Abstract
The interactions of drugs with iron are of interest in relation to the potential effects of iron-rich foods and iron supplements on sorption and bioavailability. Doxycycline (DOX), a member of the tetracycline class of broad-spectrum antibiotics, is frequently administered by oral route. In the digestive tract, DOX can be exposed to iron at different pH values (stomach pH 1.5–4, duodenum pH 5–6, distal jejunum and ileum pH 7–8). In relation to this, we analyzed the impact of pH on Fe3+-DOX complex formation. The optimal conditions for Fe3+-DOX complex formation are pH = 4 and [Fe3+]/[DOX] = 6 molar ratio. HESI-MS showed that Fe3+-DOX complex has 1:1 stoichiometry. Raman spectra of Fe3+-DOX complex indicate the presence of two Fe3+-binding sites in DOX structure: tricarbonylamide group of ring A and phenolic-diketone oxygens of BCD rings. The Fe3+-DOX complex formed at pH = 4 is less susceptible to oxidation than DOX at this pH. The increase of pH induces the decomposition of Fe3+-DOX complex without oxidative degradation of DOX. The pH dependence of Fe3+-DOX complex formation may promote unwanted effects of DOX, impeding the absorption that mainly takes place in duodenum. This could further result in higher concentrations in the digestive tract and to pronounced impact on gut microbiota.
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The data that support the findings of this study are available from the corresponding authors upon request.
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Acknowledgements
This work was supported by the Ministry of Science, Technological Development and Innovation of Republic of Serbia (contract no. 451-03-47/2023-01/200053, 451-03-47/2023-01/200168, 451-03-47/2023-01/200146).
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JKJ: Writing—original draft, Investigation, Conceptualization, Visualization, Data curation, Supervision. MD: Writing—review and editing, Formal analysis, Data curation. DB-B: Writing—review and editing, Formal analysis, Data curation. DS: Writing—review and editing, Formal analysis, Data curation. SS: Writing—review and editing, Methodology, Formal analysis. IS: Writing—review and editing, Visualization, Conceptualization. MRM: Writing—original draft, Investigation, Conceptualization, Visualization, Data curation, Supervision. All the authors approved the final version of the manuscript.
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Korać Jačić, J., Dimitrijević, M., Bajuk-Bogdanović, D. et al. The formation of Fe3+-doxycycline complex is pH dependent: implications to doxycycline bioavailability. J Biol Inorg Chem 28, 679–687 (2023). https://doi.org/10.1007/s00775-023-02018-w
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DOI: https://doi.org/10.1007/s00775-023-02018-w