are no reports on the effects of M. speciosa extract or its alkaloids on the transcriptional activity of PXR.…”