Abstract

Off-target Effects of COX-2 Selective Inhibitors Defined by Metabolomics

Cecilia Castro, Research Associate, University of Cambridge

COX-2 selective inhibitors belong to the class of non-steroidal anti-inflammatory drugs (NSAID). They provide analgesic, antipyretic and anti-inflammatory effects and are used for the treatment of rheumatoid arthritis, osteoarthritis, acute pain, and fever. These drugs are designed to reduce inflammation by directly targeting COX-2 without inhibiting the production of prostaglandins by COX-1, avoiding the gastric lesions associated with the consumption of non-selective inhibitors. The aim of this study was to evaluate the effects of the chronic administration of COX-2 selective inhibitors on healthy mice. Two COX-2 selective inhibitors were administered for three weeks to young healthy male mice, together with control, and the effects on metabolism were investigated in the presence or in absence of inflammation induced by interleukin-1. Blood, urine, and selected organs (skeletal muscle, liver, heart, kidney and aorta) were analysed using NMR spectroscopy, GC-MS for the analysis of the fatty acids and LC-MS for the analysis of the carnitines. The main results show changes in the metabolome of the kidney, both in the aqueous and lipid fraction, and an increase in short chain carnitines in the heart and plasma consistent with stimulated beta-oxidation which may contribute to the off-target effects of this class of drugs.