[{"id":170,"uid":"NPDI-JHPnhA","name":"The inhibitory effects of mitragynine on P-glycoprotein in vitro","napdiIdentifier":null,"overallSummary":"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.","pubmedId":30604191,"embaseId":625786142,"croIdentifier":"SAINS","croInformation":"Universiti Sains Malaysia","dateStart":null,"dateEnd":null,"internalComment":null,"status":"published","compoundId":null,"naturalProductUid":"NP-00ed1235-cbd8-4117-85df-298b8b3cdcad","naturalProductSampleId":null,"studySourceTypeId":1,"naturalProduct":{"uid":"NP-00ed1235-cbd8-4117-85df-298b8b3cdcad","binomial":"Mitragyna speciosa","name":"Kratom","itis":null,"srs":"d469b67d-e9a6-459f-b209-c59451936336","source_id":"","conceptId":null},"compound":null,"studySourceType":{"id":1,"name":"Published report"},"experiments":[{"id":836,"uid":"NPDI-WL-VKw","name":"Control inhibition of P-gp digoxin transport by quinidine","overallEffect":1,"isControlData":true,"isIc50Shift":false,"croCutoff":"
(not provided)
","croIdentifier":null,"comment":null,"experimentalConditionsComment":null,"resultsComment":null,"internalComment":null,"objectCompoundId":15,"objectMetaboliteCompoundId":null,"precipitantCompoundId":101,"cytochromeB5Id":null,"studyId":170,"experimentTypeId":5,"testSystemId":35,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":5,"name":"In Vitro Transporter Inhibition","isInVitro":true,"isTransporter":true,"isEnzyme":false,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000060"},"objectCompound":{"id":15,"name":"digoxin","unii":"73K4184T59","inChIKey":"LTMHDMANZUZIPE-PUGKRICDSA-N","publicDescription":null,"internalComment":null,"conceptId":1326303,"enantiomerOfId":null},"precipitantCompound":{"id":101,"name":"quinidine","unii":null,"inChIKey":"LOUPRKONTZGTKE-LHHVKLHASA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":null,"enzymes":[],"transporters":[{"id":11,"name":"P-gp (ABCB1)","conceptId":null,"experiment_transporter_xref":{"experiment":836,"transporte":11}}],"quantifiedMetabolites":[]},{"id":899,"uid":"NPDI-DEOq7g","name":"Down regulation of P-gp mRNA expression by 10 µM mitragynine","overallEffect":-1,"isControlData":false,"isIc50Shift":false,"croCutoff":"p < 0.05 compared with control
","croIdentifier":null,"comment":null,"experimentalConditionsComment":null,"resultsComment":"Mean taken from text. SD estimated from Figure 3a.","internalComment":null,"objectCompoundId":null,"objectMetaboliteCompoundId":null,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":170,"experimentTypeId":6,"testSystemId":35,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":6,"name":"In Vitro Transporter Induction","isInVitro":true,"isTransporter":true,"isEnzyme":false,"purl":"http://purl.obolibrary.org/obo/DIDEO_00005002"},"objectCompound":null,"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":null,"enzymes":[],"transporters":[{"id":11,"name":"P-gp (ABCB1)","conceptId":null,"experiment_transporter_xref":{"experiment":899,"transporte":11}}],"quantifiedMetabolites":[]},{"id":898,"uid":"NPDI-ye4dPw","name":"Down regulation of P-gp mRNA expression by 1 µM quinidine","overallEffect":-1,"isControlData":false,"isIc50Shift":false,"croCutoff":"p < 0.05 compared with control
","croIdentifier":null,"comment":null,"experimentalConditionsComment":null,"resultsComment":"% Inhibition mean taken from text. SD estimated from Figure 3b.","internalComment":null,"objectCompoundId":null,"objectMetaboliteCompoundId":null,"precipitantCompoundId":101,"cytochromeB5Id":null,"studyId":170,"experimentTypeId":6,"testSystemId":35,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":6,"name":"In Vitro Transporter Induction","isInVitro":true,"isTransporter":true,"isEnzyme":false,"purl":"http://purl.obolibrary.org/obo/DIDEO_00005002"},"objectCompound":null,"precipitantCompound":{"id":101,"name":"quinidine","unii":null,"inChIKey":"LOUPRKONTZGTKE-LHHVKLHASA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":null,"enzymes":[],"transporters":[{"id":11,"name":"P-gp (ABCB1)","conceptId":null,"experiment_transporter_xref":{"experiment":898,"transporte":11}}],"quantifiedMetabolites":[]},{"id":891,"uid":"NPDI-4k7d3A","name":"Induction of P-gp protein expression by 1 µM rifampicin","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"p < 0.05 compared with control
","croIdentifier":null,"comment":null,"experimentalConditionsComment":null,"resultsComment":null,"internalComment":null,"objectCompoundId":null,"objectMetaboliteCompoundId":null,"precipitantCompoundId":181,"cytochromeB5Id":null,"studyId":170,"experimentTypeId":6,"testSystemId":35,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":6,"name":"In Vitro Transporter Induction","isInVitro":true,"isTransporter":true,"isEnzyme":false,"purl":"http://purl.obolibrary.org/obo/DIDEO_00005002"},"objectCompound":null,"precipitantCompound":{"id":181,"name":"rifampicin","unii":null,"inChIKey":"FZYOVNIOYYPUPY-UXKYPCFPSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":null,"enzymes":[],"transporters":[{"id":11,"name":"P-gp (ABCB1)","conceptId":null,"experiment_transporter_xref":{"experiment":891,"transporte":11}}],"quantifiedMetabolites":[]},{"id":897,"uid":"NPDI-nWIYpA","name":"Down regulation of P-gp mRNA expression by 1 µM mitragynine","overallEffect":-1,"isControlData":false,"isIc50Shift":false,"croCutoff":"p < 0.05 compared with control
","croIdentifier":null,"comment":null,"experimentalConditionsComment":null,"resultsComment":"Estimate from Fig 3a","internalComment":null,"objectCompoundId":null,"objectMetaboliteCompoundId":null,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":170,"experimentTypeId":6,"testSystemId":35,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":6,"name":"In Vitro Transporter Induction","isInVitro":true,"isTransporter":true,"isEnzyme":false,"purl":"http://purl.obolibrary.org/obo/DIDEO_00005002"},"objectCompound":null,"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":null,"enzymes":[],"transporters":[{"id":11,"name":"P-gp (ABCB1)","conceptId":null,"experiment_transporter_xref":{"experiment":897,"transporte":11}}],"quantifiedMetabolites":[]},{"id":896,"uid":"NPDI-cxxGnA","name":"Control P-gp digoxin transport","overallEffect":1,"isControlData":true,"isIc50Shift":false,"croCutoff":"(not provided)
","croIdentifier":null,"comment":null,"experimentalConditionsComment":null,"resultsComment":null,"internalComment":null,"objectCompoundId":15,"objectMetaboliteCompoundId":null,"precipitantCompoundId":null,"cytochromeB5Id":null,"studyId":170,"experimentTypeId":7,"testSystemId":35,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":7,"name":"In Vitro Transporter Kinetics","isInVitro":true,"isTransporter":true,"isEnzyme":false,"purl":"http://purl.obolibrary.org/obo/DIDEO_00005003"},"objectCompound":{"id":15,"name":"digoxin","unii":"73K4184T59","inChIKey":"LTMHDMANZUZIPE-PUGKRICDSA-N","publicDescription":null,"internalComment":null,"conceptId":1326303,"enantiomerOfId":null},"precipitantCompound":null,"objectMetaboliteCompound":null,"enzymes":[],"transporters":[{"id":11,"name":"P-gp (ABCB1)","conceptId":null,"experiment_transporter_xref":{"experiment":896,"transporte":11}}],"quantifiedMetabolites":[]},{"id":889,"uid":"NPDI-U0t5zQ","name":"Induction of P-gp protein expression by 0.01 µM rifampicin","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"p < 0.05 compared with control
","croIdentifier":null,"comment":null,"experimentalConditionsComment":null,"resultsComment":null,"internalComment":null,"objectCompoundId":null,"objectMetaboliteCompoundId":null,"precipitantCompoundId":181,"cytochromeB5Id":null,"studyId":170,"experimentTypeId":6,"testSystemId":35,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":6,"name":"In Vitro Transporter Induction","isInVitro":true,"isTransporter":true,"isEnzyme":false,"purl":"http://purl.obolibrary.org/obo/DIDEO_00005002"},"objectCompound":null,"precipitantCompound":{"id":181,"name":"rifampicin","unii":null,"inChIKey":"FZYOVNIOYYPUPY-UXKYPCFPSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":null,"enzymes":[],"transporters":[{"id":11,"name":"P-gp (ABCB1)","conceptId":null,"experiment_transporter_xref":{"experiment":889,"transporte":11}}],"quantifiedMetabolites":[]},{"id":892,"uid":"NPDI-8GmUTQ","name":"Induction of P-gp protein expression by 10 µM rifampicin","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"p < 0.05 compared with control
","croIdentifier":null,"comment":null,"experimentalConditionsComment":null,"resultsComment":null,"internalComment":null,"objectCompoundId":null,"objectMetaboliteCompoundId":null,"precipitantCompoundId":181,"cytochromeB5Id":null,"studyId":170,"experimentTypeId":6,"testSystemId":35,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":6,"name":"In Vitro Transporter Induction","isInVitro":true,"isTransporter":true,"isEnzyme":false,"purl":"http://purl.obolibrary.org/obo/DIDEO_00005002"},"objectCompound":null,"precipitantCompound":{"id":181,"name":"rifampicin","unii":null,"inChIKey":"FZYOVNIOYYPUPY-UXKYPCFPSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":null,"enzymes":[],"transporters":[{"id":11,"name":"P-gp (ABCB1)","conceptId":null,"experiment_transporter_xref":{"experiment":892,"transporte":11}}],"quantifiedMetabolites":[]},{"id":888,"uid":"NPDI-GETspg","name":"Induction of P-gp protein expression by 0.001 µM rifampicin","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"p < 0.05 compared with control
","croIdentifier":null,"comment":null,"experimentalConditionsComment":null,"resultsComment":null,"internalComment":null,"objectCompoundId":null,"objectMetaboliteCompoundId":null,"precipitantCompoundId":181,"cytochromeB5Id":null,"studyId":170,"experimentTypeId":6,"testSystemId":35,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":6,"name":"In Vitro Transporter Induction","isInVitro":true,"isTransporter":true,"isEnzyme":false,"purl":"http://purl.obolibrary.org/obo/DIDEO_00005002"},"objectCompound":null,"precipitantCompound":{"id":181,"name":"rifampicin","unii":null,"inChIKey":"FZYOVNIOYYPUPY-UXKYPCFPSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":null,"enzymes":[],"transporters":[{"id":11,"name":"P-gp (ABCB1)","conceptId":null,"experiment_transporter_xref":{"experiment":888,"transporte":11}}],"quantifiedMetabolites":[]},{"id":890,"uid":"NPDI-gdI_mg","name":"Induction of P-gp protein expression by 0.1 µM rifampicin","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"p < 0.05 compared with control
","croIdentifier":null,"comment":null,"experimentalConditionsComment":null,"resultsComment":null,"internalComment":null,"objectCompoundId":null,"objectMetaboliteCompoundId":null,"precipitantCompoundId":181,"cytochromeB5Id":null,"studyId":170,"experimentTypeId":6,"testSystemId":35,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":6,"name":"In Vitro Transporter Induction","isInVitro":true,"isTransporter":true,"isEnzyme":false,"purl":"http://purl.obolibrary.org/obo/DIDEO_00005002"},"objectCompound":null,"precipitantCompound":{"id":181,"name":"rifampicin","unii":null,"inChIKey":"FZYOVNIOYYPUPY-UXKYPCFPSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":null,"enzymes":[],"transporters":[{"id":11,"name":"P-gp (ABCB1)","conceptId":null,"experiment_transporter_xref":{"experiment":890,"transporte":11}}],"quantifiedMetabolites":[]},{"id":895,"uid":"NPDI-Ue8YDg","name":"Permeability of mitragynine across Caco-2 monolayer cells","overallEffect":0,"isControlData":false,"isIc50Shift":false,"croCutoff":"(not provided)
","croIdentifier":null,"comment":null,"experimentalConditionsComment":null,"resultsComment":"Figure 2a for Papp ratio","internalComment":null,"objectCompoundId":94,"objectMetaboliteCompoundId":null,"precipitantCompoundId":null,"cytochromeB5Id":null,"studyId":170,"experimentTypeId":7,"testSystemId":35,"ic50ShiftExperimentId":null,"controlDataExperimentId":896,"controlDataForExperimentId":896,"naturalProductSampleId":null,"experimentType":{"id":7,"name":"In Vitro Transporter Kinetics","isInVitro":true,"isTransporter":true,"isEnzyme":false,"purl":"http://purl.obolibrary.org/obo/DIDEO_00005003"},"objectCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"precipitantCompound":null,"objectMetaboliteCompound":null,"enzymes":[],"transporters":[{"id":11,"name":"P-gp (ABCB1)","conceptId":null,"experiment_transporter_xref":{"experiment":895,"transporte":11}}],"quantifiedMetabolites":[]}]}]