Protective Role of Amlodipine Against Cyclophosphamide- and Acetaminophen-Induced Nephrotoxicity: Modulation of Gamma-Glutamyl Transpeptidase and Oxidative Stress Pathways in Rats

Background:
Cyclophosphamide (Cyclo) is a widely used chemotherapeutic agent that induces nephrotoxicity via oxidative stress and dysregulation of gamma-glutamyl transpeptidase (GGT). Acetaminophen (Aceta) may exacerbate these effects by increasing the oxidative burden, whereas amlodipine (Amlo), a calcium channel blocker with antioxidant properties, may confer nephroprotection.
Objective :
This study aimed to evaluate the protective role of amlo against cyclophosphamide- and acetaminophen-induced nephrotoxicity, focusing on GGT modulation and oxidative stress markers.
Methods:
Fifty-six male albino rats were randomly assigned to seven groups: control, cyclophosphamide (Cyclo), amlodipine (Amlo), acetylsalicylic acid (Aceta), Cyclo + Amlo, Cyclo + Aceta, and Cyclo + Amlo + Aceta. Treatments were administered for 14 days, with a single intraperitoneal dose of cyclo (200 mg/kg) on day 10. Renal function (BUN, serum creatinine, and urea), renal GGT activity, and oxidative stress parameters (GSH, GPx, MDA, CAT, NO, and SOD) were assessed at the study endpoint. Histopathological analysis, including glomerular capillary space measurements, was also performed.
Results:
Cyclo and Aceta significantly increased renal GGT and MDA levels and reduced antioxidant enzyme levels (GSH, GPx, CAT, NO, and SOD), confirming oxidative nephrotoxicity. Amlo alone preserved renal function and antioxidant status. Co-administration of amlodipine with cyclophosphamide markedly attenuated oxidative stress, restored antioxidant enzyme activity, and improved histological integrity. Conversely, the combination of Cyclo and
Aceta exacerbated oxidative and structural renal damage. Notably, the triple combination (Cyclo + Amlo + Aceta) demonstrated partial protection, highlighting the dominant nephroprotective effect of amlodipine.
Conclusion:
Amlodipine demonstrated a protective effect against cyclophosphamide- and acetaminophen-induced nephrotoxicity by reducing oxidative stress and preserving renal structure. In contrast, acetaminophen exacerbated renal injury. Cyclophosphamide-induced nephrotoxicity may not be detected by conventional renal function tests but is evident at the oxidative and histopathological levels. These findings highlight the importance of oxidative stress biomarkers, including GGT, and support amlodipine as a potential renoprotective strategy; however, caution is advised when it is combined with acetaminophen.