Zomepirac Acyl Glucuronide Is Responsible for Zomepirac-Induced Acute Kidney Injury in Mice.
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 Zomepirac (ZP) was withdrawn from the market because of adverse effects such as renal toxicity.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 nonselective 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 cotreatment 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.
Drug Metabolism and Pharmacokinetics Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (A.I., T.K.); Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan (K.W., S.A., T.N., S.O., T.Y.); Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima, Japan (K.T.); and Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan (A.I.) Iwamura.Atsushi@mf.mt-pharma.co.jp.
Atsushi
A
Iwamura
Drug Metabolism and Pharmacokinetics Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (A.I., T.K.); Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan (K.W., S.A., T.N., S.O., T.Y.); Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima, Japan (K.T.); and Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan (A.I.).
Katsuhito
K
Watanabe
Drug Metabolism and Pharmacokinetics Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (A.I., T.K.); Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan (K.W., S.A., T.N., S.O., T.Y.); Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima, Japan (K.T.); and Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan (A.I.).
Sho
S
Akai
Drug Metabolism and Pharmacokinetics Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (A.I., T.K.); Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan (K.W., S.A., T.N., S.O., T.Y.); Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima, Japan (K.T.); and Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan (A.I.).
Tsubasa
T
Nishinosono
Drug Metabolism and Pharmacokinetics Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (A.I., T.K.); Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan (K.W., S.A., T.N., S.O., T.Y.); Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima, Japan (K.T.); and Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan (A.I.).
Koichi
K
Tsuneyama
Drug Metabolism and Pharmacokinetics Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (A.I., T.K.); Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan (K.W., S.A., T.N., S.O., T.Y.); Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima, Japan (K.T.); and Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan (A.I.).
Shingo
S
Oda
Drug Metabolism and Pharmacokinetics Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (A.I., T.K.); Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan (K.W., S.A., T.N., S.O., T.Y.); Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima, Japan (K.T.); and Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan (A.I.).
Toshiyuki
T
Kume
Drug Metabolism and Pharmacokinetics Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan (A.I., T.K.); Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan (K.W., S.A., T.N., S.O., T.Y.); Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima, Japan (K.T.); and Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan (A.I.).
Tsuyoshi
T
Yokoi
D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D001711:Biotransformation; D001806:Blood Urea Nitrogen; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects; D013113:Spin Labels; D013997:Time Factors; D014046:Tolmetin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity; D014317:Tritolyl Phosphates / Q000494:pharmacology
D000975:Antioxidants; D015415:Biomarkers; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D013113:Spin Labels; D014317:Tritolyl Phosphates; D019328:Buthionine Sulfoximine; C027368:zomepirac glucuronide; C020549:zomepirac; D003404:Creatinine; D014046:Tolmetin; C001803:tempol; C025541:tri-o-cresyl phosphate