Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Reagents
2.2. Stability Assay of DPP-4 Inhibitors after Incubation with Cysteine
2.3. Metabolite Profiling in Rat Liver Microsomes
2.4. Cysteine and Glutathione Adduct Identification of 5-Hydroxysaxagliptin
2.5. Metabolite Profiling in Rats
3. Results and Discussions
3.1. Stability of DPP-4 Inhibitors under Nonenzymatic Conditions
3.2. Metabolite Profiling in Rat Liver Microsomes
3.3. Metabolite Profiling in Rat Plasma, Bile, and Liver
3.4. Identification of the Reactive Metabolites
3.5. Limitations of the Study
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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No. | Metabolites | tR (min) | [M+H]+ | Mass Error (ppm) | Reaction Type | |
---|---|---|---|---|---|---|
Theoretical | Measured | |||||
P | Saxagliptin | 5.3 | 316.2020 | 316.2017 | −0.95 | |
M1 | Saxagliptin cyclic amidine | 4.9 | 316.2020 | 316.2017 | −0.95 | cyclization |
M2 | 5-Hydroxysaxagliptin | 4.2 | 332.1969 | 332.1965 | −1.2 | hydroxylation |
M3 | Saxagliptin–cysteine conjugate | 4.4 | 420.1952 | 420.1931 | −4.99 | cysteine conjugation |
M4 | 5-Hydroxysaxagliptin–cysteine conjugate | 3.5 | 436.1901 | 436.1895 | −1.40 | Hydroxylation and cysteine conjugation |
M5 | Saxagliptin–cysteinylglycine conjugate | 4.7 | 477.2166 | 477.2163 | −0.63 | glutathione conjugation |
M6 | 5-Hydroxysaxagliptin–cysteinylglycine conjugate | 3.9 | 493.2115 | 493.2113 | −0.41 | Hydroxylation and glutathione conjugation |
M7 | Saxagliptin-O-sulfate | 4.6 | 396.1588 | 396.1581 | −1.77 | sulfation |
M8 | Saxagliptin-O-glucuronide | 4.3 | 492.2340 | 492.2335 | −1.01 | glucuronidation |
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Kim, K.-Y.; Jeong, Y.-J.; Park, S.-Y.; Park, E.-J.; Jeon, J.-H.; Song, I.-S.; Liu, K.-H. Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats. Pharmaceutics 2024, 16, 106. https://doi.org/10.3390/pharmaceutics16010106
Kim K-Y, Jeong Y-J, Park S-Y, Park E-J, Jeon J-H, Song I-S, Liu K-H. Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats. Pharmaceutics. 2024; 16(1):106. https://doi.org/10.3390/pharmaceutics16010106
Chicago/Turabian StyleKim, Ki-Young, Yeo-Jin Jeong, So-Young Park, Eun-Ji Park, Ji-Hyeon Jeon, Im-Sook Song, and Kwang-Hyeon Liu. 2024. "Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats" Pharmaceutics 16, no. 1: 106. https://doi.org/10.3390/pharmaceutics16010106
APA StyleKim, K.-Y., Jeong, Y.-J., Park, S.-Y., Park, E.-J., Jeon, J.-H., Song, I.-S., & Liu, K.-H. (2024). Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats. Pharmaceutics, 16(1), 106. https://doi.org/10.3390/pharmaceutics16010106