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 is associated with hepatotoxicity characterized by elevations in serum aminotransferases, hepatocyte necrosis and fibrosis. The time of medication administration significantly impacts treatment outcomes. Hence this study evaluated the protective effect of timemodulated cimetidine (CT) against MTXinduced hepatotoxicity in albino rats. Methods: Thirtysix 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 D (pretreatment) was injected IP with CT one hour before MTX administration for 24 h. Group E (cotreatment group) was cotreated IP with CT and MTX for 24 h. Group F (posttreatment group) was treated IP with one dose of MTX one hour before treatment with CT for 24 h. After treatments, the rats were weighed and euthanized. Blood samples were collected and were evaluated for serum liver function markers, also liver samples were excised and used for biochemical and histological studies. Results: The liver of MTXtreated rats was characterized by hepatocyte necrosis. Aminotransferases, gammaglutamyl transferase, lactate dehydrogenase, alkaline phosphatase, conjugated bilirubin, total bilirubin, and malondialdehyde activities were significantly (P 0.001) upregulated in MTXtreated rats. However, glutathione, catalase, superoxide dismutase, and glutathione peroxidase activities were significantly (P 0.001) downregulated in MTXtreated rats. The above hepatotoxic changes were significantly attenuated in rats pretreated (P 0.001), cotreated (P 0.01), and posttreated (P 0.05) with CT when compared to MTX group. Conclusion: Pretreatment with CT was most effective, hence it may be clinically useful as treatment for MTXinduced hepatotoxicity.