TY - JOUR T1 - Zomepirac Acyl Glucuronide Is Responsible for Zomepirac-induced Acute Kidney Injury in Mice JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.116.069575 SP - dmd.116.069575 AU - Atsushi Iwamura AU - Katsuhito Watanabe AU - Sho Akai AU - Tsubasa Nishinosono AU - Koichi Tsuneyama AU - Shingo Oda AU - Toshiyuki Kume AU - Tsuyoshi Yokoi Y1 - 2016/01/01 UR - http://dmd.aspetjournals.org/content/early/2016/04/25/dmd.116.069575.abstract N2 - Glucuronidation, an important phase II metabolic route, is generally considered to be a detoxification pathway. However, acyl glucuronides (AGs) have been implicated in the toxicity of carboxylic acid drugs due to their electrophilic reactivity. Zomepirac (ZP) was withdrawn from the market because of adverse effects such as renal toxicity. Although ZP is mainly metabolized to acyl glucuronide (ZP-AG) by UDP-glucuronosyltransferase, the role of ZP-AG in renal toxicity is unknown. In this study, we established a ZP-induced kidney injury mouse model by pretreatment with tri-o-tolyl phosphate (TOTP), a non-selective esterase inhibitor, and L-buthionine-(S,R)-sulfoximine (BSO), a glutathione synthesis inhibitor. The role of ZP-AG in renal toxicity was investigated using this model. The model showed significant increases in blood urea nitrogen (BUN) and creatinine (CRE), but not alanine aminotransferase. The ZP-AG concentrations were elevated by co-treatment with TOTP in the plasma and liver and especially in the kidney. The ZP-AG concentrations in the kidney correlated with values for BUN and CRE. Upon histopathological examination, vacuoles and infiltration of mononuclear cells were observed in the model mouse. In addition to immune-related responses, oxidative stress markers such as the glutathione/disulfide glutathione ratio and malondialdehyde levels were different in the mouse model. The suppression of ZP-induced kidney injury by tempol, an antioxidant agent, suggested the involvement of oxidative stress in ZP-induced kidney injury. This is the first study to demonstrate that AG accumulation in the kidney by TOTP and BSO treatment could explain renal toxicity and to show the in vivo toxicological potential of AGs. ER -