Identification of Enzymes Responsible for the N-Oxidation of Darexaban Glucuronide, the Pharmacologically Active Metabolite of Darexaban, and the Glucuronidation of Darexaban N-Oxides in Human Liver Microsomes

Darexaban maleate is a novel oral direct factor Xa inhibitor. Darexaban glucuronide (YM-222714) was the major component in plasma after oral administration of darexaban to humans and is the pharmacologically active metabolite. Additionally, YM-222714 N-oxides were detected as minor metabolites in human plasma and urine. It is possible that YM-222714 N-oxides are formed by the N-oxidation of YM-222714 and/or the glucuronidation of darexaban N-oxides (YM-542845) in vivo. The former reaction is the pharmacological inactivation process. In this study, we identified the human enzymes responsible for YM-222714 N-oxidation and the uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) isoforms involved in YM-542845 glucuronidation in vitro. YM-222714 N-oxidation activity was detected in human liver microsomes (HLM), but not in human intestinal microsomes. In HLM, YM-222714 N-oxidation activities were significantly correlated with flavin-containing monooxygenase (FMO) marker enzyme activities (p