Development of UPLC-MS/MS Method to Study the Pharmacokinetic Interaction between Sorafenib and Dapagliflozin in Rats
Abstract
:1. Introduction
2. Results
2.1. Method Validation
2.1.1. Selectivity
2.1.2. Calibration Curve and LLOQ
2.1.3. Precision and Accuracy
2.1.4. Matrix Effects and Extraction Recovery
2.1.5. Stability
2.2. Pharmacokinetic Interactions between SOR and DAPA
2.2.1. Effect of DAPA on SOR Pharmacokinetics
2.2.2. Effect of SOR on DAPA Pharmacokinetics
2.3. mRNA Expression in the Liver and Intestines
3. Discussion
4. Materials and Methods
4.1. Chemicals and Regents
4.2. Instrumentation and Chromatographic Conditions
4.3. Preparation of Stock Solution and Working Solution
4.4. Preparation of Calibration Standards and Quality Control (QC) Samples
4.5. Plasma Sample Preparation
4.6. Method Validation
4.6.1. Selectivity
4.6.2. Calibration Curve and LLOQ
4.6.3. Precision and Accuracy
4.6.4. Matrix Effects and Extraction Recovery
4.6.5. Stability
4.7. Pharmacokinetic Experiments in Rats
4.8. Quantitative Real-Time PCR (qRT-PCR) Analysis
4.9. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Analytes | Concentration (ng/mL) | Intra-Day (n = 6) | Inter-Day (n = 18) | ||||
---|---|---|---|---|---|---|---|
Mean ± SD | RSD (%) | RE (%) | Mean ± SD | RSD (%) | RE (%) | ||
SOR | 5 | 5.14 ± 0.27 | 5.3 | 2.7 | 5.03 ± 0.27 | 5.5 | 0.6 |
10 | 10.35 ± 0.47 | 4.6 | 3.5 | 10.22 ± 0.51 | 5.0 | 2.2 | |
1500 | 1538.33 ± 31.89 | 2.1 | 2.6 | 1558.33 ± 82.69 | 5.3 | 3.9 | |
3750 | 3786.67 ± 77.11 | 2.0 | 1.0 | 3745.56 ± 150.30 | 4.0 | −0.1 | |
DAPA | 5 | 5.16 ± 0.24 | 4.6 | 3.2 | 5.12 ± 0.31 | 6.1 | 2.3 |
15 | 15.55 ± 0.80 | 5.1 | 3.7 | 15.42 ± 0.70 | 4.6 | 2.8 | |
800 | 824.50 ± 14.40 | 1.8 | 3.1 | 815.33 ± 28.31 | 3.5 | 1.9 | |
1500 | 1546.67 ± 52.03 | 3.4 | 3.1 | 1523.89 ± 95.37 | 6.3 | 1.6 |
Analytes | Concentration (ng/mL) | Matrix Effect | Extraction Recovery | ||
---|---|---|---|---|---|
Mean ± SD (%) | RSD (%) | Mean ± SD (%) | RSD (%) | ||
SOR | 10 | 100.30 ± 3.30 | 3.3 | 97.29 ± 3.54 | 3.6 |
1500 | 96.97 ± 8.80 | 9.1 | 106.94 ± 3.90 | 3.7 | |
3750 | 100.78 ± 4.17 | 4.1 | 100.41 ± 2.67 | 2.7 | |
DAPA | 15 | 106.20 ± 5.61 | 5.3 | 91.80 ± 2.78 | 3.0 |
800 | 103.86 ± 4.47 | 4.3 | 104.94 ± 4.16 | 4.0 | |
1500 | 101.33 ± 4.65 | 4.6 | 105.44 ± 3.44 | 3.3 |
Analytes | Conditions | Concentration (ng/mL) | Mean ± SD (ng/mL) | Precision (RSD%) | Accuracy (RE%) |
---|---|---|---|---|---|
SOR | Autosampler for 6 h | 10 | 10.09 ± 0.53 | 5.3 | 0.9 |
1500 | 1538.33 ± 36.56 | 2.4 | 2.6 | ||
3750 | 3716.67 ± 66.23 | 1.8 | −0.9 | ||
Room temperature for 4 h | 10 | 10.68 ± 0.55 | 5.2 | 6.8 | |
1500 | 1448.33 ± 18.35 | 1.3 | −3.4 | ||
3750 | 3533.33 ± 66.23 | 1.9 | −5.8 | ||
−80 °C for 30 days | 10 | 10.20 ± 0.39 | 3.8 | 2.0 | |
1500 | 1533 ± 40.33 | 2.6 | 2.2 | ||
3750 | 3593.33 ± 142.22 | 4.0 | −4.2 | ||
Freeze–thaw stability for three times | 10 | 9.84 ± 0.34 | 3.4 | −1.7 | |
1500 | 1550.00 ± 12.65 | 0.8 | 3.3 | ||
3750 | 3601.67 ± 164.00 | 4.6 | −4.0 | ||
DAPA | Autosampler for 6 h | 15 | 14.93 ± 0.83 | 5.5 | −0.4 |
800 | 830.00 ± 15.05 | 1.8 | 3.8 | ||
1500 | 1643.33 ± 32.66 | 2.0 | 9.6 | ||
Room temperature for 4 h | 15 | 14.90 ± 0.49 | 3.3 | −0.7 | |
800 | 889.00 ± 15.43 | 1.7 | 11.1 | ||
1500 | 1653.33 ± 21.60 | 1.3 | 10.2 | ||
−80 °C for 30 days | 15 | 15.43 ± 1.07 | 6.9 | 2.9 | |
800 | 822.17 ± 21.66 | 2.6 | 2.8 | ||
1500 | 1483.33 ± 19.66 | 1.3 | −1.1 | ||
Freeze–thaw stability for three times | 15 | 15.18 ± 0.87 | 5.7 | 1.2 | |
800 | 769.83 ± 44.56 | 5.8 | −3.8 | ||
1500 | 1388.33 ± 54.19 | 3.9 | −7.4 |
Parameters (Unit) | SOR (100 mg/kg) | DAPA (1 mg/kg) | ||
---|---|---|---|---|
Alone | With Multiple-Doses DAPA | Alone | With Multiple-Doses SOR | |
AUC0-t (μg/L × h) | 62,701.33 ± 16,697.65 | 31,044.48 ± 11,555.87 ** | 5156.50 ± 1028.25 | 8572.00 ± 2861.57 ** |
AUC0–∞ (μg/L × h) | 63,708.42 ± 17,561.72 | 34,299.86 ± 12,031.05 ** | 5180.03 ± 1048.61 | 9300.01 ± 4261.40 ** |
Cmax (μg/L) | 1547.87 ± 136.94 | 904.59 ± 249.56 ** | 846.00 ± 76.39 | 870.83 ± 166.87 |
Tmax (h) | 7.50 ± 0.55 | 6.00 ± 1.27 * | 0.58 ± 0.20 | 0.83 ± 0.41 ** |
t1/2z (h) | 17.456 ± 5.65 | 24.82 ± 20.13 | 4.51 ± 0.67 | 7.95 ± 4.03 ** |
CLz/F (L/h/kg) | 1.69 ± 0.52 | 3.35 ± 1.52 * | 0.20 ± 0.04 | 0.12 ± 0.03 ** |
Vz/F (L/kg) | 37.43 ± 9.78 | 106.53 ± 69.61 * | 1.27 ± 0.19 | 1.12 ± 0.10 |
MRT0-t (h) | 47.08 ± 9.48 | 54.99 ± 13.07 | 6.10 ± 0.96 | 9.01 ± 1.22 ** |
MRT0–∞ (h) | 48.73 ± 10.48 | 67.64 ± 33.94 | 6.25 ± 1.07 | 11.22 ± 4.86 ** |
Experimental Setting | SOR | DAPA | SOR-d3 | 2H4-DAPA |
---|---|---|---|---|
MRM transition | 465.3→270.1 | 426.1→167.2 | 468.2→255.4 | 466.3→195.3 |
Delustering potential (DP), V | 100 | 80 | 100 | 100 |
Collision energy (CE), V | 45 | 30 | 45 | 45 |
Collision cell exit potential (CXP), V | 7 | 7 | 7 | 7 |
Entrance potential (EP), V | 10 | 10 | 10 | 10 |
Gene | Forward Primer | Reverse Primer |
---|---|---|
Ugt1a7 | 5′ AGTGTCCGTTTGGTTGTT-3′ | 5′-TTCCATCGCTTTCTTCTC-3′ |
NAPDH | 5′-GCCTTCCGTGTTCCTACC-3′ | 5′-GCCTGCTTCACCACCTTC-3′ |
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He, X.; Li, Y.; Ma, Y.; Fu, Y.; Xun, X.; Cui, Y.; Dong, Z. Development of UPLC-MS/MS Method to Study the Pharmacokinetic Interaction between Sorafenib and Dapagliflozin in Rats. Molecules 2022, 27, 6190. https://doi.org/10.3390/molecules27196190
He X, Li Y, Ma Y, Fu Y, Xun X, Cui Y, Dong Z. Development of UPLC-MS/MS Method to Study the Pharmacokinetic Interaction between Sorafenib and Dapagliflozin in Rats. Molecules. 2022; 27(19):6190. https://doi.org/10.3390/molecules27196190
Chicago/Turabian StyleHe, Xueru, Ying Li, Yinling Ma, Yuhao Fu, Xuejiao Xun, Yanjun Cui, and Zhanjun Dong. 2022. "Development of UPLC-MS/MS Method to Study the Pharmacokinetic Interaction between Sorafenib and Dapagliflozin in Rats" Molecules 27, no. 19: 6190. https://doi.org/10.3390/molecules27196190