High Performance Liquid Chromatography-Tandem Mass Spectrometric determination of carcinogen nitrosamine impurities from pharmaceuticals and DNA binding confirmation aided by molecular docking application

Year 2024, Volume: 54 Issue: 3, 386 - 394, 30.12.2024

İbrahim Daniş , Soykan Agar , Mine Yurtsever , Durişehvar Özer Ünal

https://doi.org/10.26650/IstanbulJPharm.2024.1500047

Abstract

Background and Aims: Nitrosamines are amine compounds attached to a nitroso group. The reaction of amines and nitrosating agents forms nitrosamines. Nitrosamine impurities are classified as Class 1 based on the carcinogenicity and mutagenicity data by ICH M7 (R1). The recent discovery of nitrosamines in some pharmaceutical products has caused concern. Nitrosamines are carcinogenic, so it is necessary to determine the possible nitrosamines in pharmaceutical products.
Methods: An Inertsil ODS-3, (4.6x250 mm, 5 μm) column was used for separation. A triple quadrupole mass detector with electrospray Ionisation (ESI) was used for detection. Multiple reaction monitoring (MRM) was used for quantification. The transition ions are 75.1 > 43.3 for NDMA and 103.0 > 75.1 for NDEA. The calibration curves consist of 5 concentration levels, including NDMA and NDEA (5, 10, 50, 100, 150 ng/mL). The mean r2 value was 0.997 for NDMA and 0.999 for NDEA. For NDMA and NDEA, LOD: 2 ng/mL, LOQ: 5 ng/mL.
Results: Comprehensive in silico and in vitro results indicate that the method has good accuracy and precision
Conclusion: DNA binding interactions of the molecules NDMA and NDEA, were investigated through the molecular docking and molecular dynamics methods. Molecular Docking simulations showed that these small organic molecules have high-affinity scores and strongly bind to the minor groove of the hDNA via strong hydrogen bonds.

Keywords

DNA binding, molecular docking, MD, mass spectrometry, nitrosamine, NDMA, NDEA

References

• Al-Kaseem, M., Al-Assaf, Z., & Karabeet, F. (2014). A Rapid, Vali-dated RP-HPLC Method for the Determination of Seven Volatile N-Nitrosamines in Meat. Pharmacology Pharmacy, 05(03), 298308. https://doi.org/10.4236/pp.2014.53037 google scholar
• arnes, J. M., & Magee, P. N. (1954). Some Toxic Proper-ties of Dimethylnitrosamine. Occupational and Environmental Medicine, 11(3), 167-174. https://doi.org/10.1136/oem.11.3.167 google scholar
• Becke, A. D. (1993). Density-functional thermochemistry. III. The role of exact exchange. The Journal of Chemical Physics, 98(7), 5648-5652. https://doi.org/10.1063/1.464913 google scholar
• Cheraghi, S., Şenel, P., Dogan Topal, B., Agar, S., Majidian, M., Yurtsever, M., . . . Ozkan, S. A. (2023). Elucidation of DNA-Eltrombopag Binding: Electrochemical, Spectroscopic and Molecular Docking Techniques. Biosensors, 13(3), 300. https://doi.org/10.3390/bios13030300 google scholar
• Control of nitrosamine impurities in human drugs. (2021). https:// www.fda.gov/media/141720/download. (Accessed December 11, 2024). google scholar
• Dennington, R., Keith, T., & Millam, J. (2009). GaussView, version 5. Desmond, D. (2017). Shaw Research: New York. In: NY. google scholar
• Evans, D. J., & Holian, B. L. (1985). The nose-hoover thermostat. The Journal of Chemical Physics, 83(8), 4069-4074. google scholar
• Frisch, M., Trucks, G., Schlegel, H., Scuseria, G., Robb, M., Cheese-man, J., . . . Petersson, G. (2009). 09, Revision D. 01, Gaussian. Inc., Wallingford, CT. google scholar
• Gaillard, T. (2018). Evaluation of AutoDock and AutoDock Vina on the CASF-2013 Benchmark. Journal of Chemical Informa-tion and Modeling, 58(8), 1697-1706. https://doi.org/10.1021/acs. jcim.8b00312 google scholar
• ICH Q2 (R1). (2005). Validation of Analytical Procedures: Text and Methodology, https://database.ich.org/sites/default/files/Q2% 28R1%29%20Guideline.pdf. (Accessed December 11, 2024). google scholar
• Kul, A., & Sagirli, O. (2023). Elimination of matrix effects in urine for determination of ethyl glucuronide by liquid chromatography-tandem mass spectrometry. Rapid Communications in Mass Spec-trometry, 37(23), e9643. https://doi.org/10.1002/rcm.9643 google scholar
• Li, W., Chen, N., Zhao, Y., Guo, W., Muhammed, N., Zhu, Y., & Huang, Z. (2018). Online coupling of tandem liquid-phase extraction with HPLC-UV for the determination of trace N-nitrosamines in food products. Analytical Methods, 10(15), 17331739. https://doi.org/10.1039/c8ay00014j google scholar
• Li, Y., & Hecht, S. S. (2022). Metabolic Activation and DNA In-teractions of Carcinogenic N-Nitrosamines to Which Humans Are Commonly Exposed. International Journal of Molecular Sci-ences, 23(9). https://doi.org/10.3390/ijms23094559 google scholar
• Lv, J., Wang, L., & Li, Y. (2017). Characterization of N-nitrosodimethylamine formation from the ozonation of raniti-dine. Journal of Environmental Sciences, 58, 116-126. https: //doi.org/10.1016/j.jes.2017.05.028 google scholar
• M7(R1) assessment and control of DNA reactive (mutagenic) impuri-ties in pharmaceuticals to limit potential carcinogenic risk. (2018). https://www.fda.gov/media/85885/download. (Accessed Decem-ber 11, 2024). google scholar
• Magee, P. N., & Barnes, J. M. (1956). The production of malig-nant primary hepatic tumours in the rat by feeding dimethyl-nitrosamine. British Journal of Cancer, 10(1), 114-122. https: //doi.org/10.1038/bjc.1956.15 google scholar
• Martyna, G. J., Tobias, D. J., & Klein, M. L. (1994). Constant pressure molecular dynamics algorithms. The Journal of Chemical Physics, 101(5), 4177-4189. google scholar
• Masada, S., Tsuji, G., Arai, R., Uchiyama, N., Demizu, Y., Tsutsumi, T., . . . Okuda, H. (2019). Rapid and efficient high-performance liq-uid chromatography analysis of N-nitrosodimethylamine impurity in valsartan drug substance and its products. Scientific Reports, 9(1). https://doi.org/10.1038/s41598-019-48344-5 google scholar
• McConkey, B. J., Sobolev, V., & Edelman, M. (2002). The perfor-mance of current methods in ligand-protein docking. CurrentSci-ence, 83(7), 845-856. Retrieved from http://www.jstor.org/stable/ 24107087 google scholar
• Nawrocki, J., & Andrzejewski, P. (2011). Nitrosamines and water. Journal of Hazardous Materials, 189(1), 1-18. doi:https://doi.org/ 10.1016/j.jhazmat.2011.02.005 google scholar
• Ngongang, A. D., Duy, S. V., & Sauve, S. (2015). Analysis of nine N-nitrosamines using liquid chromatography-accurate mass high resolution-mass spectrometry on a Q-Exactive instrument. Analytical Methods, 7(14), 5748-5759. https://doi.org/10.1039/ c4ay02967d google scholar
• Nitrosamine impurities in human medicinal products. (2020). https://www.ema.europa.eu/en/human-regulatory-overview/ post- authorisation/pharmacovigilance-post- authorisation/ referral-procedures-human-medicines/nitrosamine-impurities. (Accessed December 11, 2024). google scholar
• Ponting, D. J., Dobo, K. L., Kenyon, M. O., & Kalgutkar, A. S. (2022). Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredi-ents. Journal of Medicinal Chemistry, 65(23), 15584-15607. https://doi.org/10.1021/acs.jmedchem.2c01498 google scholar
• Preussmann, R. (1984). Carcinogenic N-nitroso compounds and their environmental significance. Naturwissenschaften, 71(1), 25-30. https://doi.org/10.1007/bf00365976 google scholar
• Roux, J. L., Gallard, H., Croue, J.-P., Papot, S., & Deborde, M. (2012). NDMA Formation by Chloramination of Ranitidine: Kinetics and Mechanism. Environmental Science & Technology, 46(20), 11095-11103. https://doi.org/10.1021/es3023094 google scholar
• cherf-Clavel, O., Kinzig, M., Besa, A., Schreiber, A., Bidmon, C., Abdel-Tawab, M., . . . Holzgrabe, U. (2019). The contamination of valsartan and other sartans, Part 2: Untargeted screening reveals contamination with amides additionally to known nitrosamine impurities. Journal of Pharmaceutical and Biomedical Analysis, 172, 278-284. https://doi.org/10.1016/j.jpba.2019.04.035 google scholar
• Sedlo, I., Kolonic, T., & Tomic, S. (2021). Presence of ni-trosamine impurities in medicinal products. Archives of Indus-trial Hygiene and Toxicology, 72(1), 1-5. https://doi.org/10.2478/ aiht-2021-72-3491 google scholar
• haikh, T., Gosar, A., & Sayyed, H. (2020). Nitrosamine Impurities in Drug Substances and Drug Products. 2, 48-57. https://doi.org/10. 5281/zenodo.3629095 google scholar
• Şenel, P., Agar, S., İş, Y. S., Altay, F., Gölcü, A., & Yurtsever, M. (2022). Deciphering the mechanism and binding interactions of Pemetrexed with dsDNA with DNA-targeted chemotherapeutics via spectroscopic, analytical, and simulation studies. Journal of Pharmaceutical and Biomedical Analysis, 209, 114490. https: //doi.org/10.1016/j.jpba.2021.114490 google scholar
• Şenel, P., Agar, S., Sayin, V. O., Altay, F., Yurtsever, M., & Gölcü, A. (2020). Elucidation of binding interactions and mechanism of Flu-darabine with dsDNA via multispectroscopic and molecular dock-ing studies. Journal of Pharmaceutical and Biomedical Analysis, 179, 112994. https://doi.org/10.1016/j.jpba.2019.112994 google scholar
• Thresher, A., Foster, R., Ponting, D. J., Stalford, S. A., Tennant, R. E., & Thomas, R. (2020). Are all nitrosamines concerning? A review of mutagenicity and carcinogenicity data. Regulatory Toxicology and Pharmacology, 116, 104749. https://doi.org/10.1016/j.yrtph. 2020.104749 google scholar
• Zhao, Y. Y., Boyd, J., Hrudey, S. E., & Li, X. F. (2006). Charac-terization of New Nitrosamines in Drinking Water Using Liquid Chromatography Tandem Mass Spectrometry. Environmental Sci-ence & Technology, 40(24), 7636-7641. https://doi.org/10.1021/ es061332s google scholar