title: Protective effect of infliximab on methotrexate-induced liver injury in rats: unexpected drug interaction.
abstract: OBJECTIVE
  Although methotrexate (mtx) is a widely used agent to treat cancer and inflammatory diseases, its hepatotoxic effect limits for clinical utility. We aimed to investigate whether infliximab (inf), an inhibitor of tumor necrosis factor-alpha (TNF-α) has a protective effect against mtx-induced hepatotoxicity.
  
  
  METHODS
  For mtx group, the animals received an intraperitoneal single dose injection of mtx at a dose of 20 mg/kg. For inf group, the animals received an intraperitoneal single dose injection of inf at a dose of 7 mg/kg. For mtx + inf group, the single dose of inf at a dose of 7 mg/kg was given 72 h prior to mtx injection. After 72 h, a single dose of mtx 20 mg/kg was given. All rats were sacrificed 5 days after mtx injection.
  
  
  RESULTS
  TNF-α and nitric oxide (NO) levels of mtx group was significantly higher than the control (P < 0.001), inf (P < 0.001) and mtx + inf (P < 0.001) groups. Total score of histological damage was higher in the mtx group when compared with the mtx + inf group. Arginase and carbamoyl phosphate synthetase 1 (CPS-1) of mtx group was suppressed in comparison with the control group and was markedly increased in mtx + inf group.
  
  
  CONCLUSIONS
  Inf may partially prevent mtx-induced hepatic damage in rats. However, the combined usage of mtx and inf increases arginase and CPS-1 enzyme activities and at the same time blocks TNF-α. This combination especially in cancer patients may lead to cancer cell invasion and metastasis.
authors: Department of Internal Medicine, School of Medicine, Recep Tayyip Erdogan University, Rize, Turkey.
authors: Erkan
authors: E
authors: Cure
authors: Aynur
authors: A
authors: Kirbas
authors: Levent
authors: L
authors: Tumkaya
authors: Medine Cumhur
authors: MC
authors: Cure
authors: Yildiray
authors: Y
authors: Kalkan
authors: Arif
authors: A
authors: Yilmaz
authors: Suleyman
authors: S
authors: Yuce
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D000069285:Infliximab / Q000008:administration & dosage / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D009569:Nitric Oxide / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D053583:Interleukin-1beta; D020011:Protective Agents; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000069285:Infliximab; D008727:Methotrexate