Isolation, characterization, and NMR spectroscopic data of indole and oxindole alkaloids from Mitragyna speciosa

Ali, Zulfiqar; Demiray, Hatice; Khan, Ikhlas A.

doi:10.1016/j.tetlet.2013.11.031

Cited by 29 publications

(23 citation statements)

References 11 publications

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“…This constituent was isolated and identified as the known kratom oxindole alkaloid speciofoline (3, Fig. 1) ([M + H] + = 401.2071, Δ = 1.7 ppm) based on comparison of NMR, ECD, and mass spectrometry data with literature values [23][24][25][26] (Table S2, Figure S1 and S2). Several other ions were also observed to vary in content across the samples (Fig.…”

Section: Resultsmentioning

confidence: 99%

Chemical composition and biological effects of kratom (Mitragyna speciosa): In vitro studies with implications for efficacy and drug interactions

Todd

Kellogg

Wallace

et al. 2020

Sci Rep

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The safety and efficacy of kratom (Mitragyna speciosa) for treatment of pain is highly controversial. Kratom produces more than 40 structurally related alkaloids, but most studies have focused on just two of these, mitragynine and 7-hydroxymitragynine. Here, we profiled 53 commercial kratom products using untargeted LC–MS metabolomics, revealing two distinct chemotypes that contain different levels of the alkaloid speciofoline. Both chemotypes were confirmed with DNA barcoding to be M. speciosa. To evaluate the biological relevance of variable speciofoline levels in kratom, we compared the opioid receptor binding activity of speciofoline, mitragynine, and 7-hydroxymitragynine. Mitragynine and 7-hydroxymitragynine function as partial agonists of the human µ-opioid receptor, while speciofoline does not exhibit measurable binding affinity at the µ-, δ- or ƙ-opioid receptors. Importantly, mitragynine and 7-hydroxymitragynine demonstrate functional selectivity for G-protein signaling, with no measurable recruitment of β-arrestin. Overall, the study demonstrates the unique binding and functional profiles of the kratom alkaloids, suggesting potential utility for managing pain, but further studies are needed to follow up on these in vitro findings. All three kratom alkaloids tested inhibited select cytochrome P450 enzymes, suggesting a potential risk for adverse interactions when kratom is co-consumed with drugs metabolized by these enzymes.

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Section: Resultsmentioning

confidence: 99%

Chemical composition and biological effects of kratom (Mitragyna speciosa): In vitro studies with implications for efficacy and drug interactions

Todd

Kellogg

Wallace

et al. 2020

Sci Rep

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“…The ethyl acetate soluble part, separated from basic media, was dried under reduced pressure to get an alkaloid‐rich fraction. The isolation of eight alkaloids was based on the conditions reported earlier (Ali et al, ). The purity of the compounds was confirmed by chromatographic analysis to be ≥95%.…”

Section: Methodsmentioning

confidence: 99%

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

Manda

Avula

Dale

et al. 2017

Phytotherapy Research

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Kratom (Mitragyna speciosa), a native herb of Southeast Asia, is widely known for its psychoactive properties. Recent increase in the use of kratom as a recreational drug has increased the risk of its interaction with conventional drugs if taken concomitantly. A few reports are available related to the effects of kratom on the activity of cytochrome P450 enzymes (CYPs), but there are no reports of its effects on pregnane X receptor (PXR), a transcription factor that regulates the expression of CYPs and P-glycoprotein (P-gp). This study was carried out to evaluate the effects of a methanolic extract of kratom leaves, an alkaloid rich fraction and its 5 indole and 4 oxindole alkaloids on PXR activation and the resulting changes in the mRNA expression of PXR target genes (CYP3A4, CYP1A2, and P-gp). A significant activation of PXR was observed by the extract (3-fold), alkaloidal fraction (4-fold) and all 9 alkaloids (4- to 6-fold) that was associated with an increased mRNA expression which resulted into an increase in the activity of CYP3A4, CYP1A2, and P-gp. These results indicate that high consumption of Mitragyna speciosa extract along with the conventional drugs may lead to potential herb-drug interactions due to its effects on PXR.

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“…The purity of all the positive controls used in this study was ≥ 98 %. Mitragynine was isolated as described earlier [27] and its purity was confirmed by chromatographic analysis to be ≥ 95%. Mitraphylline and 7-hydroxymitragynine (purity > 90 %) were purchased from ChromaDex ® .…”

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

et al. 2014

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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.

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Isolation, characterization, and NMR spectroscopic data of indole and oxindole alkaloids from Mitragyna speciosa

Cited by 29 publications

References 11 publications

Chemical composition and biological effects of kratom (Mitragyna speciosa): In vitro studies with implications for efficacy and drug interactions

Chemical composition and biological effects of kratom (Mitragyna speciosa): In vitro studies with implications for efficacy and drug interactions

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

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

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