Kratom (Mitragyna speciosa)
P-glycoprotein interactions of novel psychoactive substances – Stimulation of ATP consumption and transport across Caco-2 monolayers
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In contrast to drugs for therapeutic use, there are only few data available concerning interactions between P-glycoprotein (P-gp) and drugs of abuse (DOA). In this work, interactions between structurally diverse DOA and P-gp were investigated using different strategies. First, the effect on the P-gp ATPase activity was studied by monitoring of ATP consumption after addition to recombinant, human P-gp. Second, DOA showing an increased ATP consumption were further characterized regarding their transport across filter grown Caco-2- monolayers. Analyses were performed by luminescence and liquid chromatography–mass spectrometry, respectively. Among the nine DOA initially screened, benzedrone, diclofensine, glaucine, JWH-200, MDBC, WIN-55,212-2 showed an increase of ATP consumption in the ATPase stimulation assay. In Caco-2 transport studies, Glaucine, JWH-200, mitragynine, WIN-55,212-2 could moreover be identified as non-transported substrates, but inhibitors of P-gp activity. Thus, drug– drug or drug–food interactions should be very likely for these compounds
1 . Mitragynine Inhibition (id=NPDI-E56YVg)
In Vitro Transporter Inhibition Experiment
Inhibition was detected. Cutoff used —
Unspecified
- P-gp (ABCB1)
Cell system Caco-2 cells
p<0.05 Values determined from Fig. 5
Results
Results for Mitragynine+R123 were statistically significant (p<0.05) vs R123 alone. Values from Fig. 5
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Preincubated with KRB for 60 min
60,000 cells/well
Transwell
21-23
54–72
>300 V cm2
Epithelial Voltohmmeter (EVOM2) coupled with a STX2 ‘chopstick’ electrode (World Precision Instruments)
180 m
37 deg C
7.4
5 µM
5 µM
Department of Forensic Medicine, Johannes Gutenberg University (Mainz, Germany), where it was isolated from Kratom leaves obtained from head&nature
Control Experiment Information
1 . R123 Transport Substrate (id=NPDI-vs2diA)
In Vitro Transporter Kinetics Experiment
Transport Activity was detected. Cutoff used —
Unspecified
- P-gp (ABCB1)
Cell system Caco-2 cells
Positive control - verapamil (5 µM) ER of 7.4
Results
Values from Fig 5
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
60,000 cells/well
Transwell
21-23
54-72
>300 V cm2
Epithelial Voltohmmeter (EVOM2) coupled with a STX2 ‘chopstick’ electrode (World Precision Instruments)
180 min
37 deg C
7.4
1 µM, 5 µM