The inhibitory effects of mitragynine on P-glycoprotein in vitro

Rusli, N.; Amanah, Azimah; Kaur, Gurjeet; Adenan, Mohd Ilham; Sulaiman, Shaida Fariza; Wahab, Habibah A.; Tan, Mei Lan

doi:10.1007/s00210-018-01605-y

Cited by 26 publications

(22 citation statements)

References 73 publications

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“…Cases involving multiple toxicity and fatal outcomes after mitragynine or kratom use have been reported, but the underlying causes remain unclear. Recently, in 2019, Rusli et al [94] attempted to correlate the effects of mitragynine with glycoprotein-P, a multidrug transporter which modulates xenobiotic pharmacokinetics and plays a key role in the mediation of drug–drug interactions. Using biomolecular techniques, these authors concluded that mitragynine interacted with important residues at the nucleotide binding domain site of glycoprotein-P’s structure, but not with the residues from the substrate binding site.…”

Section: Toxicologymentioning

confidence: 99%

Mitragyna speciosa: Clinical, Toxicological Aspects and Analysis in Biological and Non-Biological Samples

et al. 2019

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The abuse of psychotropic substances is a well-known phenomenon, and many of them are usually associated with ancestral traditions and home remedies. This is the case of Mitragyna speciosa (kratom), a tropical tree used to improve work performance and to withstand great heat. According to several published studies, the main reasons for kratom consumption involve improving sexual performance and endurance, but also social and recreational uses for the feeling of happiness and euphoria; it is also used for medical purposes as a pain reliever, and in the treatment of diarrhea, fever, diabetes, and hypertension. However, this plant has gained more popularity amongst young people over the last years. Since it is available on the internet for purchase, its use is now widely as a drug of abuse, namely as a new psychoactive substance, being a cheaper alternative to opioids that does not require medical prescription in most countries. According to internet surveys by the European Monitoring Centre for Drugs and Drug Addiction in 2008 and 2011, kratom was one of the most widely supplied new psychoactive substances. The composition of kratom is complex; in fact, more than 40 different alkaloids have been identified in Mitragyna speciosa so far, the major constituent being mitragynine, which is exclusive to this plant. Besides mitragynine, alkaloids such as corynantheidine and 7-hydroxamitragynine also present pharmacological effects, a feature that may be attributed to the remaining constituents as well. The main goal of this review is not only to understand the origin, chemistry, consumption, and analytical methodologies for analysis and mechanism of action, but also the use of secondary metabolites of kratom as therapeutic drugs and the assessment of potential risks associated with its consumption, in order to aid health professionals, toxicologists, and police authorities in cases where this plant is present.

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Section: Toxicologymentioning

confidence: 99%

Mitragyna speciosa: Clinical, Toxicological Aspects and Analysis in Biological and Non-Biological Samples

et al. 2019

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“…Data from nine published in vitro studies were entered into the repository ( Hanapi et al, 2010 , 2013 ; Kong et al, 2011 ; Haron and Ismail, 2014 ; Manda et al, 2014 ; Meyer et al, 2015 ; Kamble et al, 2019 , 2020 ; Rusli et al, 2019 ). One study using recombinant P450 enzymes reported that a methanolic extract of kratom inhibited CYP2D6 but not CYP2C9 or CYP3A4 ( Hanapi et al, 2010 ).…”

Section: Resultsmentioning

confidence: 99%

“…Three studies reported inhibition of P-glycoprotein by mitragynine, two using Caco-2 cells ( Meyer et al, 2015 ; Rusli et al, 2019 ), and one using MDCK-transfected cells ( Manda et al, 2014 ). The same MDCK-transfected cell study reported inhibition of P-glycoprotein by 7-hydroxymitragynine.…”

Section: Resultsmentioning

confidence: 99%

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A New Data Repository for Pharmacokinetic Natural Product-Drug Interactions: From Chemical Characterization to Clinical Studies

et al. 2020

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There are many gaps in scientific knowledge about the clinical significance of pharmacokinetic natural product-drug interactions (NPDIs) in which the natural product (NP) is the precipitant and a conventional drug is the object. The National Center for Complimentary and Integrative Health created the Center of Excellence for NPDI Research (NaPDI Center) (www.napdi.org) to provide leadership and guidance on the study of pharmacokinetic NPDIs. A key contribution of the Center is the first user-friendly online repository that stores and links pharmacokinetic NPDI data across chemical characterization, metabolomics analyses, and pharmacokinetic in vitro and clinical experiments (repo.napdi.org). The design is expected to help researchers more easily arrive at a complete understanding of pharmacokinetic NPDI research on a particular NP. The repository will also facilitate multidisciplinary collaborations, as the repository links all of the experimental data for a given NP across the study types. The current work describes the design of the repository, standard operating procedures used to enter data, and pharmacokinetic NPDI data that have been entered to date. To illustrate the usefulness of the NaPDI Center repository, more details on two high-priority NPs, cannabis and kratom, are provided as case studies. SIGNIFICANCE STATEMENT The data and knowledge resulting from natural product-drug interaction (NPDI) studies is distributed across a variety of information sources, rendering difficulties to find, access, and reuse. The Center of Excellence for NPDI Research addressed these difficulties by developing the first user-friendly online repository that stores data from in vitro and clinical pharmacokinetic NPDI experiments and links them with study data from chemical characterization and metabolomics analyses of natural products that are also stored in the repository.

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“…For the intestinal barrier, the Caco-2 cell line developed from human colorectal adenocarcinoma epithelium is commonly used to establish a model for the barrier, to determine intestinal absorption ( Volpe, 2020 ). The model was used to investigate intestinal permeability of kratom alkaloids mitragynine ( Manda et al, 2014 ; Rusli et al, 2019 ), 7-hydroxymitragynine, and mitraphylline ( Manda et al, 2014 ). Mitragynine was found to be the most permeable across the Caco-2 cells, followed by 7-hydroxymitragynine and mitraphylline with P app of 24.2 × 10 –6 cm/s, 16.1 × 10 –6 cm/s and 6.3 × 10 –6 cm/s respectively, when tested at 5 μM in the absorptive direction (apical to basolateral).…”

Section: Interactions Of Kratom Alkaloids With Cellular Barriersmentioning

confidence: 99%

Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers

et al. 2021

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Parallel to the growing use of kratom, there is a wealth of evidence from self-report, preclinical, and early clinical studies on therapeutic benefits of its alkaloids in particular for treating pain, managing substance use disorder, and coping with emotional or mental health conditions. On the other hand, there are also reports on potential health risks concerning kratom use. These two aspects are often discussed in reviews on kratom. Here, we aim to highlight specific areas that are of importance to give insights into the mechanistic of kratom alkaloids pharmacological actions. This includes their interactions with drug-metabolizing enzymes and predictions of clinical drug-drug interactions, receptor-binding properties, interactions with cellular barriers in regards to barrier permeability, involvement of membrane transporters, and alteration of barrier function when exposed to the alkaloids.

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The inhibitory effects of mitragynine on P-glycoprotein in vitro

Cited by 26 publications

References 73 publications

Mitragyna speciosa: Clinical, Toxicological Aspects and Analysis in Biological and Non-Biological Samples

Mitragyna speciosa: Clinical, Toxicological Aspects and Analysis in Biological and Non-Biological Samples

A New Data Repository for Pharmacokinetic Natural Product-Drug Interactions: From Chemical Characterization to Clinical Studies

Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers

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