Drug Interaction Study between Domperidone and Azithromycin in Mice

The widespread use of multidrug therapies in veterinary medicine raises concerns regarding unexpected pharmacodynamic and toxicological interactions, even among drugs considered safe individually. Domperidone and azithromycin are often co-prescribed without thorough preclinical safety assessments. This study investigated the potential synergistic toxicity of domperidone and azithromycin in twenty healthy adult male Swiss albino mice (n = 5 per group), randomly divided into four groups: control, domperidone (20 mg/kg), azithromycin (100 mg/kg), and their combination, administered orally for 15 days. Neurobehavioral outcomes were evaluated using open field testing, while serum neurotransmitters (serotonin and acetylcholine) were quantified, and renal and cardiac tissues were assessed histologically and via immunohistochemical detection of Caspase-3. Co-administration of both drugs significantly increased defecation and urination frequencies, mechanistically linked to elevated peripheral serotonin and acetylcholine levels, suggesting enhanced parasympathetic output. Histopathology revealed pronounced renal tubular necrosis and myocardial fiber degeneration, corroborated by marked overexpression of Caspase-3, indicating apoptotic activation. Meanwhile, locomotor and anxiety-like behaviors remained unchanged, implying selective autonomic disruption without central neurotoxicity. In conclusion, the concurrent use of domperidone and azithromycin induces synergistic cardiorenal toxicity in mice, driven by parasympathetic overactivation and apoptotic signaling pathways. These findings underscore the necessity for preclinical toxicological evaluation before combining these agents in veterinary practice.