Role of UDP-Glucuronosyltransferase 1A1 in the Metabolism and Pharmacokinetics of Silymarin Flavonolignans in Patients with HCV and NAFLD
Abstract
:1. Introduction
2. Results
2.1. Enzyme Kinetics of Silymarin Glucuronidation in Recombinant Human UGT1A1 by Substrate Depletion Assay
2.2. Influence UGT1A1*28 Polymorphism on SA and SB Plasma Exposures
2.3. Effect of Liver Disease Type on Metabolic Ratios for SA and SB
2.4. Metabolites Profile of Silymarin and UGT1A1*28 Effects
3. Materials and Methods
3.1. Subjects and Study Design
3.2. Chemicals and Reagents
3.3. LC/MS Conditions
3.4. UGT Genotyping
3.5. UGT1A1 Substrate Depletion Assay
3.6. Biosynthesis of Glucuronides for Each Silymarin Flavonolignan
3.7. Quantification of Total Glucuronide and Sulfate Concentrations in Pooled Plasma Samples
3.8. Pharmacokinetics Analysis
3.9. Statistical Analysis
4. Discussion
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
References
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Flavonolignan | Km (μM) | Vmax (pmol/mg/min) | Clint (μL/mg/min) |
---|---|---|---|
Silybin A | 23.7 ± 17.7 | 2610 ± 1500 | 110.0 |
Silybin B | 8.7 ± 0.8 | 5920 ± 4550 | 691.0 |
Silydianin | 9.0 ± 0.8 | 12,740 ± 3710 | 1411.0 |
Demographics and Laboratory Values | UGT1A1 Genotype | ||
---|---|---|---|
*1/*1 | *1/*28 | *28/*28 | |
Number of subjects | 10 | 14 | 5 |
Male:Female | 3:7 | 8:6 | 4:1 |
HCV:NAFLD | 6:4 | 10:4 | 3:2 |
White:Black:Hispanic | 9:1:0 | 13:0:1 | 1:4:0 |
Age (year) a | 51.4 (27.8, 60.6) | 50.5 (43.0, 57.2) | 48.7 (43.1, 55.9) |
BMI (kg/m2) a | 28.9 (21.1, 42.4) | 29.5 (21.5, 36.6) | 34.8 (25.7, 39.2) |
Total Bilirubin (mg/dL) a | 0.45 (0.1, 1.1) | 0.65 (0.3, 0.8) | 0.7 (0.3, 2.6) |
Direct Bilirubin (mg/dL) a | 0.29 (0.1, 0.8) | 0.26 (0.1, 0.6) | 0.47 (0.3, 0.6) |
ALT (U/L) a | 88.5 (48, 164) | 94 (58, 322) | 79 (52, 158) |
Platelet Count (cells/mm3) a | 228.5 (139, 339) | 194.5 (162, 319) | 254 (108, 327) |
Flavonolignan | UGT1A1*1/*1 (n = 10) | UGT1A1*1/*28 (n = 14) | UGT1A1*28/*28 (n = 5) | p-Value |
---|---|---|---|---|
Median (25th, 75th) | Median (25th, 75th) | Median (25th, 75th) | *1/*1 vs. *1/*28 vs. *28/*28 | |
Silybin A | 0.17 (0.13, 0.2) | 0.19 (0.15, 0.23) | 0.12 (0.1, 0.23) | 0.78 |
Silybin B | 0.02 (0.02, 0.03) | 0.02 (0.01, 0.03) | 0.02 (0.02, 0.04) | 0.76 |
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Xie, Y.; Miranda, S.R.; Hoskins, J.M.; Hawke, R.L. Role of UDP-Glucuronosyltransferase 1A1 in the Metabolism and Pharmacokinetics of Silymarin Flavonolignans in Patients with HCV and NAFLD. Molecules 2017, 22, 142. https://doi.org/10.3390/molecules22010142
Xie Y, Miranda SR, Hoskins JM, Hawke RL. Role of UDP-Glucuronosyltransferase 1A1 in the Metabolism and Pharmacokinetics of Silymarin Flavonolignans in Patients with HCV and NAFLD. Molecules. 2017; 22(1):142. https://doi.org/10.3390/molecules22010142
Chicago/Turabian StyleXie, Ying, Sonia R. Miranda, Janelle M. Hoskins, and Roy L. Hawke. 2017. "Role of UDP-Glucuronosyltransferase 1A1 in the Metabolism and Pharmacokinetics of Silymarin Flavonolignans in Patients with HCV and NAFLD" Molecules 22, no. 1: 142. https://doi.org/10.3390/molecules22010142