Utilizing the Combination of Binding Kinetics and Micro-Pharmacokinetics Link in Vitro α-Glucosidase Inhibition to in Vivo Target Occupancy
Abstract
:1. Introduction
- Firstly, determining the values of kon and koff for two compounds investigated with AGH interaction.
- Secondly, micro-pharmacokinetics models of free compounds in target vicinity (TPK) were established to assess the compound concentrations changes over time in the UWL (i.e., target vicinity).
- Finally, TO simulation modelling was used to evaluate complex potential pharmacological effect of tested compounds by kon, koff in in vivo and the compound concentration versus time change in the biological target vicinity.
2. Materials and Methods
2.1. Chemicals and Materials
2.2. Assay for Steady-State AGH activity
2.3. IC50 Determination
2.4. Binding Kinetics Survey of AGH
2.5. Micro-Pharmacokinetics Model of Free Compound in the Target Vicinity
2.5.1. The free Compound Concentration Versus Time Profile in the Intestine (Ci(t)) Using PBPK Model
2.5.2. The Free Compound Concentration Profile Over Time in the Unstirred Water Layer
2.6. The Development of BK-TPK Model
3. Results
3.1. Inhibition of Tea Polyphenols Against AGH
3.2. Binding Kinetics Survey of Tested Compounds Targeting the AGH by Progress Curve Analysis
3.3. Micro-Pharmacokinetics Profiles Model of Free Compounds in the Target Vicinity
3.4. Link Binding Kinetics Rate Constants to in Vivo Target Occupancy with BK-TPK Model
4. Discussion
- The on-rate is >103 M−1s−1 for the fast association with AGH target.
- The off-rate is <10−4s−1 (corresponding to BK-t1/2 > 1.9 h) for the slow dissociation from AGH target.
- The molecule characterizations with a reasonable high aqueous solubility, a low drug permeability and high stability in intestinal tract are required to obtain high enough compound concentration in the UWLs.
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Compound | kon (103 M−1s−1) | koff (10−3 s−1) | Ki* (μM) |
---|---|---|---|
ECG | 0.2 ± 0.05 | 1.6 ± 0.3 | 1.0 ± 0.3 |
EGCG | 2.4 ± 0.3 | 1.9 ± 0.2 | 0.16 ± 0.03 |
Parameters | Cmax (μM) | AUC0-inf (103 μM·h) a | Terminal UWL Half-Lifes (h) a | Dissociation Half-Life (h) b | Ratio c | |
---|---|---|---|---|---|---|
ECG | Duodenum | 160.9 | 63 | 0.13 | 0.12 | 0.92 |
Jejunum | 7.7 | 14 | 1.1 | 0.11 | ||
Ileum | 15.0 | 21 | 0.28 | 0.43 | ||
Colon | 16.6 | 63 | 1.7 | 0.07 | ||
EGCG | Duodenum | 187.5 | 94 | 0.17 | 0.10 | 0.59 |
Jejunum | 9.3 | 17 | 1.5 | 0.07 | ||
Ileum | 18.2 | 25 | 0.17 | 0.59 | ||
Colon | 22.8 | 92 | 1.1 | 0.09 | ||
Acarbose | Duodenum | 2.86 | 1.97 | 0.81 | 10.1 | 12.5 |
Jejunum | 0.88 | 1.92 | 0.82 | 12.3 | ||
Ileum | 0.60 | 1.90 | 0.87 | 11.6 | ||
Colon | 3.57 | 82 | 9.6 | 1.1 |
Parameters | TOmax | The Duration of >70% TO (h) | AUC0-inf a | |
---|---|---|---|---|
ECG | Duodenum | 95.3% | 0.64 | 84 |
Jejunum | 48.9% | 0 | 118 | |
Ileum | 65.2% | 0 | 121 | |
Colon | 67.5% | 0 | 346 | |
EGCG | Duodenum | 99.8% | 1.5 | 180 |
Jejunum | 96.0% | 2.6 | 449 | |
Ileum | 97.9% | 2.9 | 330 | |
Colon | 98.3% | 8.9 | 1164 | |
Acarbose | Duodenum | 100.0% | 3.6 | 402 |
Jejunum | 100.0% | >12 | 1500 | |
Ileum | 100.0% | 14.2 | 1885 | |
Colon | 100.0% | >24 | >2330 |
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Wang, G.; Ji, Y.; Li, X.; Wang, Q.; Gong, H.; Wang, B.; Liu, Y.; Pan, Y. Utilizing the Combination of Binding Kinetics and Micro-Pharmacokinetics Link in Vitro α-Glucosidase Inhibition to in Vivo Target Occupancy. Biomolecules 2019, 9, 493. https://doi.org/10.3390/biom9090493
Wang G, Ji Y, Li X, Wang Q, Gong H, Wang B, Liu Y, Pan Y. Utilizing the Combination of Binding Kinetics and Micro-Pharmacokinetics Link in Vitro α-Glucosidase Inhibition to in Vivo Target Occupancy. Biomolecules. 2019; 9(9):493. https://doi.org/10.3390/biom9090493
Chicago/Turabian StyleWang, Guopeng, Yanhua Ji, Xueyan Li, Qian Wang, Hang Gong, Baoshun Wang, Yang Liu, and Yanli Pan. 2019. "Utilizing the Combination of Binding Kinetics and Micro-Pharmacokinetics Link in Vitro α-Glucosidase Inhibition to in Vivo Target Occupancy" Biomolecules 9, no. 9: 493. https://doi.org/10.3390/biom9090493
APA StyleWang, G., Ji, Y., Li, X., Wang, Q., Gong, H., Wang, B., Liu, Y., & Pan, Y. (2019). Utilizing the Combination of Binding Kinetics and Micro-Pharmacokinetics Link in Vitro α-Glucosidase Inhibition to in Vivo Target Occupancy. Biomolecules, 9(9), 493. https://doi.org/10.3390/biom9090493