Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate

doi:10.1124/dmd.118.081182

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	Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate
	Hou, Xiangyu 1,2; Zhou, Jialan 1; Yu, Songda 1; Zhou, Lei 1; Zhang, Yifan1 ; Zhong, Dafang1,2 ; Chen, Xiaoyan1,2
刊名	DRUG METABOLISM AND DISPOSITION
	2018-09-01
卷号	46 期号:9 页码:1320-1328
ISSN号	0090-9556
DOI	10.1124/dmd.118.081182
文献子类	Article
英文摘要	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 four times higher than those of both M0 and M1 in humans. However, this metabolite is rarely formed in in vitro experiments. Therefore, this 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 (HLMs), human liver cytosols (HLCs), 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 HLMs, mainly mediated by CYP3A4 and CYP2D6, and to subsequently formaldehyde imrecoxib (M-CHO) in HLMs and HLCs. 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 HLMs and HLCs, 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.
资助项目	National Natural Science Foundation of China[81573500] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA 12050306]
WOS关键词	HEALTHY MALE-VOLUNTEERS ; ALCOHOL-DEHYDROGENASE ; CYTOCHROMES P450 ; CYCLOOXYGENASE-2 INHIBITOR ; OXIDATIVE-METABOLISM ; LIVER ; EXCRETION ; CELECOXIB ; REDUCTASE ; ENZYMES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000444250400008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279596]
专题	上海药物代谢研究中心
通讯作者	Chen, Xiaoyan
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Hou, Xiangyu,Zhou, Jialan,Yu, Songda,et al. Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate[J]. DRUG METABOLISM AND DISPOSITION,2018,46(9):1320-1328.
APA	Hou, Xiangyu.,Zhou, Jialan.,Yu, Songda.,Zhou, Lei.,Zhang, Yifan.,...&Chen, Xiaoyan.(2018).Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate.DRUG METABOLISM AND DISPOSITION,46(9),1320-1328.
MLA	Hou, Xiangyu,et al."Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate".DRUG METABOLISM AND DISPOSITION 46.9(2018):1320-1328.