Chronic Use Safety of Agomelatine and Combinations: Impact on Hematological, Biochemical, and Histopathological Parameters in Gender-Specified Rats

Introduction: Polypharmacy may lead to changes in the action profile and toxicity of medicines. Objective: This study evaluated the effect of the association of the antidepressant agomelatine (AGO) with losartan (LOS), simvastatin (SIM), and metformin (MET), after subchronic treatment, on hematological, biochemical, and histopathological parameters in Wistar rats. Methods: The animals were randomly divided into ten groups for each sex and treated for 90 days, per os, with saline, AGO, LOS, SIM, MET, or combinations (AGO+LOS, AGO+SIM, AGO+MET, LOS+SIM+MET, and AGO+LOS+SIM+MET). We evaluated hematological, biochemical, and histopathological parameters. Regarding hematological alterations, the main changes occurred in the erythrogram. Results: Females in polypharmacy were more prone to develop hematological and biochemical alterations. Hepatic and renal functions were the most affected among biochemical parameters. Agomelatine, in association, increased the risk of histopathological changes in males and females, especially in the liver, kidneys, and spleen. Females presented more intense hepatic histopathological changes when AGO was associated with SIM and MET. Females using MET or AGO+MET were more prone to develop histopathological changes than males. The spleen was significantly affected in females, corroborating erythrogram alterations. Conclusion: Agomelatine in association altered the safety profile of drugs, especially in females, indicating caution in their use in polypharmacy with commonly prescribed drugs.