Protective Effect of Time-Modulated Cimetidine on Methotrexate-induced Liver Toxicity

Background: Methotrexate (MTX) is one of the frequently used chemotherapeutic agents, especially in hematological malignancies and solid tumors. Objectives: MTX hepatotoxicity symptoms range from elevations in serum aminotransferases to hepatocyte necrosis and fibrosis. The time of medication administration significantly impacts treatment outcomes. Hence this study evaluated the protective effect of time-modulated cimetidine (CT) against MTX-induced hepatotoxicity in albino rats. Methods: Thirty-six adult male albino rats were randomized into 6 groups. Group A (control) was injected intraperitoneally (IP) with normal saline (0.2 mL) for 24 h. Group B received CT (20 mg/kg IP) for 24 h. Group C was treated IP with MTX (20 mg/kg) for 24 h. Group C (pre-treatment) was injected IP with CT one hour before MTX administration for 24 h. Group E (co-treatment group) was co-treated IP with CT and MTX for 24 h. Group F (post-treatment group) was treated IP with one dose of MTX one hour before CT injection for 24 h. After treatments, the rats were weighed and euthanized. Blood samples were collected and their blood samples were evaluated for serum liver function markers, also liver samples were excised and used for biochemical and histological studies. Results: The liver of MTX-treated rats was characterized by hepatocyte necrosis. Aminotransferases, gamma-glutamyl transferase, lactate dehydrogenase, alkaline phosphatase, conjugated bilirubin, total bilirubin, and malondialdehyde activities were significantly (P<0.001) up-regulated in MTX-treated rats. However, glutathione, catalase, superoxide dismutase, and glutathione peroxidase activities were significantly (P<0.001) down-regulated in MTX-treated rats. The above hepatotoxic changes were significantly attenuated in rats pre-treated (P<0.001), co-treated (P<0.01), and post-treated (P<0.05) with CT when compared to MTX group.  Conclusion: However, pre-treatment with CT was most effective, hence it may be clinically useful for MTX-induced hepatotoxicity.