[{"id":143,"uid":"NPDI-d8OUzg","name":"Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations","napdiIdentifier":null,"overallSummary":"\r\n- All kratom extracts inhibited CYP2C9, CYP2D6 and CYP3A (hepatic and intestinal) activities by similar extents, indicating minimal product to product variability with respect to CYP inhibition. Mitragynine inhibited CYP2C9, CYP2D6, and CYP3A activity by greater than 50%, warranting further investigation as a reversible or a time dependent inhibitor of the CYP activities.
\r\n- The 7-fold shift observed with mitragynine against intestinal and hepatic CYP3A activity suggests mitragynine is a time dependent inhibitor. IC50values were within the concentration range reported in post-mortem human plasma and tissues. Although no leftward shift was observed for CYP2D6, the IC50was also within the concentration range reported in post-mortem human plasma and tissues.
\r\n- Mitragynine was shown to be a strong competitive inhibitor of CYP2D6 activity. The robust Ki(~1 µM) will be applied to mechanistic and PBPK models to predict drug interaction potential.
\r\n- Mitragynine is a time dependent inhibitor of both intestinal and hepatic CYP3A activity. The efficiency of inactivation (kinact/KI) was similar to that of the clinically relevant time dependent inhibitor verapamil. The kinetic parameters, KIand kinactwill be applied to mechanistic and PBPK models to predict drug interaction potential.
\r\n
","pubmedId":33093187,"embaseId":null,"croIdentifier":"Washington State University","croInformation":"Washington State University","dateStart":null,"dateEnd":null,"internalComment":"Data entered by CB and review by RB.","status":"published","compoundId":null,"naturalProductUid":"NP-00ed1235-cbd8-4117-85df-298b8b3cdcad","naturalProductSampleId":"NPS-oDLatA","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":685,"uid":"NPDI-bOmVTQ","name":"Screening of mitragynine as inhibitors of CYP2C9 activity in HLM","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition at the highest tested concentration
","croIdentifier":null,"comment":null,"experimentalConditionsComment":"Methanol (0.8 % v/v) served as solvent control. Sulphaphenazole (1 µM), quinidine (2 µM), and ketoconazole (0.01 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A, respectively.
","resultsComment":"Mitragynine and kratom extracts showed concentration-dependent inhibition of CYP activity in HLM. Mitragynine at 10 µM inhibited CYP2C9, CYP2D6, and CYP3A activity by 42%, 87%, and 50%, respectively. Kratom extracts at 20 µg/mL inhibited these activities by 81-88%, 87-93%, and 86-89%, respectively.
","internalComment":null,"objectCompoundId":14,"objectMetaboliteCompoundId":2,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":14,"name":"diclofenac","unii":"144O8QL0L1","inChIKey":"DCOPUUMXTXDBNB-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":1124300,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":2,"name":"4'-hydroxydiclofenac","unii":null,"inChIKey":"KGVXVPRLBMWZLG-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":8,"name":"CYP2C9","conceptId":4309227,"experiment_enzyme_xref":{"enzymeId":8,"experimentId":685}}],"transporters":[],"quantifiedMetabolites":[]},{"id":686,"uid":"NPDI-sfeVpQ","name":"Screening of mitragynine as inhibitors of CYP2D6 activity in HLM","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition at the highest tested concentration
","croIdentifier":null,"comment":null,"experimentalConditionsComment":"Methanol (0.8 % v/v) served as solvent control. Sulphaphenazole (1 µM), quinidine (2 µM), and ketoconazole (0.01 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A, respectively.
","resultsComment":"Mitragynine and kratom extracts showed concentration-dependent inhibition of CYP activity in HLM. Mitragynine at 10 µM inhibited CYP2C9, CYP2D6, and CYP3A activity by 42%, 87%, and 50%, respectively. Kratom extracts at 20 µg/mL inhibited these activities by 81-88%, 87-93%, and 86-89%, respectively.
","internalComment":null,"objectCompoundId":12,"objectMetaboliteCompoundId":13,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":12,"name":"dextromethorphan","unii":"7355X3ROTS","inChIKey":"MKXZASYAUGDDCJ-NJAFHUGGSA-N","publicDescription":null,"internalComment":null,"conceptId":1119510,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":13,"name":"dextrorphan","unii":null,"inChIKey":"JAQUASYNZVUNQP-PVAVHDDUSA-N","publicDescription":null,"internalComment":null,"conceptId":4349487,"enantiomerOfId":null},"enzymes":[{"id":10,"name":"CYP2D6","conceptId":4173631,"experiment_enzyme_xref":{"enzymeId":10,"experimentId":686}}],"transporters":[],"quantifiedMetabolites":[]},{"id":687,"uid":"NPDI-ov597g","name":"Screening of mitragynine as inhibitors of CYP3A activity in HLM","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition at the highest tested concentration
","croIdentifier":null,"comment":null,"experimentalConditionsComment":"Methanol (0.8 % v/v) served as solvent control. Sulphaphenazole (1 µM), quinidine (2 µM), and ketoconazole (0.01 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A, respectively.
","resultsComment":"Mitragynine and kratom extracts showed concentration-dependent inhibition of CYP activity in HLM. Mitragynine at 10 µM inhibited CYP2C9, CYP2D6, and CYP3A activity by 42%, 87%, and 50%, respectively. Kratom extracts at 20 µg/mL inhibited these activities by 81-88%, 87-93%, and 86-89%, respectively.
","internalComment":null,"objectCompoundId":26,"objectMetaboliteCompoundId":1,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":26,"name":"midazolam","unii":"R60L0SM5BC","inChIKey":"DDLIGBOFAVUZHB-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":708298,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":1,"name":"1'-hydroxymidazolam","unii":null,"inChIKey":"QHSMEGADRFZVNE-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":30,"name":"CYP3A","conceptId":null,"experiment_enzyme_xref":{"enzymeId":30,"experimentId":687}}],"transporters":[],"quantifiedMetabolites":[]},{"id":688,"uid":"NPDI-71pBaQ","name":"Screening of kratom extracts as inhibitors of CYP2C9 activity in HLM","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition at the highest tested concentration
","croIdentifier":null,"comment":"Three methanolic Kratom extracts were tested, K-50, K-51 and K-52.
","experimentalConditionsComment":"Methanol (0.8 % v/v) served as solvent control. Sulphaphenazole (1 µM), quinidine (2 µM), and ketoconazole (0.01 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A, respectively.
","resultsComment":"Mitragynine and kratom extracts showed concentration-dependent inhibition of CYP activity in HLM. Mitragynine at 10 µM inhibited CYP2C9, CYP2D6, and CYP3A activity by 42%, 87%, and 50%, respectively. Kratom extracts at 20 µg/mL inhibited these activities by 81-88%, 87-93%, and 86-89%, respectively.
","internalComment":null,"objectCompoundId":14,"objectMetaboliteCompoundId":2,"precipitantCompoundId":182,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":14,"name":"diclofenac","unii":"144O8QL0L1","inChIKey":"DCOPUUMXTXDBNB-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":1124300,"enantiomerOfId":null},"precipitantCompound":{"id":182,"name":"methanolic extract of kratom","unii":null,"inChIKey":null,"publicDescription":null,"internalComment":"Often refers to the leaves of M. speciosa","conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":2,"name":"4'-hydroxydiclofenac","unii":null,"inChIKey":"KGVXVPRLBMWZLG-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":8,"name":"CYP2C9","conceptId":4309227,"experiment_enzyme_xref":{"enzymeId":8,"experimentId":688}}],"transporters":[],"quantifiedMetabolites":[]},{"id":689,"uid":"NPDI-o6FZsw","name":"Screening of kratom extracts as inhibitors of CYP2D6 activity in HLM","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition at the highest tested concentration
","croIdentifier":null,"comment":"Three methanolic Kratom extracts were tested, K-50, K-51 and K-52.
","experimentalConditionsComment":"Methanol (0.8 % v/v) served as solvent control. Sulphaphenazole (1 µM), quinidine (2 µM), and ketoconazole (0.01 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A, respectively.
","resultsComment":"Mitragynine and kratom extracts showed concentration-dependent inhibition of CYP activity in HLM. Mitragynine at 10 µM inhibited CYP2C9, CYP2D6, and CYP3A activity by 42%, 87%, and 50%, respectively. Kratom extracts at 20 µg/mL inhibited these activities by 81-88%, 87-93%, and 86-89%, respectively.
","internalComment":null,"objectCompoundId":12,"objectMetaboliteCompoundId":13,"precipitantCompoundId":182,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":12,"name":"dextromethorphan","unii":"7355X3ROTS","inChIKey":"MKXZASYAUGDDCJ-NJAFHUGGSA-N","publicDescription":null,"internalComment":null,"conceptId":1119510,"enantiomerOfId":null},"precipitantCompound":{"id":182,"name":"methanolic extract of kratom","unii":null,"inChIKey":null,"publicDescription":null,"internalComment":"Often refers to the leaves of M. speciosa","conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":13,"name":"dextrorphan","unii":null,"inChIKey":"JAQUASYNZVUNQP-PVAVHDDUSA-N","publicDescription":null,"internalComment":null,"conceptId":4349487,"enantiomerOfId":null},"enzymes":[{"id":10,"name":"CYP2D6","conceptId":4173631,"experiment_enzyme_xref":{"enzymeId":10,"experimentId":689}}],"transporters":[],"quantifiedMetabolites":[]},{"id":690,"uid":"NPDI-7-Gg-g","name":"Screening of kratom extracts as inhibitors of CYP3A activity in HLM","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition at the highest tested concentration
","croIdentifier":null,"comment":"Three methanolic Kratom extracts were tested, K-50, K-51 and K-52.
","experimentalConditionsComment":"Methanol (0.8 % v/v) served as solvent control. Sulphaphenazole (1 µM), quinidine (2 µM), and ketoconazole (0.01 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A, respectively.
","resultsComment":"Mitragynine and kratom extracts showed concentration-dependent inhibition of CYP activity in HLM. Mitragynine at 10 µM inhibited CYP2C9, CYP2D6, and CYP3A activity by 42%, 87%, and 50%, respectively. Kratom extracts at 20 µg/mL inhibited these activities by 81-88%, 87-93%, and 86-89%, respectively.
","internalComment":null,"objectCompoundId":26,"objectMetaboliteCompoundId":1,"precipitantCompoundId":182,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":26,"name":"midazolam","unii":"R60L0SM5BC","inChIKey":"DDLIGBOFAVUZHB-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":708298,"enantiomerOfId":null},"precipitantCompound":{"id":182,"name":"methanolic extract of kratom","unii":null,"inChIKey":null,"publicDescription":null,"internalComment":"Often refers to the leaves of M. speciosa","conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":1,"name":"1'-hydroxymidazolam","unii":null,"inChIKey":"QHSMEGADRFZVNE-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":30,"name":"CYP3A","conceptId":null,"experiment_enzyme_xref":{"enzymeId":30,"experimentId":690}}],"transporters":[],"quantifiedMetabolites":[]},{"id":691,"uid":"NPDI-vr5BAA","name":"Screening of mitragynine as inhibitors CYP3A activity in HIM","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition at the highest tested concentration
","croIdentifier":null,"comment":null,"experimentalConditionsComment":"Methanol (0.8 % v/v) served as solvent control. Sulphaphenazole (1 µM), quinidine (2 µM), and ketoconazole (0.01 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A, respectively.
","resultsComment":"Mitragynine and kratom extracts showed concentration-dependent inhibition of CYP3A activity in HIM. Mitragynine at 10 µM inhibited CYP3A activity by 44%. Kratom extracts at 20 µg/mL inhibited CYP3A activity by 82-90%.
","internalComment":null,"objectCompoundId":26,"objectMetaboliteCompoundId":1,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":8,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":26,"name":"midazolam","unii":"R60L0SM5BC","inChIKey":"DDLIGBOFAVUZHB-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":708298,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":1,"name":"1'-hydroxymidazolam","unii":null,"inChIKey":"QHSMEGADRFZVNE-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":30,"name":"CYP3A","conceptId":null,"experiment_enzyme_xref":{"enzymeId":30,"experimentId":691}}],"transporters":[],"quantifiedMetabolites":[]},{"id":692,"uid":"NPDI-QbMPuw","name":"Screening of kratom extracts as inhibitors CYP3A activity in HIM","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition at the highest tested concentration
","croIdentifier":null,"comment":"Three methanolic Kratom extracts were tested, K-50, K-51 and K-52.
","experimentalConditionsComment":"Methanol (0.8 % v/v) served as solvent control. Sulphaphenazole (1 µM), quinidine (2 µM), and ketoconazole (0.01 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A, respectively.
","resultsComment":"Mitragynine and kratom extracts showed concentration-dependent inhibition of CYP3A activity in HIM. Mitragynine at 10 µM inhibited CYP3A activity by 44%. Kratom extracts at 20 µg/mL inhibited CYP3A activity by 82-90%.
","internalComment":null,"objectCompoundId":26,"objectMetaboliteCompoundId":1,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":8,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":26,"name":"midazolam","unii":"R60L0SM5BC","inChIKey":"DDLIGBOFAVUZHB-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":708298,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":1,"name":"1'-hydroxymidazolam","unii":null,"inChIKey":"QHSMEGADRFZVNE-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":30,"name":"CYP3A","conceptId":null,"experiment_enzyme_xref":{"enzymeId":30,"experimentId":692}}],"transporters":[],"quantifiedMetabolites":[]},{"id":693,"uid":"NPDI-Xrn4xQ","name":"IC50 shift determination for mitragynine towards CYP2C9 activity in HLM with NADPH","overallEffect":1,"isControlData":false,"isIc50Shift":true,"croCutoff":"IC50<10 µM for reversible inhibition and IC50shift ≥1.5 fold for time dependent inhibition
","croIdentifier":null,"comment":null,"experimentalConditionsComment":"A cocktail of probe substrates for CYP2C9 (diclofenac), CYP2D6 (dextromethorphan), and CYP3A (midazolam) was used for the IC50shift determination.
Methanol (0.8 % v/v) served as solvent control. Tienilic acid (0.4 and 0.8 µM), paroxetine (0.25 and 0.5 µM), and 6',7'-dihydroxybergamottin (1 and 2 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A activities, respectively.","resultsComment":null,"internalComment":null,"objectCompoundId":14,"objectMetaboliteCompoundId":2,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":697,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":14,"name":"diclofenac","unii":"144O8QL0L1","inChIKey":"DCOPUUMXTXDBNB-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":1124300,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":2,"name":"4'-hydroxydiclofenac","unii":null,"inChIKey":"KGVXVPRLBMWZLG-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":8,"name":"CYP2C9","conceptId":4309227,"experiment_enzyme_xref":{"enzymeId":8,"experimentId":693}}],"transporters":[],"quantifiedMetabolites":[]},{"id":694,"uid":"NPDI-ksOM2w","name":"Inhibition kinetics of CYP2D6 activity by mitragynine in HLM","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"N/A
","croIdentifier":null,"comment":null,"experimentalConditionsComment":"Methanol (0.8 % v/v) served as solvent control. Quinidine (2 µM) served as positive control inhibitors of CYP2D6 activity.
","resultsComment":"Mitragynine was shown to be a strong competitive inhibitor of CYP2D6 activity, with a Kiof 0.97 ± 0.07 µM, 1.25 ± 0.09 µM, and 0.95 ± 0.11 µM, respectively, for three individual experiments. [Ki(Mean ± SEM) values were determined using nonlinear least-squares regression and competitive inhibition model.]
","internalComment":null,"objectCompoundId":12,"objectMetaboliteCompoundId":13,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":12,"name":"dextromethorphan","unii":"7355X3ROTS","inChIKey":"MKXZASYAUGDDCJ-NJAFHUGGSA-N","publicDescription":null,"internalComment":null,"conceptId":1119510,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":13,"name":"dextrorphan","unii":null,"inChIKey":"JAQUASYNZVUNQP-PVAVHDDUSA-N","publicDescription":null,"internalComment":null,"conceptId":4349487,"enantiomerOfId":null},"enzymes":[{"id":10,"name":"CYP2D6","conceptId":4173631,"experiment_enzyme_xref":{"enzymeId":10,"experimentId":694}}],"transporters":[],"quantifiedMetabolites":[]},{"id":695,"uid":"NPDI-515DHw","name":"Inhibition kinetics of CYP3A activity by mitragynine in HLM","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"N/A
","croIdentifier":null,"comment":null,"experimentalConditionsComment":"Methanol (0.8 % v/v) served as solvent control. 6',7'-Dihydroxybergamottin (1 and 2 µM) served as a positive control inhibitor of CYP3A activity.
","resultsComment":"The KIand kinactvalues for mitragynine towards CYP3A activity in HLM were 4.1 ± 0.7 µM and 0.051 ± 0.002 min-1, 4.0 ± 0.5 µM and 0.057 ± 0.002 min-1, and 5.9 ± 0.9 µM and 0.17 ± 0.01 min-1, respectively, for three individual experiments.
\r\n[KIand kinact(Mean ± SEM) values were determined using nonlinear least-squares regression.]
","internalComment":null,"objectCompoundId":26,"objectMetaboliteCompoundId":1,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":26,"name":"midazolam","unii":"R60L0SM5BC","inChIKey":"DDLIGBOFAVUZHB-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":708298,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":1,"name":"1'-hydroxymidazolam","unii":null,"inChIKey":"QHSMEGADRFZVNE-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":30,"name":"CYP3A","conceptId":null,"experiment_enzyme_xref":{"enzymeId":30,"experimentId":695}}],"transporters":[],"quantifiedMetabolites":[]},{"id":696,"uid":"NPDI-Tr3Eyg","name":"Inhibition kinetics of CYP3A activity by mitragynine in HIM","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"N/A
","croIdentifier":null,"comment":null,"experimentalConditionsComment":"Methanol (0.8 % v/v) served as solvent control. 6',7'-Dihydroxybergamottin (1 and 2 µM) served as a positive control inhibitor of CYP3A activity.
","resultsComment":"The KIand kinactvalues for mitragynine towards CYP3A activity in HIM were 4.5 ± 1.1 µM and 0.072 ± 0.006 min-1, 6.0 ± 0.5 µM and 0.074 ± 0.002 min-1, and 7.3 ± 2.5 µM and 0.17 ± 0.02 min-1, respectively, for three individual experiments.[KIand kinact(Mean ± SEM) values were determined using nonlinear least-squares regression.]
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Methanol (0.8 % v/v) served as solvent control. Tienilic acid (0.4 and 0.8 µM), paroxetine (0.25 and 0.5 µM), and 6',7'-dihydroxybergamottin (1 and 2 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A activities, respectively.","resultsComment":null,"internalComment":null,"objectCompoundId":14,"objectMetaboliteCompoundId":2,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":693,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":14,"name":"diclofenac","unii":"144O8QL0L1","inChIKey":"DCOPUUMXTXDBNB-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":1124300,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":2,"name":"4'-hydroxydiclofenac","unii":null,"inChIKey":"KGVXVPRLBMWZLG-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":8,"name":"CYP2C9","conceptId":4309227,"experiment_enzyme_xref":{"enzymeId":8,"experimentId":697}}],"transporters":[],"quantifiedMetabolites":[]},{"id":698,"uid":"NPDI-XFPmtA","name":"IC50 shift determination for mitragynine towards CYP2D6 activity in HLM with NADPH","overallEffect":1,"isControlData":false,"isIc50Shift":true,"croCutoff":"IC50<10 µM for reversible inhibition and IC50shift ≥1.5 fold for time dependent inhibition
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Methanol (0.8 % v/v) served as solvent control. Tienilic acid (0.4 and 0.8 µM), paroxetine (0.25 and 0.5 µM), and 6',7'-dihydroxybergamottin (1 and 2 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A activities, respectively.
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","croIdentifier":null,"comment":null,"experimentalConditionsComment":"A cocktail of probe substrates for CYP2C9 (diclofenac), CYP2D6 (dextromethorphan), and CYP3A (midazolam) was used for the IC50shift determination.
Methanol (0.8 % v/v) served as solvent control. Tienilic acid (0.4 and 0.8 µM), paroxetine (0.25 and 0.5 µM), and 6',7'-dihydroxybergamottin (1 and 2 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A activities, respectively.","resultsComment":null,"internalComment":null,"objectCompoundId":12,"objectMetaboliteCompoundId":13,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":698,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":12,"name":"dextromethorphan","unii":"7355X3ROTS","inChIKey":"MKXZASYAUGDDCJ-NJAFHUGGSA-N","publicDescription":null,"internalComment":null,"conceptId":1119510,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":13,"name":"dextrorphan","unii":null,"inChIKey":"JAQUASYNZVUNQP-PVAVHDDUSA-N","publicDescription":null,"internalComment":null,"conceptId":4349487,"enantiomerOfId":null},"enzymes":[{"id":10,"name":"CYP2D6","conceptId":4173631,"experiment_enzyme_xref":{"enzymeId":10,"experimentId":699}}],"transporters":[],"quantifiedMetabolites":[]},{"id":700,"uid":"NPDI-4_UdSg","name":"IC50 shift determination for mitragynine towards CYP3A activity in HLM with NADPH","overallEffect":1,"isControlData":false,"isIc50Shift":true,"croCutoff":"IC50<10 µM for reversible inhibition and IC50shift ≥1.5 fold for time dependent inhibition
\n
","croIdentifier":null,"comment":null,"experimentalConditionsComment":"A cocktail of probe substrates for CYP2C9 (diclofenac), CYP2D6 (dextromethorphan), and CYP3A (midazolam) was used for the IC50shift determination.
Methanol (0.8 % v/v) served as solvent control. Tienilic acid (0.4 and 0.8 µM), paroxetine (0.25 and 0.5 µM), and 6',7'-dihydroxybergamottin (1 and 2 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A activities, respectively.","resultsComment":"A 7-fold shift in IC50was observed towards CYP3A activity in HLM, 18.9 ±1.8 vs. 2.6 ±0.3 µM, in absence and presence of NADPH, respectively. [IC50values (Mean ± SEM) were determined using nonlinear least-squares regression]
","internalComment":null,"objectCompoundId":26,"objectMetaboliteCompoundId":1,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":701,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":26,"name":"midazolam","unii":"R60L0SM5BC","inChIKey":"DDLIGBOFAVUZHB-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":708298,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":1,"name":"1'-hydroxymidazolam","unii":null,"inChIKey":"QHSMEGADRFZVNE-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":30,"name":"CYP3A","conceptId":null,"experiment_enzyme_xref":{"enzymeId":30,"experimentId":700}}],"transporters":[],"quantifiedMetabolites":[]},{"id":701,"uid":"NPDI-EjMg0g","name":"IC50 shift determination for mitragynine towards CYP3A activity in HLM without NADPH","overallEffect":1,"isControlData":false,"isIc50Shift":true,"croCutoff":"IC50<10 µM for reversible inhibition and IC50shift ≥1.5 fold for time dependent inhibition
","croIdentifier":null,"comment":null,"experimentalConditionsComment":"A cocktail of probe substrates for CYP2C9 (diclofenac), CYP2D6 (dextromethorphan), and CYP3A (midazolam) was used for the IC50shift determination.
Methanol (0.8 % v/v) served as solvent control. Tienilic acid (0.4 and 0.8 µM), paroxetine (0.25 and 0.5 µM), and 6',7'-dihydroxybergamottin (1 and 2 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A activities, respectively.","resultsComment":"A 7-fold shift in IC50was observed towards CYP3A activity in HLM, 18.9 ±1.8 vs. 2.6 ±0.3 µM, in presence and absence of NADPH, respectively. [IC50values (Mean ± SEM) were determined using nonlinear least-squares regression]
","internalComment":null,"objectCompoundId":26,"objectMetaboliteCompoundId":1,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":6,"ic50ShiftExperimentId":700,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":26,"name":"midazolam","unii":"R60L0SM5BC","inChIKey":"DDLIGBOFAVUZHB-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":708298,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":1,"name":"1'-hydroxymidazolam","unii":null,"inChIKey":"QHSMEGADRFZVNE-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":30,"name":"CYP3A","conceptId":null,"experiment_enzyme_xref":{"enzymeId":30,"experimentId":701}}],"transporters":[],"quantifiedMetabolites":[]},{"id":702,"uid":"NPDI-A66pwQ","name":"IC50 shift determination for mitragynine towards CYP3A activity in HIM with NADPH","overallEffect":1,"isControlData":false,"isIc50Shift":true,"croCutoff":"IC50<10 µM for reversible inhibition and IC50shift ≥1.5 fold for time dependent inhibition
","croIdentifier":null,"comment":null,"experimentalConditionsComment":"A cocktail of probe substrates for CYP2C9 (diclofenac), CYP2D6 (dextromethorphan), and CYP3A (midazolam) was used for the IC50shift determination.
Methanol (0.8 % v/v) served as solvent control. Tienilic acid (0.4 and 0.8 µM), paroxetine (0.25 and 0.5 µM), and 6',7'-dihydroxybergamottin (1 and 2 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A activities, respectively.","resultsComment":"A 7-fold shift in IC50was observed towards CYP3A activity in HIM, 21.9 ±2.7 vs. 3.2 ±0.3 µM, in absence and presence of NADPH, respectively. [IC50values (Mean ± SEM) were determined using nonlinear least-squares regression]
","internalComment":null,"objectCompoundId":26,"objectMetaboliteCompoundId":1,"precipitantCompoundId":94,"cytochromeB5Id":null,"studyId":143,"experimentTypeId":1,"testSystemId":8,"ic50ShiftExperimentId":703,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":26,"name":"midazolam","unii":"R60L0SM5BC","inChIKey":"DDLIGBOFAVUZHB-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":708298,"enantiomerOfId":null},"precipitantCompound":{"id":94,"name":"mitragynine","unii":null,"inChIKey":"LELBFTMXCIIKKX-QVRQZEMUSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":1,"name":"1'-hydroxymidazolam","unii":null,"inChIKey":"QHSMEGADRFZVNE-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":30,"name":"CYP3A","conceptId":null,"experiment_enzyme_xref":{"enzymeId":30,"experimentId":702}}],"transporters":[],"quantifiedMetabolites":[]},{"id":703,"uid":"NPDI-o8WmjA","name":"IC50 shift determination for mitragynine towards CYP3A activity in HIM without NADPH","overallEffect":1,"isControlData":false,"isIc50Shift":true,"croCutoff":"IC50<10 µM for reversible inhibition and IC50shift ≥1.5 fold for time dependent inhibition
","croIdentifier":null,"comment":null,"experimentalConditionsComment":"A cocktail of probe substrates for CYP2C9 (diclofenac), CYP2D6 (dextromethorphan), and CYP3A (midazolam) was used for the IC50shift determination.
Methanol (0.8 % v/v) served as solvent control. Tienilic acid (0.4 and 0.8 µM), paroxetine (0.25 and 0.5 µM), and 6',7'-dihydroxybergamottin (1 and 2 µM) served as positive control inhibitors of CYP2C9, CYP2D6, and CYP3A activities, respectively.","resultsComment":"A 7-fold shift in IC50was observed towards CYP3A activity in HIM, 21.9 ±2.7 vs. 3.2 ±0.3 µM, in presence and absence of NADPH, respectively. [IC50values (Mean ± SEM) were determined using nonlinear least-squares regression]
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