CHARACTERIZATION OF HUMAN CYP450 ISOZYMES RESPONSIBLE FOR THE IN VITRO OXIDATIVE METABOLISM OF MESALAMINE USED FOR COLITIS

Abstract

Mesalamine [5-aminosalicylic acid (5-ASA)] is a substantial supportive agent in the treatment of inflammatory bowel diseases (IBD), particularly in ulcerative colitis (UC). It is well known that 5-ASA is metabolized by phase II enzymes. And most likely cytochrome P450 enzymes have an important role in this process. However, there is no information to the accuracy of this and which CYP isoforms affect this potential pathway of metabolism. In this study, it was aimed to find out whether other alternative drug metabolism pathways other than N-acetylation, are involved in 5-ASA metabolism, particularly cytochrome P450s. For this purpose, first, a colorimetric method was developed to measure the 5-ASA. Then, it was applied to determine whether mesalamine was metabolized by in vitro with each pure CYP450 isozymes (CYP1A2, CYP2C9, CYP3A4, CYP2C19, CYP2D6). It has shown that 5-ASA acted as a substrate for the CYP3A4 and CYP2D6 isoforms. The incubation of pure CYP isoforms in the presence of prototype substrates together with 5-ASA have led to inhibition of prototype activities of CYP3A4 and CYP1A2. As a consequence, this study demonstrated that the 5-ASA is both a substrate and an inhibitor for CYP3A4, a substrate for CYP2D6, and an inhibitor for CYP1A2. Thus, the prescription of mesalamine together with the drugs metabolized with these CYP isozymes could cause unanticipated adverse reactions or therapeutic failures. These are the new contributions to the literature.