Glucuronidation of fimasartan, a new angiotensin receptor antagonist, is mainly mediated by UGT1A3

• DOI: 10.3109/00498254.2014.942810
• Publication Date: 2014-07-18T11:13:14Z
• Authors: Eun-Sook Jeong; Yang-Weon Kim; Hyo-Ji Kim; Ho-Jung Shin; Jae-Gook Shin; Kwang Hee Kim; Yong Ha Chi; Soo Heui Paik; Dong-Hyun Kim
• Keywords: UGT2B7; Glucuronide; Glucuronosyltransferase

1. Fimasartan is an angiotensin receptor II antagonist used to treat patients with hypertension. This drug mainly excreted into bile as either the parent compound or a glucuronide conjugate. In this study, we examined glucuronidation of fimasartan and characterized UDP-glucuronosyltransferases (UGTs) responsible for glucuronidation.2. Only one type was observed after incubation pooled human liver microsomes (HLMs) identified N2-glucuronide based on comparison authentic standard.3. Among 12 UGT isoforms tested, UGT1A1, UGT1A3 UGT2B7 showed catalytic activity toward glucuronidation. The intrinsic clearance (CLint) 68.5- 21.4-fold higher than that UGT1A1 UGT2B7, respectively, estimated relative contribution in 94.1%. Both chemical inhibition correlation studies demonstrated HLMs significantly related activity. substrate P-glycoprotein (Pgp) breast cancer response protein (BCRP).4. These findings collectively indicate major isoform fimasartan, from hepatocytes via MDR1 BCRP.