The formation of Fe³⁺-doxycycline complex is pH dependent: implications to doxycycline bioavailability

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.