TY - JOUR T1 - Differences of the in vivo and in vitro metabolism of imrecoxib in humans: formation of rate-limiting aldehyde intermediate JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.081182 SP - dmd.118.081182 AU - Xiangyu Hou AU - Jialan Zhou AU - Songda Yu AU - Lei Zhou AU - Yifan Zhang AU - Dafang Zhong AU - Xiaoyan Chen Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/07/06/dmd.118.081182.abstract N2 - Imrecoxib is a typical cyclooxygenase-2 inhibitor and the benzylic carbon motif is its major site of oxidative metabolism, producing a hydroxymethyl metabolite (M1) and a carboxylic acid metabolite (M2). The plasma exposure of M2 is both four times higher than those of M0 and M1 in humans. However, this metabolite is rarely formed in in vitro experiments. Therefore, the present study aims to investigate the formation mechanism of M2, and to further elucidate the reason for the discrepancy between in vitro and in vivo metabolic data. By employing human hepatocytes, human liver microsomes (HLM), human liver cytosols (HLC), recombinant enzymes, and selective enzyme inhibitors, the metabolic map of imrecoxib was elaborated as follows: the parent drug was initially hydroxylated to form M1 in HLM, mainly mediated by CYP3A4 and CYP2D6; and subsequently form aldehyde imrecoxib (M-CHO) in HLM and HLC. The latter process is the rate-limiting step in generating the end-product M2. In further M-CHO metabolism, two opposite reactions namely, rapid oxidation catalyzed by CYP3A4, CYP2D6, and cytosolic aldehyde oxidase to form M2 versus reduction to regenerate M1 mediated by NADPH-dependent reductases in HLM and HLC, such as cytochrome P450 reductase, led to marked underestimation of the M2 amount in static in vitro incubations. The findings provided a possible explanation for the difference between in vitro and in vivo metabolism of imrecoxib, suggesting that the effect of competitive reduction on the static oxidation metabolism in in vitro metabolic experiments should be considered. ER -