Abstract
Opicapone, is a novel catechol‐O‐methyltransferase inhibitor, currently in phase III of clinical trials. In this study the glucuronide derivatives of opicapone, as well as the other detected opicapone metabolites, were quantified in mouse plasma and the enzymes involved in opicapone glucuronidation in humans were investigated. Following orally administration to mouse, opicapone reached plasma Cmax within 1 h and was completely eliminated from circulation by 48 h. Although opicapone sulphate and nitro reduced derivatives were detected, the primary metabolic pathway of opicapone in mouse model involved 3‐O‐glucuronidation. Opicapone glucuronidation was observed in liver and intestinal human microsomes with a Km of 27.9±6.47 µM and 41.9±26.9 µM, respectively. Among the 12 commercially available human recombinant UGT enzymes, only UGT 1A7, 1A8, 1A9 and 1A10 exhibited high opicapone glucuronidation specific activity. UGTs 1A1, 1A3 and 2B7 exhibited low glucuronidation rate, whereas no glucuronidation was observed with 1A4, 2B15, 2B17 and 2B4. UGT 1A9 had the highest formation rate of 3‐O‐glucuronide‐opicapone, with a Km similar to that obtained for UGT 1A1 and UGT 2B7 but with significantly higher intrinsic clearance. Nevertheless multiple UGT enzymes, most notable UGT 1A9 widely expressed in human liver, seems to be involved in the opicapone glucuronidation.
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