Nimesulide increases the aldehyde oxidase activity of humans and rats

doi:10.1038/s41401-019-0336-3

	Nimesulide increases the aldehyde oxidase activity of humans and rats
	Zhou, Lei; Pang, Xiao-yan; Hou, Xiang-yu; Liu, Lu; Guo, Zi-tao; Chen, Xiao-yan
刊名	ACTA PHARMACOLOGICA SINICA
	2020-01-08
页码	9
关键词	nimesulide aldehyde oxidase induction methotrexate hepatocytes pharmacokinetics drug interaction
ISSN号	1671-4083
DOI	10.1038/s41401-019-0336-3
通讯作者	Chen, Xiao-yan(xychen@simm.ac.cn)
英文摘要	An increasing number of drugs are metabolized by aldehyde oxidase (AOX), but AOX-mediated drug interactions are seldom reported due to the lack of appropriate inhibitors and inducers. A recent study reported that nimesulide (NIM) could increase the liver injury risk of methotrexate. The latter was mainly metabolized by AOX to form hepatotoxic 7-hydroxymethotrexate (7-OH MTX). Thus, we speculated that NIM could induce AOX. In this study, we investigated the potential induction of AOX activity by NIM using methotrexate as the probe substrate. Treatment of primary human and rat hepatocytes with NIM (20 mu M) for 24 h caused a 2.0- and 3.1-fold, respectively, increase in 7-OH MTX formation. Oral administration of NIM (100 mg center dot kg(-1)center dot d(-1), for 5 days) to rats significantly increased the systematic exposure (6.5-fold), liver distribution (2.5-fold), and excretion (5.2-fold for urinary excretion and 2.1-fold for fecal excretion) of 7-OH MTX. The 7-OH MTX formation in liver cytosol from rats pretreated with 20, 50, and 100 mg center dot kg(-1)center dot d(-1) NIM for 5 days increased by 1.9-, 3.2-, and 3.7-fold, respectively, compared with that of rats pretreated with the vehicle. We revealed that the elevation of AOX activity was accompanied by an increase in AOX1 protein levels but not the corresponding mRNA levels. Collectively, our results demonstrate for the first time that NIM can increase the AOX activity of humans and rats, and may raise concerns regarding the risk of drug interactions between NIM and AOX substrates in clinical practice.
资助项目	National Natural Science Foundation of China[81573500] ; National Natural Science Foundation of China[81573351] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA 12050306]
WOS关键词	HIGH-DOSE 7-HYDROXYMETHOTREXATE ; TISSUE DISTRIBUTION ; ACUTE TOXICITY ; METHOTREXATE ; LIVER ; METABOLITE ; PHARMACOKINETICS ; RABBIT ; MOUSE ; TRANSFORMATIONS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000508143900002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282445]
专题	中国科学院上海药物研究所
通讯作者	Chen, Xiao-yan
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Lei,Pang, Xiao-yan,Hou, Xiang-yu,et al. Nimesulide increases the aldehyde oxidase activity of humans and rats[J]. ACTA PHARMACOLOGICA SINICA,2020:9.
APA	Zhou, Lei,Pang, Xiao-yan,Hou, Xiang-yu,Liu, Lu,Guo, Zi-tao,&Chen, Xiao-yan.(2020).Nimesulide increases the aldehyde oxidase activity of humans and rats.ACTA PHARMACOLOGICA SINICA,9.
MLA	Zhou, Lei,et al."Nimesulide increases the aldehyde oxidase activity of humans and rats".ACTA PHARMACOLOGICA SINICA (2020):9.