Proton pump inhibitors, such as omeprazole, pantoprazole and lansoprazole, are an important group of clinically used drugs. Generally, they are considered safe without direct toxicity. Nevertheless, their long-term use can be associated with a higher risk of some serious pathological states (e.g. amnesia and oncological and neurodegenerative states). It is well known that dysregulation of the metabolism of transition metals (especially iron ions) plays a significant role in these pathological states and that the above drugs can form complexes with metal ions. However, to the best of our knowledge, this phenomenon has not yet been described in water systems. Therefore, we studied the interaction between these drugs and transition metal ions in the surrounding water environment (water/DMSO, 99:1, v/v) by absorption spectroscopy. In the presence of Fe(III), a strong redshift was observed, and more importantly, the affinities of the drugs (represented as binding constants) were strong enough, especially in the case of omeprazole, so that the formation of a metallocomplex cannot be excluded during the explanation of their side effects.

1st Department of Surgery Department of Abdominal Thoracic Surgery and Traumatology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague 2 Czech Republic

BIOCEV 1st Faculty of Medicine Charles University Vestec Czech Republic

Department of Analytical Chemistry Faculty of Chemical Engineering University of Chemistry and Technology Prague Czech Republic

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

General University Hospital Prague Prague 2 Czech Republic

Institute of Multidisciplinary Research for Advanced Materials Tohoku University Katahira Japan

Institute of pathological physiology 1st Faculty of Medicine Charles University Prague Prague Czech Republic

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Abbas, M. K., Zaidi, A. R. Z., Robert, C. A., Thiha, S., & Malik, B. H. (2019). The safety of long-term daily usage of a proton pump inhibitor: A literature review. Cureus, 11(9), e5563. https://doi.org/10.7759/cureus.5563

Belaidi, A. A., & Bush, A. I. (2016). Iron neurochemistry in Alzheimer's disease and Parkinson's disease: Targets for therapeutics. Journal of Neurochemistry, 139(Suppl 1), 179-197. https://doi.org/10.1111/jnc.13425

Bistri, O., & Reinaud, O. (2015). Supramolecular control of transition metal complexes in water by a hydrophobic cavity: A bio-inspired strategy. Organic & Biomolecular Chemistry, 13(10), 2849-2865. https://doi.org/10.1039/C4OB02511C

Campbell, N. R. C., & Hasinoff, B. B. (1991). Iron Supplements - a Common Cause of Drug-Interactions. British Journal of Clinical Pharmacology, 31(3), 251-255. https://doi.org/10.1111/j.1365-2125.1991.tb05525.x

Dyrssen, D., Ingri, N., & Sillén, L. (1961). "Pit-mapping" -- a General Approach for Computer Refining of Equilibrium Constants. Acta Chemica Scandinavica, 15, 694-696. https://doi.org/10.3891/acta.chem.scand.15-0694

Eghbali, A., Khalilpour, A., Taherahmadi, H., & Bagheri, B. (2019). Pantoprazole reduces serum ferritin in patients with thalassemia major and intermedia: A randomized, controlled study. Therapie. https://doi.org/10.1016/j.therap.2018.11.013

Fernandez-Real, J. M., McClain, D., & Manco, M. (2015). Mechanisms linking glucose homeostasis and iron metabolism toward the onset and progression of type 2 diabetes. Diabetes Care, 38(11), 2169-2176. https://doi.org/10.2337/dc14-3082

Fuentes, A. V., Pineda, M. D., & Venkata, K. C. N. (2018). Comprehension of top 200 prescribed drugs in the US as a resource for pharmacy teaching, training and practice. Pharmacy (Basel), 6(2). https://doi.org/10.3390/pharmacy6020043

Galaris, D., Barbouti, A., & Pantopoulos, K. (2019). Iron homeostasis and oxidative stress: An intimate relationship. Biochim Biophys Acta Mol Cell Res, 1866(12), 118535. https://doi.org/10.1016/j.bbamcr.2019.118535

Imai, R., Higuchi, T., Morimoto, M., Koyamada, R., & Okada, S. (2018). Iron deficiency anemia due to the long-term use of a proton pump inhibitor. Internal Medicine, 57(6), 899-901. https://doi.org/10.2169/internalmedicine.9554-17

Jakubek, M., Kejík, Z., Antonyová, V., Kaplánek, R., Sýkora, D., Hromádka, R., … Král, V. (2019). Benzoisothiazole-1,1-dioxide-based synthetic receptor for zinc ion recognition in aqueous medium and its interaction with nucleic acids. Supramolecular Chemistry, 31(1), 19-27. https://doi.org/10.1080/10610278.2018.1523409

Jakubek, M., Kejík, Z., Kaplánek, R., Antonyová, V., Hromádka, R., Šandriková, V., … Král, V. (2019). Hydrazones as novel epigenetic modulators: Correlation between TET 1 protein inhibition activity and their iron(II) binding ability. Bioorganic Chemistry, 88. https://doi.org/10.1016/j.bioorg.2019.02.034

Jakubek, M., Kejík, Z., Kaplánek, R., Veselá, H., Sýkora, D., Martásek, P., & Král, V. (2018). Perimidine-based synthetic receptors for determination of copper(II) in water solution. Supramolecular Chemistry, 30(3), 218-226. https://doi.org/10.1080/10610278.2017.1414216

Jakubek, M., Kejík, Z., Parchaňský, V., Kaplánek, R., Vasina, L., Martásek, P., & Král, V. (2017). Water soluble chromone Schiff base derivatives as fluorescence receptor for aluminium(III). Supramolecular Chemistry, 29(1), 1-7. https://doi.org/10.1080/10610278.2016.1153095

Kasai, S., Mimura, J., Ozaki, T., Itoh, K. (2018). Emerging regulatory role of Nrf2 in iron, heme, and hemoglobin metabolism in physiology and disease. Frontiers in Veterinary Science, 5, 242.

Mohamed, G. G., Nour El-Dien, F. A., Khalil, S. M., & Mohammad, A. S. (2009). Metal Metal complexes of omeprazole. Preparation, spectroscopic and thermal characterization and biological activity. Journal of Coordination Chemistry, 62(4), 645-654. https://doi.org/10.1080/00958970802244992

Munro, A. W., McLean, K. J., Grant, J. L., & Makris, T. M. (2018). Structure and function of the cytochrome P450 peroxygenase enzymes. Biochemical Society Transactions, 46, 183-196. https://doi.org/10.1042/BST20170218

Novotny, M., Klimova, B., & Valis, M. (2019). PPI long term use: Risk of neurological adverse events? Frontiers in Neurology, 9. https://doi.org/10.3389/fneur.2018.01142

Petronek, M. S., Spitz, D. R., Buettner, G. R., & Allen, B. G. (2019). Linking Cancer Metabolic Dysfunction and Genetic Instability through the Lens of Iron Metabolism. Cancers, 11(8). https://doi.org/10.3390/cancers11081077

Puig, S., Ramos-Alonso, L., Romero, A. M., & Martínez-Pastor, M. T. (2017). The elemental role of iron in DNA synthesis and repair. Metallomics, 9(11), 1483-1500. https://doi.org/10.1039/C7MT00116A

Rahman, N., & Kashif, M. (2010). Hypothesis testing for the validation of the kinetic spectrophotometric methods for the determination of lansoprazole in bulk and drug formulations via Fe(III) and Zn(II) chelates. Drug Test Anal, 2(3), 137-143. https://doi.org/10.1002/dta.111

Robinson, M., & Horn, J. (2003). Clinical pharmacology of proton pump inhibitors - What the practising physician needs to know. Drugs, 63(24), 2739-2754. https://doi.org/10.2165/00003495-200363240-00004

Russoa, M. G., Vega, E. G., Hissib, A. C., Rizzic, C. D., Brondinoc, Á. G., Ibañezd, S., … Narda, G. E. (2014). Synthesis, physicochemical characterization, DFT calculation and biological activities of Fe(III) and Co(II)-omeprazole complexes. Potential application in the Helicobacter pylon eradication. Journal of Molecular Structure, 1061, 5-13.

Sarzynski, Erin, Puttarajappa, Chethan, Xie, Yan, Grover, Madhusudan, & Laird-Fick, Heather (2011). Association between proton pump inhibitor use and anemia: A retrospective cohort study. Digestive Diseases and Sciences, 56(8), 2349-2353. https://doi.org/10.1007/s10620-011-1589-y

Schneider, S. A., Zorzi, G., & Nardocci, N. (2013). Pathophysiology and treatment of neurodegeneration with brain iron accumulation in the pediatric population. Current Treatment Options in Neurology, 15(5), 652-667. https://doi.org/10.1007/s11940-013-0254-5

Siddiqi, K., Mohd, A., Khan, A., & Shaista, B. (2010). Binding constant: Fluorescence quenching of ciprofloxacin with Fe (III) and Zn (II). Asian Journal of Chemistry, 22, 1957-1965.

Sun, S., Cui, Z., Zhou, M., Li, R., Li, H., Zhang, S., … Cheng, G. (2017). Proton pump inhibitor monotherapy and the risk of cardiovascular events in patients with gastro-esophageal reflux disease: A meta-analysis. Neurogastroenterology and Motility, 29(2). https://doi.org/10.1111/nmo.12926

Zhang, Y., Shi, S., Liu, Y., Chen, X., & Peng, M. (2011). Differential effects of Cu(II) and Fe(III) on the binding of omeprazole and pantoprazole to bovine serum albumin: Toxic effect of metal ions on drugs. Journal of Pharmaceutical and Biomedical Analysis, 56(5), 1064-1068. https://doi.org/10.1016/j.jpba.2011.08.012

Zhu, B., Liang, C., Xia, X., Huang, K., Yan, S., Hao, J., … Tao, F. (2019). Iron-related factors in early pregnancy and subsequent risk of gestational diabetes mellitus: The Ma'anshan Birth Cohort (MABC) Study. Biological Trace Element Research, 191(1), 45-53. https://doi.org/10.1007/s12011-018-1595-4

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