Nimesulide increases the aldehyde oxidase activity of humans and rats  

作　　者：Lei Zhou Xiao-yan Pang Xiang-yu Hou Lu Liu Zi-tao Guo Xiao-yan Chen 

机构地区：[1]Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China

出　　处：《Acta Pharmacologica Sinica》2020年第6期843-851,共9页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(Grants 81573500 and 81573351);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA 12050306).

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(20μM)for 24 h caused a 2.0-and 3.1-fold,respectively,increase in 7-OH MTX formation.Oral administration of NIM(100 mg·kg^-1·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·kg-1·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.

关 键 词：NIMESULIDE aldehyde oxidase induction METHOTREXATE HEPATOCYTES PHARMACOKINETICS drug interaction 

分 类 号：R965[医药卫生—药理学]