Determination Of Mitragynine As A Substrate, Inducer, Or Inhibitor Of P-Glycoprotein Drug Transporter, And Prediction Of Drug-Herb Interaction Risks
| dc.contributor.author | Rusli, Noradliyanti | |
| dc.date.accessioned | 2018-10-08T07:24:56Z | |
| dc.date.available | 2018-10-08T07:24:56Z | |
| dc.date.issued | 2017-06 | |
| dc.description.abstract | P-glycoprotein (P-gp) is a multidrug transporter, mainly expressed in the intestinal tissue as a secretory efflux protein. Changes in the activity, gene and protein expression of P-gp caused by drugs or herbal compounds will affect oral drug bioavailability and may potentially lead to drug-drug or drug-herb interactions. Mitragyna speciosa Korth or Ketum is traditionally used for various ailments but due to its euphoric effects, this plant is often misused by the local population. Although Ketum is a controlled substance in most Asian countries, including Malaysia, its use is not strictly regulated in other parts of the world. Mitragynine is a major bioactive component in the crude extract of the plant and the safety of this alkaloid causing adverse drug interaction via P-gp has not been fully investigated. Therefore our main objective is to determine if mitragynine is a substrate of P-gp or has the potential to inhibit or induce the P-gp transport activity and expression in Caco-2 cells. An in silico computational method to predict the binding conformation of mitragynine to the substrate binding site as well as the nucleotide binding domain (NBD) of the P-gp was carried out using Autodock 4.2 and further validated using in vitro bidirectional transport assay. Optimization of the bidirectional transport assay was carried out and both mitragynine and digoxin were analyzed using HPLC/UV detector with isocratic elution. The effects of mitragynine on mRNA and protein expression of P-gp were carried out using an optimized RT-qPCR, Western blot analysis and immunofluorescence. Mitragynine is unlikely a P-gp substrate based on both the molecular docking simulation and bidirectional transport assay. However, it appears to form hydrogen bonds and hydrophobic interactions with P-gp and was found to inhibit the P-gp transport activity by 30% reduction when compared with control. Mitragynine was found to inhibit mRNA and protein expression of P-gp. For the highest concentration of 10 μM, inhibition of mRNA and protein were approximately 35% and 40% that of the control respectively and were consistent with the decrease in the transport activity of digoxin via P-gp. | en_US |
| dc.identifier.uri | http://hdl.handle.net/123456789/6704 | |
| dc.language.iso | en | en_US |
| dc.publisher | Universiti Sains Malaysia | en_US |
| dc.subject | Inhibitor of p-glycoprotein drug transporter | en_US |
| dc.subject | and prediction of drug-herb interaction risks | en_US |
| dc.title | Determination Of Mitragynine As A Substrate, Inducer, Or Inhibitor Of P-Glycoprotein Drug Transporter, And Prediction Of Drug-Herb Interaction Risks | en_US |
| dc.type | Thesis | en_US |
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