LC-ESI-MS/MS Analysis and Pharmacokinetics of GP205, an Innovative Potent Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease in Rats
Abstract
:1. Introduction
2. Results and Discussion
2.1. Method Development
2.1.1. Sample Preparation
2.1.2. LC-MS/MS Optimization
2.2. Method Validation
2.2.1. Selectivity
2.2.2. Sensitivity and Linearity
2.2.3. Accuracy and Precision
Nominal Concentration (ng/mL) | Intra-Day (n = 5) | Inter-Day (n = 15) | ||||
---|---|---|---|---|---|---|
Measured Concentration (ng/mL) (Mean ± S.D.) | RSD (%) | RE (%) | Measured Concentration (ng/mL) (Mean ± S.D.) | RSD (%) | RE (%) | |
5 | 5.07 ± 0.36 | 7.1 | 0.8 | 5.18 ± 0.26 | 5.0 | 3.0 |
100 | 106.15 ± 2.99 | 2.9 | 5.5 | 103.53 ± 5.16 | 5.0 | 2.9 |
4000 | 4062.09 ± 93.81 | 2.4 | 1.0 | 4059.29 ± 110.69 | 2.8 | 0.9 |
2.2.4. Extraction Recovery and Matrix Effect
Nominal Concentration (ng/mL) | Peak Area a (e5) (A) (Mean ± S.D.) | Peak Area b (e5) (B) (Mean ± S.D.) | Peak area c (e5) (C) (Mean ± S.D.) | Extraction Recovery d (%) (A/B) | Matrix Effect e (%) (B/C) |
---|---|---|---|---|---|
5 | 0.39 ± 0.02 | 0.45 ± 0.02 | 0.47 ± 0.02 | 86.7 | 95.7 |
100 | 5.20 ± 0.11 | 5.91 ± 0.19 | 6.09 ± 0.16 | 88.0 | 97.0 |
4000 | 192.50 ± 12.01 | 206.90 ± 5.62 | 215.47 ± 5.44 | 93.0 | 96.0 |
100 (I.S.) | 7.27 ± 0.47 | 7.83 ± 0.46 | 8.45 ± 0.22 | 92.9 | 92.7 |
2.2.5. Stability
2.2.6. Sample Dilution
Sample Condition | Nominal Conc. (ng/mL) | Measured Conc. (ng/mL) | Accuracy (%) |
---|---|---|---|
Bench top stability a | 5 | 4.84 | −3.3 |
100 | 98.39 | −1.6 | |
4000 | 3884.71 | −2.9 | |
Auto-sampler stability b | 5 | 4.79 | −4.2 |
100 | 96.13 | −3.9 | |
4000 | 3904.44 | −2.4 | |
Freeze-thaw stability c | 5 | 4.73 | −5.5 |
100 | 94.90 | −5.1 | |
4000 | 3925.86 | −1.9 | |
Long time stability d | 5 | 4.61 | −7.7 |
100 | 92.84 | −7.2 | |
4000 | 3812.43 | −4.7 | |
Room temperature stabilityfor stock solution e | 5 | 5.09 | 1.8 |
100 | 103.26 | 3.3 | |
4000 | 3987.91 | −0.3 | |
At 4 °C stability for stock solution f | 5 | 5.14 | 2.8 |
100 | 100.63 | 0.6 | |
4000 | 3992.75 | −0.2 |
Dilution Factor | Assayed Concentration (ng/mL) | Reported Concentration (ng/mL) |
---|---|---|
2 | 4426.87 | 8853.74 |
4234.72 | 8469.44 | |
4347.85 | 8695.70 | |
Mean | 8672.96 | |
RSD (%) | 2.3 | |
Accuracy (%) | 8.4 | |
5 | 4365.77 | 21,828.85 |
4039.57 | 20,197.85 | |
4104.06 | 20,520.30 | |
Mean | 20,849.01 | |
RSD (%) | 4.2 | |
Accuracy (%) | 4.3 |
2.3. Pharmacokinetic Study
Pharmacokinetic Parameters | GP205 | ||
---|---|---|---|
Oral | 2.5 mg/Kg | 5 mg/Kg | 10 mg/Kg |
Tmax (h) | 6.30 ± 0.80 | 6.30 ± 1.50 | 6.30 ± 0.80 |
Cmax (ng/mL) | 4260.32 ± 400.35 | 6782.15 ± 749.52 | 9406.12 ± 582.99 |
t1/2 (h) | 12.38 ± 1.51 | 13.91 ± 1.48 | 17.21 ± 2.73 |
MRT (h) | 19.35 ± 3.22 | 22.17 ± 2.18 | 25.55 ± 3.48 |
AUC0-τ (ng·h/mL) | 64,342.95 ± 13,770.51 | 122,230.48 ± 9225.20 | 176,357.52 ± 16,331.60 |
AUC0-∞ (ng·h/mL) | 70,136.75 ± 16,623.71 | 135,312.81 ± 13,439.93 | 204,693.19 ± 15,949.70 |
IV | 1 mg/Kg | ||
C0 (ng/mL) | 9511.56 ± 442.31 | ||
t1/2 (h) | 16.26 ± 2.99 | ||
MRT (h) | 20.76 ± 3.41 | ||
Cl(L/h/Kg) | 0.02 ± 0.01 | ||
VD(L) | 0.31 ± 0.12 | ||
AUC0-τ (ng·h/mL) | 66,640.04 ± 21,721.23 | ||
AUC0-∞ (ng·h/mL) | 75,210.88 ± 23,751.74 |
3. Experimental Section
3.1. Chemicals and Reagents
3.2. LC-MS/MS Instrumentation
3.3. Liquid Chromatographic Conditions
3.4. Mass Spectrometer Conditions
3.5. Preparation of Standard and Quality Control (QC) Samples
3.6. Extraction Procedure
3.7. Pharmacokinetic Study in Rats
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Yang, N.; Sun, Q.; Xu, Z.; Wang, X.; Zhao, X.; Cao, Y.; Chen, L.; Fan, G. LC-ESI-MS/MS Analysis and Pharmacokinetics of GP205, an Innovative Potent Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease in Rats. Molecules 2015, 20, 4319-4336. https://doi.org/10.3390/molecules20034319
Yang N, Sun Q, Xu Z, Wang X, Zhao X, Cao Y, Chen L, Fan G. LC-ESI-MS/MS Analysis and Pharmacokinetics of GP205, an Innovative Potent Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease in Rats. Molecules. 2015; 20(3):4319-4336. https://doi.org/10.3390/molecules20034319
Chicago/Turabian StyleYang, Nan, Qiushi Sun, Zihua Xu, Xiuyun Wang, Xin Zhao, Yuqing Cao, Li Chen, and Guorong Fan. 2015. "LC-ESI-MS/MS Analysis and Pharmacokinetics of GP205, an Innovative Potent Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease in Rats" Molecules 20, no. 3: 4319-4336. https://doi.org/10.3390/molecules20034319