Effects of simvastatin, atorvastatin, ezetimibe, and ezetimibe + simvastatin combination on the inflammatory process and on the liver metabolic changes of arthritic rats

• Published in: Fundamental & clinical pharmacology Vol. 26; no. 6; pp. 722 - 734
• Main Authors: Bracht, Lívia, Barbosa, Carmem Patrícia, Caparroz-Assef, Silvana Martins, Cuman, Roberto Kenji Nakamura, Ishii-Iwamoto, Emy Luiza, Bracht, Adelar, Bersani-Amado, Ciomar Aparecida
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2012; Blackwell
• Subjects: adjuvant arthritis; Alanine; Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - adverse effects; Anti-Inflammatory Agents - therapeutic use; Arthritis; Arthritis, Experimental - blood; Arthritis, Experimental - drug therapy; Arthritis, Experimental - metabolism; Atorvastatin; Atorvastatin Calcium; Azetidines - administration & dosage; Azetidines - therapeutic use; Biological and medical sciences; Cholesterol; Diseases of the osteoarticular system; Drug Therapy, Combination; Ezetimibe; ezetimibe + simvastatin combination; Freund's adjuvant; Glucose; Heptanoic Acids - administration & dosage; Heptanoic Acids - adverse effects; Heptanoic Acids - therapeutic use; Inflammation; Inflammatory joint diseases; Joint diseases; Kidney; Leukocyte Count; Leukocytes - cytology; Leukocytes - drug effects; Liver; Liver - drug effects; Liver - enzymology; Liver - metabolism; Liver Function Tests; Medical sciences; mineral oil; Mycobacterium tuberculosis; Oxygen; Perfusion; Pharmacology. Drug treatments; Pyrroles - administration & dosage; Pyrroles - adverse effects; Pyrroles - therapeutic use; Rats; Rats, Sprague-Dawley; Simvastatin; Simvastatin - administration & dosage; Simvastatin - adverse effects; Simvastatin - therapeutic use; Spleen; transaminase; Animal model; Rat; Liver; Diseases of the osteoarticular system; Ezetimibe; Autoimmune disease; Inflammatory joint disease; adjuvant arthritis; Hypocholesterolemic agent; HMG-CoA reductase inhibitor; Drug; Immunopathology; Digestive system; Enzyme; Simvastatin; Rodentia; Enzyme inhibitor; Statin derivative; Inflammation; Metabolism; Vertebrata; Chronic; Mammalia; Animal; Rheumatoid arthritis; Atorvastatin; Hydroxymethylglutaryl-CoA reductase; liver metabolism; Oxidoreductases; Pharmacokinetics; ezetimibe + simvastatin combination; Antilipemic agent
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1111/j.1472-8206.2011.00976.x

In this study, simvastatin, atorvastatin, ezetimibe, and ezetimibe + simvastatin combination were administered to arthritic rats, first to determine their effects on the inflammatory response, employing a low‐dose adjuvant‐induced arthritis model in rats. Arthritis was induced by the subcutaneous injection of a suspension of Mycobacterium tuberculosis (100 μg) in mineral oil [complete Freund’s adjuvant used (CFA)] into the plantar surface of the hind paws. Simvastatin40mg/kg, atorvastatin10mg/kg, ezetimibe10mg/kg, ezetimibe10mg/kg + simvastatin20mg/kg or 40mg/kg were given intragastrically and the treatment began on the day of CFA injection and continued daily up to the 28th day after arthritis induction. The ezetimibe + simvastatin combination was more effective in reducing the inflammatory response in arthritic rats than in atorvastatin, simvastatin, or ezetimibe monotherapy. The observed effect seems to be cholesterol‐independent as there were no changes in plasma cholesterol levels. In spite of the benefits on joint lesions, treatment with ezetimibe + simvastatin combination caused a marked increment in liver, kidneys, spleen size, and plasma transaminases activities. Therefore, animals treated with the ezetimibe10mg/kg + simvastatin40mg/kg combination were also submitted to liver perfusion experiments. In this regard, ezetimibe + simvastatin did not improve the liver metabolic alterations seen in control arthritic rats, on the contrary, a worsening was observed in liver production of glucose from alanine, as well as in oxygen uptake. All of these metabolic changes appear to be induced by treatment with ezetimibe + simvastatin combination, as the same metabolic effects were observed in normal and treated arthritic animals.