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The inhibitory effects of mitragynine on P-glycoprotein in vitro

  • Noradliyanti Rusli
  • Azimah Amanah
  • Gurjeet Kaur
  • Mohd Ilham Adenan
  • Shaida Fariza Sulaiman
  • Habibah Abdul Wahab
  • Mei Lan Tan
Original Article
  • 32 Downloads

Abstract

Mitragynine is a major component isolated from Mitragyna speciosa Korth or kratom, a medicinal plant known for its opiate-like and euphoric properties. Multiple toxicity and fatal cases involving mitragynine or kratom have been reported but the underlying causes remain unclear. P-glycoprotein (P-gp) is a multidrug transporter which modulates the pharmacokinetics of xenobiotics and plays a key role in mediating drug-drug interactions. This study investigated the effects of mitragynine on P-gp transport activity, mRNA, and protein expression in Caco-2 cells using molecular docking, bidirectional assay, RT-qPCR, Western blot analysis, and immunocytochemistry techniques, respectively. Molecular docking simulation revealed that mitragynine interacts with important residues at the nucleotide binding domain (NBD) site of the P-gp structure but not with the residues from the substrate binding site. This was consistent with subsequent experimental work as mitragynine exhibited low permeability across the cell monolayer but inhibited digoxin transport at 10 μM, similar to quinidine. The reduction of P-gp activity in vitro was further contributed by the downregulation of mRNA and protein expression of P-gp. In summary, mitragynine is likely a P-gp inhibitor in vitro but not a substrate. Hence, concurrent administration of mitragynine-containing kratom products with psychoactive drugs which are P-gp substrates may lead to clinically significant toxicity. Further clinical study to prove this point is needed.

Keywords

Mitragyna speciosa Korth Kratom Mitragynine P-glycoprotein Bidirectional transport assay 

Notes

Acknowledgements

The authors would like to acknowledge MyBrain15 program and USM fellowship for sponsoring NR.

Author contribution statement

TML, MIA, GK, and SFS conceived and designed research. NR and AA conducted experiments. HAW contributed analytical tools for in silico screening. TML and NR analyzed data. TML wrote the manuscript. All authors read and approved the manuscript.

Funding

This fundamental work was supported in parts by the Fundamental Research Grant Scheme (Ministry of Education Malaysia) and RUI (USM) grant awarded to TML.

Compliance with ethical standards

No animals or human were used in this study.

Conflict of interest

The authors declare that they have no conflict of interests.

Supplementary material

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Supplementary Fig. 1 The structure and identity of the mitragynine confirmed using 1H-NMR and 13C-NMR analysis. (DOCX 20 kb)
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Supplementary Fig. 2

(a) The growth inhibition curve of mitragynine and etoposide in Caco-2 cells. Positive values (< 100%) represent growth inhibition and negative values (< 0%) represent cytotoxicity as compared with initial cells plated (T0). Retention time and chromatogram of (b) 20 μM mitragynine) (c) 20 μM of digoxin using optimized HPLC parameters. Linear regression curve of (d) mitragynine (e) digoxin (f) Bidirectional permeability of digoxin in the presence and absence of P-gp inhibitor in Caco-2 cells. All data are presented as mean ± SD of three independent experiments (n = 3). (PNG 1039 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Advanced Medical & Dental InstituteUniversiti Sains MalaysiaKepala BatasMalaysia
  2. 2.Malaysian Institute of Pharmaceuticals & Nutraceuticals, National Institutes of Biotechnology Malaysia (NIBM)Ministry of Energy, Science, Technology, Environment and Climate Change (MESTECC)GeorgetownMalaysia
  3. 3.Institute for Research in Molecular Medicine (INFORMM)Universiti Sains MalaysiaGeorgetownMalaysia
  4. 4.Atta-ur-Rahman Institute for Natural Product DiscoveryUniversiti Teknologi MARA (UiTM)Shah AlamMalaysia
  5. 5.School of Biological SciencesUniversiti Sains MalaysiaPenangMalaysia
  6. 6.Pharmaceutical Drug Simulation Laboratory (PhDS), School of Pharmaceutical SciencesUniversiti Sains MalaysiaGeorgetownMalaysia

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