A Metabolism-Based Synergy for Total Coumarin Extract of Radix Angelicae Dahuricae and Ligustrazine on Migraine Treatment in Rats
Abstract
:1. Introduction
2. Results
2.1. TCE Enhanced the Anti-Migraine Effects of Ligustrazine
2.2. TCE (or Isoimperatorin) Increased the Ligustrazine Plasma Concentration in Rats and Inhibited Its Metabolism In Vitro
2.3. Isoimperatorin (or Imperatorin) Inhibited CYP450s Activity and Their Metabolic Information
3. Materials and Methods
3.1. Materials
3.2. Total Coumarin Extract (TCE) of Radix Angelicae Dahuricae Preparation
3.3. Animals, Treatment, and Sampling
3.4. Ligustrazine Metabolism Interference Study in Liver Microsomes
3.5. IC50 of Imperatorin or Isoimperatorin on CYP450s Enzymes
3.6. Metabolism of Imperatorin or Isoimperatorin in Human Liver Microsomes and Recombinant CYP450s
3.7. Analysis of Samples
3.7.1. Determination of Ligustrazine Concentration
3.7.2. Determination of Hydroxy-Ligustrazine Concentration
3.7.3. Determination of Imperatorin or Isoimperatorin Concentration
3.7.4. Analysis of Imperatorin and Isoimperatorin Metabolite Using Ultra-Performance Liquid Chromatography–Mass Spectrometry (UPLC–MS/MS)
3.8. Data Analysis
3.8.1. IC50 Value Calculation
3.8.2. Metabolic Kinetic Constant
3.8.3. Pharmacokinetic Parameters
3.9. Statistical Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
Abbreviations
CGRP | calcitonin gene–related peptide |
ET | endothelin |
NO | nitric oxide |
NADPH | β-nicotinamide adenine dinucleotide phosphate |
TCE | total coumarin extract of Radix Angelicae dahuricae |
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Sample Availability: Samples of the compounds are not available from the authors. |
Group | Dose (mg/kg) | Time after Injection of Nitroglycerin | |||
---|---|---|---|---|---|
0–30 min | 30–60 min | 60–120 min | 120–180 min | ||
Control | 0.80 ± 0.34 | 1.21 ± 0.67 | 0.92 ± 0.45 | 1.01 ± 0.42 | |
Model (nitroglycerin) | 10 | 43.07 ± 5.87 ## | 47.90 ± 3.87 ## | 73.96 ± 3.24 ## | 51.61 ± 2.80 ## |
Sumatriptan | 0.005 | 39.17 ± 3.92 | 41.02 ± 5.67 | 45.30 ± 4.57 ** | 23.57 ± 4.43 ** |
TCE | 50 | 46.06 ± 8.23 | 46.78 ± 4.45 | 53.24 ± 4.06 ** | 47.93 ± 4.26 |
Ligustrazine | 15 | 42.90 ± 8.70 | 45 36 ± 2.45 | 50.50 ± 5.47 ** | 38.40 ± 2.95 ** |
TCE + ligustrazine | 50 + 15 | 38.20 ± 4.43 | 44.81 ± 3.72 | 40.20 ± 4.48 **& | 28.20 ± 3.05 **&& |
Ligustrazine | Ligustrazine–Isoimperatorin | Ligustrazine–TCE | |
---|---|---|---|
Tmax (min) | 30 | 40 | 130 |
Cmax (µg/mL) | 8.52 ± 0.87 | 8.83 ± 0.38 | 17.68 ± 2.62 ** |
t1/2 (min) | 35.59 ± 2.54 | 95.59 ± 5.88 ** | 90.43 ± 7.96 ** |
ke (min−1) | 0.01947 ± 0.0019 | 0.00725 ± 0.001 * | 0.007 ± 0.0007 ** |
CL (ml/min) | 244.19 ± 88.55 | 15.67 ± 2.33 ** | 2.38 ± 0.67 ** |
MRT (min) | 58.41 ± 0.637 | 103.6 ± 6.27 * | 152.8 ± 16.6 ** |
AUC 0-∞ (µg/mL*min) | 43.000 ± 20.000 | 670.000 ± 180.000 * | 4411.2 ± 988.9 ** |
CYP450 Isoform | IC50 (µM) (95% Confidence Interval) | ||
---|---|---|---|
Imperatorin | Isoimperatorin | Positive Control a | |
CYP1A2 | 0.08 (0.052–0.13) | 8.26 (5.75–11.88) | 0.09 (0.06–0.12) |
CYP2C9 | 4.81 (3.05–7.71) | 5.69 (3.21–10.09) | 0.14 (0.10–0.18) |
CYP2C19 | 83.34 (0.66–104.85) | 19.58 (12.72–30.15) | 6.00 (2.76–13.00) |
CYP2D6 | 9.10 (5.328–15.56) | 1.56 (0.54–4.5) | 0.05 (0.02–0.11) |
CYP3A4 | 1.10 (0.71–1.71) | 1.47 (0.99–2.17) | 1.38 (0.74–2.56) |
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Feng, S.; He, X.; Zhong, P.; Zhao, J.; Huang, C.; Hu, Z. A Metabolism-Based Synergy for Total Coumarin Extract of Radix Angelicae Dahuricae and Ligustrazine on Migraine Treatment in Rats. Molecules 2018, 23, 1004. https://doi.org/10.3390/molecules23051004
Feng S, He X, Zhong P, Zhao J, Huang C, Hu Z. A Metabolism-Based Synergy for Total Coumarin Extract of Radix Angelicae Dahuricae and Ligustrazine on Migraine Treatment in Rats. Molecules. 2018; 23(5):1004. https://doi.org/10.3390/molecules23051004
Chicago/Turabian StyleFeng, Shan, Xin He, Peiru Zhong, Jinyi Zhao, Cong Huang, and Zhuohan Hu. 2018. "A Metabolism-Based Synergy for Total Coumarin Extract of Radix Angelicae Dahuricae and Ligustrazine on Migraine Treatment in Rats" Molecules 23, no. 5: 1004. https://doi.org/10.3390/molecules23051004