Elias Adikwu - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa Stae, Nigeria.
Emmanuel Nnaedozie - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Madonna University, Elele, Rivers State, Nigeria.

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 time-modulated cimetidine (CT) against MTX-induced hepatotoxicity in albino rats. Methods: Thirty-six adult male albino rats were randomized into ۶ groups. Group A (control) was injected intraperitoneally (IP) with normal saline (۰.۲ mL) for ۲۴ h. Group B received CT (۲۰ mg/kg IP) for ۲۴ h. Group C was treated IP with MTX (۲۰ mg/kg) for ۲۴ h. Group D (pre-treatment) was injected IP with CT one hour before MTX administration for ۲۴ h. Group E (co-treatment group) was co-treated IP with CT and MTX for ۲۴ h. Group F (post-treatment group) was treated IP with one dose of MTX one hour before treatment with CT for ۲۴ 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 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<۰.۰۰۱) up-regulated in MTX-treated rats. However, glutathione, catalase, superoxide dismutase, and glutathione peroxidase activities were significantly (P<۰.۰۰۱) down-regulated in MTX-treated rats. The above hepatotoxic changes were significantly attenuated in rats pre-treated (P<۰.۰۰۱), co-treated (P<۰.۰۱), and post-treated (P<۰.۰۵) with CT when compared to MTX group.  Conclusion: Pre-treatment with CT was most effective, hence it may be clinically useful as treatment for MTX-induced hepatotoxicity.

Methotrexate, Liver, Toxicity, Cimetidine, Time