Nimesulide increases the aldehyde oxidase activity of humans and rats
文献类型：期刊论文
| 作者 | Zhou, Lei; Pang, Xiao-yan; Hou, Xiang-yu; Liu, Lu; Guo, Zi-tao; Chen, Xiao-yan
|
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 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. |
| WOS关键词 | HIGH-DOSE 7-HYDROXYMETHOTREXATE ; TISSUE DISTRIBUTION ; ACUTE TOXICITY ; METHOTREXATE ; LIVER ; METABOLITE ; PHARMACOKINETICS ; RABBIT ; MOUSE ; TRANSFORMATIONS |
| 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研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000508143900002 |
| 出版者 | NATURE PUBLISHING GROUP |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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