Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport
Abstract
:1. Introduction
2. Results
2.1. Molecular Docking Analysis
2.2. Effect of OPD on the Transport of VCR in MDCK-MDR1 Cell Monolayer
2.3. Pharmacokinetic Experiments
2.4. Effect of OPD on P-gp ATPase Activity
2.5. Attenuation of OPD on Rh-123 Efflux
2.6. Inhibition of OPD on P-gp Protein Expression
2.7. Downregulation of OPD on P-gp Gene Expression
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. MDCK-MDR1 Cell Culture
4.3. Molecular Docking
4.4. Transport Studies of OPD in MDCK-MDR1 Cell Model
4.5. Pharmacokinetic Parameters Measurements
4.6. P-gp ATPase Activity Assay
4.7. Rhodamine-123 Accumulation
4.8. Western Blotting
4.9. Quantitative Reverse Transcription PCR (RT-qPCR)
4.10. Statistical Analysis
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Not available. |
Compounds | The Type of Interaction | The Key Amino Acids | LibDock Score |
---|---|---|---|
Verapamil | Hydrogen Bond Hydrophobic | GLY222 ALA225 | 132.634 |
OPD | Hydrogen Bond Hydrophobic | SER729 PHE728, PHE71, PHE953, PHE974 | 106.192 |
Group | Papp (A→B) (×10−6 cm/s) |
---|---|
VCR (264.46 μmol/L) | 0.37 ± 0.04 |
VCR (264.46 μmol/L) + OPD (3.82 μmol/L) | 0.47 ± 0.07 |
VCR (264.46 μmol/L) + OPD (19.08 μmol/L) | 0.50 ± 0.04 * |
VCR (264.46 μmol/L) + OPD (76.30 μmol/L) | 0.52 ± 0.04 * |
Pharmacokinetic Parameters | Unit | DTX | DTX + OPD |
---|---|---|---|
AUC0–t | μg·h/L | 276.20 ± 19.13 | 463.90 ± 47.29 ** |
AUC0–∞ | μg·h/L | 306.40 ± 21.15 | 482.10 ± 48.69 ** |
MRT0–t | h | 2.96 ± 0.22 | 2.89 ± 0.22 |
MRT0–∞ | h | 4.29 ± 0.98 | 3.36 ± 0.38 * |
t1/2 | h | 4.13 ± 1.08 | 2.64 ± 0.39 ** |
CL/F | L/h/kg | 1.00 ± 0.00 | 1.00 ± 0.00 |
Tmax | min | 163.80 ± 11.82 | 104.60 ± 11.68 ** |
Cmax | μg/L | 118.40 ± 10.93 | 178.80 ± 8.81 ** |
Group | Fluorescence Intensity |
---|---|
Rh-123 | 226,201 ± 28,927 |
Verapamil + Rh-123 | 422,897 ± 37,088 ** |
OPD (3.5 μmol/L) + Rh-123 | 281,754 ± 19,159 * |
OPD (17.5 μmol/L) + Rh-123 | 235,766 ± 31,090 |
OPD (70 μmol/L) + Rh-123 | 273,655 ± 60,007 |
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Dong, W.; Liao, Z.-G.; Zhao, G.-W.; Guan, X.-J.; Zhang, J.; Liang, X.-L.; Yang, M. Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport. Molecules 2018, 23, 1841. https://doi.org/10.3390/molecules23081841
Dong W, Liao Z-G, Zhao G-W, Guan X-J, Zhang J, Liang X-L, Yang M. Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport. Molecules. 2018; 23(8):1841. https://doi.org/10.3390/molecules23081841
Chicago/Turabian StyleDong, Wei, Zhen-Gen Liao, Guo-Wei Zhao, Xue-Jing Guan, Jing Zhang, Xin-Li Liang, and Ming Yang. 2018. "Reversal Effect of Oxypeucedanin on P-glycoprotein-mediated Drug Transport" Molecules 23, no. 8: 1841. https://doi.org/10.3390/molecules23081841