Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry
Abstract
1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Preparation of Stock Solution, Calibration Standard (STD), and Quality Control (QC) Samples
2.3. Sample Preparation (Plasma Sample)
2.4. LC-TOF-MS/MS Conditions
2.5. Method Qualification
2.6. Software
2.7. Application for a Pharmacokinetic Study in Rat
2.8. Sample Preparation—In Vitro/In Vivo Metabolite Identification (Met ID)
3. Results and Discussion
3.1. Method Development and Qualification
3.1.1. Sample Preparation and Optimization of LC-TOF-MS/MS Parameters
3.1.2. Method Qualification
3.2. Application for Pharmacokinetic Study
3.3. In Vitro and In Vivo Metabolite Profiling for MMAF
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Quantification of MMAF | |
---|---|
Time (min) | Mobile phase B (%) |
0 | 10 |
0.5 | 10 |
1.3 | 95 |
1.9 | 95 |
2.0 | 10 |
3.5 | 10 |
Metabolite profiling of MMAF | |
Time (min) | Mobile phase B (%) |
0 | 5 |
2 | 5 |
28 | 33 |
29 | 33 |
34 | 95 |
38 | 95 |
38.1 | 5 |
45 | 5 |
Low QC (165.46 ng/mL) | High QC (1820 ng/mL) | |
---|---|---|
Mean concentration (ng/mL) | 163.94 | 1832.78 |
Accuracy % | 99.08 | 100.70 |
% CV | 2.52 | 2.83 |
n | 10 | 10 |
Low QC (165.46 ng/mL) | |||||
---|---|---|---|---|---|
Species | Mouse | Rat | Dog | Monkey | Human |
Mean concentration (ng/mL) | 184.60 | 155.72 | 171.41 | 171.36 | 164.36 |
Accuracy % | 111.57 | 94.11 | 103.60 | 103.57 | 99.34 |
% CV | 6.36 | 4.03 | 2.97 | 6.59 | 7.16 |
n | 3 | 3 | 3 | 3 | 3 |
HighQC (1820 ng/mL) | |||||
Species | Mouse | Rat | Dog | Monkey | Human |
Mean concentration (ng/mL) | 1651.07 | 1792.99 | 1796.06 | 1667.92 | 1873.39 |
Accuracy % | 90.72 | 98.52 | 98.69 | 91.64 | 102.93 |
%CV | 7.51 | 6.08 | 3.52 | 6.14 | 2 |
n | 3 | 3 | 3 | 3 | 3 |
MMAF | QC |
---|---|
Mean concentration of the post-extraction spiked QC (ng/mL) | 198.84 |
Mean concentration of the extracted QC samples (ng/mL) | 163.94 |
Extraction recovery (%) | 82.45 |
% CV | 2.12 |
n | 3 |
MMAF | Dilution QC (9100 ng/mL) |
Mean concentration (ng/mL) | 8091.72 |
Accuracy % | 88.92 |
% CV | 9.02 |
n | 3 |
(a) Short-term stability (RT, 4 h) | Low QC (165.46 ng/mL) | High QC (1820 ng/mL) | ||||
Incubation time (hr) | 0 (Control) | 4 | 0 (Control) | 4 | ||
Mean Concentration (ng/mL) | 169.87 | 149.90 | 1970.02 | 1884.23 | ||
Accuracy % | 102.67 | 90.60 | 108.24 | 103.53 | ||
% CV | 2.08 | 3.05 | 5.20 | 3.27 | ||
n | 3 | 3 | 3 | 3 | ||
(b) Long-term stability (−80 °C, 4 weeks) | Low QC (165.46 ng/mL) | High QC (1820 ng/mL) | ||||
Mean concentration (ng/mL) | 157.95 | 1657.96 | ||||
Accuracy % | 95.46 | 91.10 | ||||
% CV | 8.32 | 11.93 | ||||
n | 3 | 3 | ||||
(c) Freeze-thaw stability (−80 °C, three cycles) | Low QC (165.46 ng/mL) | High QC (1820 ng/mL) | ||||
Mean concentration (ng/mL) | 157.95 | 1657.96 | ||||
Accuracy % | 95.46 | 91.10 | ||||
% CV | 8.32 | 11.93 | ||||
n | 3 | 3 | ||||
(d) Post-preparative stability (10 °C, 12 h) | Area ratio of 1st injection | Area ratio of 10th injection (after 12hr) | Change (%) | % CV | ||
Low QC | 0.62 | 0.61 | 97.93 | 2.67 | ||
High QC | 7.43 | 7.43 | 99.98 | 0.43 |
Subject | Dose (mg/kg) | Cmax (ng/mL) | AUClast (min*ng/mL) | Clearance (CL) (mL/min/kg) | Vss (mL/kg) | Bioavailability (%) |
---|---|---|---|---|---|---|
MMAF IV (5 mg/kg) | 5 | 8276.76 | 65661.30 | 77.33 | 1057.13 | |
MMAF PO (10 mg/kg) | 10 | N/D | N/D | 0 |
Symbol | Metabolite | m/z | Retention Time (min) | Rat Liver Microsome | Human Liver Microsome | Pooled Rat Plasma (IV) | Pooled Rat Plasma (PO) |
---|---|---|---|---|---|---|---|
M1 | Oxidation-1 | 748.4624 | 21.50 | 0 | N/D | N/D | |
M2 | Demethylation-1 | 718.4519 | 22.40 | 0 | 0 | N/D | N/D |
M3 | Di-demethylation | 704.4362 | 22.96 | 0 | N/D | N/D | |
M4 | Loss of C6H11NO | 619.3813 | 23.17 | 0 | 0 | N/D | N/D |
M5 | Oxidation-2 | 748.4624 | 24.01 | 0 | N/D | N/D | |
M6 | Demethylation-2 | 718.4519 | 24.55 | 0 | 0 | N/D | N/D |
Parent | Parent | 732.4911 | 25.10 | 0 | 0 | 0 | 0 |
M7 | Oxidation-3 | 748.4624 | 32.16 | 0 | 0 | N/D | N/D |
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Park, M.-H.; Lee, B.i.; Byeon, J.-J.; Shin, S.-H.; Choi, J.; Park, Y.; Shin, Y.G. Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry. Molecules 2019, 24, 2754. https://doi.org/10.3390/molecules24152754
Park M-H, Lee Bi, Byeon J-J, Shin S-H, Choi J, Park Y, Shin YG. Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry. Molecules. 2019; 24(15):2754. https://doi.org/10.3390/molecules24152754
Chicago/Turabian StylePark, Min-Ho, Byeong ill Lee, Jin-Ju Byeon, Seok-Ho Shin, Jangmi Choi, Yuri Park, and Young G. Shin. 2019. "Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry" Molecules 24, no. 15: 2754. https://doi.org/10.3390/molecules24152754
APA StylePark, M.-H., Lee, B. i., Byeon, J.-J., Shin, S.-H., Choi, J., Park, Y., & Shin, Y. G. (2019). Pharmacokinetic and Metabolism Studies of Monomethyl Auristatin F via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry. Molecules, 24(15), 2754. https://doi.org/10.3390/molecules24152754