Development of a Rapid LC-MS/MS Method for Simultaneous Quantification of Donepezil and Tadalafil in Rat Plasma: Its Application in a Pharmacokinetic Interaction Study after Oral Administration in Rats
Abstract
:1. Introduction
2. Results and Discussion
2.1. Method Development
2.1.1. Mass Spectrometric Analysis
2.1.2. Chromatographic Conditions
2.1.3. Plasma Sample Preparation
2.2. Analytical Method Validation
2.2.1. Specificity and Lower Limit of Quantitation
2.2.2. Linearity
2.2.3. Precision and Accuracy
2.2.4. Stability
2.2.5. Recovery and Matrix Effect
2.3. Analytical Method Implementation to DDI PK Study in Rats
3. Materials and Methods
3.1. Materials
3.2. Liquid Chromatographic Conditions
3.3. Mass Spectrometric Conditions
3.4. Preparation of Calibration Standards and Plasma Samples
3.5. Preparation of Plasma Samples
3.6. Protocol Validation
3.6.1. Specificity and Lower Limit of Quantitation (LLOQ)
3.6.2. Linearity
3.6.3. Precision and Accuracy
3.6.4. Stability
3.6.5. Recovery and Matrix Effect
3.7. Application to a Pharmacokinetic Study
3.8. Statistical Analysis of the Pharmacokinetic Study
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | Nominal Concentration (ng/mL) | Intra-Day (n = 5) | Inter-Day (n = 5) | ||||
---|---|---|---|---|---|---|---|
Mean ± SD (ng/mL) | Precision (CV, %) a | Accuracy (%) b | Mean ± SD (ng/mL) | Precision (CV, %) | Accuracy (%) | ||
Donepezil | 1 | 0.93 ± 0.02 | 2.15 | 93.10 | 0.94 ± 0.04 | 3.84 | 93.80 |
2 | 1.99 ± 0.02 | 1.06 | 99.30 | 2.01 ± 0.07 | 3.33 | 100.65 | |
16 | 16.35 ± 0.25 | 1.55 | 102.17 | 16.40 ± 0.52 | 3.14 | 102.53 | |
160 | 139.08 ± 3.15 | 2.26 | 86.93 | 142.53 ± 6.77 | 4.75 | 89.08 | |
Tadalafil | 1 | 0.96 ± 0.05 | 5.52 | 96.10 | 0.97 ± 0.08 | 8.19 | 96.50 |
2 | 1.92 ± 0.06 | 3.18 | 96.05 | 1.94 ± 0.11 | 5.51 | 97.05 | |
16 | 15.95 ± 0.50 | 3.10 | 99.66 | 15.92 ± 0.54 | 3.42 | 99.48 | |
160 | 153.29 ± 2.91 | 1.90 | 95.80 | 155.40 ± 10.44 | 6.72 | 97.12 |
Stability Storage Condition | Donepezil | Tadalafil | ||
---|---|---|---|---|
Nominal Concentration (ng/mL) | (Mean ± SD, %) | Nominal Concentration (ng/mL) | (Mean ± SD, %) | |
Stock Solution Stability | ||||
Room temperature (3 h) | 103.43 ± 0.58 | 107.75 ± 10.32 | ||
Refrigeration (4 °C, 14 days) | 103.53 ± 1.71 | 106.30 ± 5.99 | ||
Plasma Sample Stability | ||||
Room temperature (5 h) | 2 | 98.05 ± 4.42 | 2 | 95.75 ± 4.54 |
160 | 89.84 ± 1.95 | 160 | 95.18 ± 0.41 | |
Refrigeration (4 °C, 14 days) | 2 | 93.33 ± 4.72 | 2 | 93.52 ± 3.03 |
160 | 97.29 ± 2.34 | 160 | 107.44 ± 5.73 | |
Freeze-thaw stability (4 cycles) | 2 | 98.05 ± 0.40 | 2 | 95.15 ± 2.69 |
160 | 92.54 ± 1.34 | 160 | 103.60 ± 1.55 | |
Autosampler (10 °C, 20 h) | 2 | 98.60 ± 2.46 | 2 | 99.63 ± 6.03 |
160 | 98.19 ± 4.87 | 160 | 102.18 ± 3.98 | |
−70 °C (28 days) | 2 | 107.57 ± 3.61 | 2 | 99.17 ± 3.88 |
160 | 93.41 ± 3.90 | 160 | 104.42 ± 4.78 |
Compound | Nominal Concentration (ng/mL) | Recovery (%) a | Matrix Effect (%) b | ||
---|---|---|---|---|---|
Mean ± SD (%) | Precision (CV, %) | Mean ± SD (%) | Precision (CV, %) | ||
Donepezil | 2 | 95.11 ± 2.59 | 2.72 | 97.05 ± 1.67 | 1.72 |
16 | 90.86 ± 4.33 | 4.77 | |||
160 | 95.99 ± 1.80 | 1.88 | 108.78 ± 2.87 | 2.64 | |
Tadalafil | 2 | 97.74 ± 11.05 | 11.31 | 58.46 ± 3.58 | 6.13 |
16 | 96.17 ± 5.34 | 5.55 | |||
160 | 98.59 ± 3.93 | 3.99 | 56.16 ± 6.48 | 11.55 | |
IS | 20 | 97.96 ± 3.40 | 3.47 | 90.90 ± 4.55 | 5.01 |
Parameter | Donepezil (3 mg/kg) | Tadalafil (0.3 mg/kg) | ||
---|---|---|---|---|
Alone | with TAD | Alone | with DPZ | |
Mean ± SD | Mean ± SD | Mean ± SD | Mean ± SD | |
Cmax (ng/mL) | 59.776 ± 15.502 | 39.235 ± 16.562 | 17.795 ± 5.998 | 13.750 ± 9.160 |
AUClast (h·ng/mL) | 129.583 ± 38.090 | 100.500 ± 29.467 | 46.987 ± 24.384 | 34.419 ± 27.372 |
AUCinf (h·ng/mL) | 133.901 ± 37.878 | 106.379 ± 32.097 | 50.362 ± 23.612 | 38.931 ± 26.821 |
Tmax (h) | 0.500 ± 0.000 | 0.500 ± 0.000 | 0.500 ± 0.000 | 0.500 ± 0.000 |
CL/F (L/h) | 2.382 ± 0.759 | 2.980 ± 0.888 | 7.355 ± 4.516 | 11.819 ± 9.852 |
T1/2 (h) | 2.630 ± 1.302 | 3.793 ± 2.032 | 1.517 ± 0.120 | 1.962 ± 0.212 |
MRTlast (h) | 2.617 ± 0.923 | 3.735 ± 1.602 | 2.532 ± 0.214 | 3.079 ± 0.444 |
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Yoon, J.; Choi, D.; Shim, W.-S.; Choi, S.; Choi, Y.J.; Paik, S.-H.; Lee, K.-T. Development of a Rapid LC-MS/MS Method for Simultaneous Quantification of Donepezil and Tadalafil in Rat Plasma: Its Application in a Pharmacokinetic Interaction Study after Oral Administration in Rats. Molecules 2023, 28, 2352. https://doi.org/10.3390/molecules28052352
Yoon J, Choi D, Shim W-S, Choi S, Choi YJ, Paik S-H, Lee K-T. Development of a Rapid LC-MS/MS Method for Simultaneous Quantification of Donepezil and Tadalafil in Rat Plasma: Its Application in a Pharmacokinetic Interaction Study after Oral Administration in Rats. Molecules. 2023; 28(5):2352. https://doi.org/10.3390/molecules28052352
Chicago/Turabian StyleYoon, Jiyoung, Doowon Choi, Wang-Seob Shim, Sanghee Choi, Yeo Jin Choi, Soo-Heui Paik, and Kyung-Tae Lee. 2023. "Development of a Rapid LC-MS/MS Method for Simultaneous Quantification of Donepezil and Tadalafil in Rat Plasma: Its Application in a Pharmacokinetic Interaction Study after Oral Administration in Rats" Molecules 28, no. 5: 2352. https://doi.org/10.3390/molecules28052352