Coordination of hydralazine with Cu2+ at acidic pH promotes its oxidative degradation at neutral pH

Hydralazine (HL), a frequently prescribed oral antihypertensive drug, shows redox interactions with transition metals such as copper that are not fully understood. Copper may be present at high concentrations in the digestive tract and can affect oral drugs. An important parameter for such interactions is pH, which changes from acidic in the gastric juice to neutral pH in intestines. In this study, we examined interactions of HL with Cu2+ ions in conditions that mimic pH shift in the digestive tract using UV–Vis, Raman and EPR spectroscopy, cyclic voltammetry and oximetry. In the acidic solution, Cu2+ formed a stable mononuclear complex with two bidentate coordinated HL molecules. On the other hand, at neutral pH, Cu2+ initiated oxidation and degradation of HL. The degradation was more rapid in the HL-Cu2+ system that was initially prepared at acidic pH and then shifted to neutral pH. The formation of the complex at acidic pH increases the availability of Cu2+ for redox reactions after the shift to neutral pH at which Cu2+ is poorly soluble. These results imply that the change of pH along the digestive tract may promote HL degradation by allowing the formation of the complex at gastric pH which makes Cu2+ available for subsequent oxidation of HL at neutral pH. The interactions of hydralazine with Cu2+ were examined in conditions mimicking pH shift in digestive tract. The change of pH along the digestive tract may promote hydralazine degradation through the formation of hydralazine-Cu2+ complex at gastric pH which makes Cu2+ more available for subsequent oxidation of hydralazine at intestine pH. [Display omitted] •Hydralazine forms a stable mononuclear complex with Cu2+ at acidic pH.•Cu2+ initiates oxidative degradation of hydralazine at neutral pH.•pH shift pH 4 → pH 7 promotes hydralazine degradation from its Cu2+ complex.