AB0200 CYP2C9 Activity in Turkish Patients with Rheumatoid Arthritis

BackgroundRheumatoid arthritis (RA) is a chronic, autoimmune, multisystemic, inflammatory and common disease with unknown etiology. Cytochrome P450 2C9 (CYP2C9) is responsible for up to 40 drugs metabolism in the liver such as oral anticoagulants (warfarin), oral antidiabetics (tolbutamide, glyburide), angiotensin II receptor antagonists (losartan, irbesartan), phenytoin (1). Most of the drugs convert to active or inactive metabolites by CYP2C9. In a recent study Goktas MT et al. showed that CYP2C9 activity reduced in Behçet's disease that an autoimmune disease (2).ObjectivesThis study aimed to investigate activity of CYP2C9 in patients with RA.MethodsLosartan and its metabolite (E-3174) concentrations were analysed in healthy subjects (n=38) and RA patients (n=32) urine by high-performance liquid chromatography (HPLC). A acetonitrile and 66/34 mixture of phosphate tamponate (NaH2PO4, 15 mM, pH=2.8) were used as mobile phase. Urine samples in mobile phase and isopropanol (2/1/1 in volume, respectively) were injected into Agilent Eclipse XDB-C18 (5 μm, 4.6x150 mm) column via Agilent Technologies 1200 HPLC system (Agilent Technologies, Waldbron, Germany). Losartan and its metabolite E-3174 were detected via a UV detector at 245 nm. The inter- and intra-day coefficient of variation (CV) was less than %4 for losartan and its metabolite. The ratio of losartan to its metabolite (E-3174) was calculated (metabolic ratio, MR) and used as a marker of the activity of the CYP2C9 enzyme.ResultsMR (losartan/its metabolite ratio) was increased in RA patients from 1.34±0.22 to 1.75±0.31. This result shows that CYP2C9 activity decreased in RA patients compared with healthy subjects.ConclusionsCYP2C9 activity decreased in RA patients so we must be carefully when using the drugs that metabolized with CYP2C9. The efficacy of some treatments would be compromised in RA patients because they were given drugs in dosages that might be ineffective or cause adverse drug reaction and toxicity. This study is continued at other centers.ReferencesHatta FH, Teh LK, Helldén A, Hellgren KE, Roh HK, Salleh MZ, Aklillu E, Bertilsson L. Search for the molecular basis of ultra-rapid CYP2C9-catalysed metabolism: relationship between SNP IVS8–109A>T and the losartan metabolism phenotype in Swedes. Eur J Clin Pharmacol. 2012;68(7):1033–42.Goktaş MT, Hatta F, Karaca O, Kalkisim S, Kilic L, Akdogan A, Babaoglu MO, Bozkurt A, Helldén A, Bertilsson L, Yasar U. Lower CYP2C9 activity in Turkish patient