A 38-year-old male sustained sequential anaphylactoid reactions to tolmetin and zomepirac. This is the first report involving these closely related non-steroidal anti-inflammatory drugs (NSAID) in a single patient. He was historically tolerant of other NSAID and tolerated a graded oral aspirin challenge (up to 625 mg) without reaction. Skin testing with aqueous albumin extracts of tolmetin and zomepirac was negative. These reactions appear to differ from previously described aspirin (NSAID) sensitivity. Physicians should beware of interrupted treatment with either of these preparations.
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Chem Biol Interact
January 2018
Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Acyl glucuronide (AG) metabolites of carboxylic acid-containing drugs have been implicated in drug toxicity. Zomepirac (ZP) is a non-steroidal anti-inflammatory drug that was withdrawn from the market because of anaphylactic reactions and renal injury. We recently established a novel mouse model of ZP-induced kidney injury by increasing zomepirac acyl-glucuronide (ZP-AG) concentration via pretreatment with tri-O-tolyl phosphate, a nonselective esterase inhibitor, and l-buthionine-(S,R)-sulfoximine, a glutathione synthesis inhibitor.
View Article and Find Full Text PDFDrug Metab Dispos
July 2016
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.).
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 Zomepirac (ZP) was withdrawn from the market because of adverse effects such as renal toxicity.
View Article and Find Full Text PDFChem Res Toxicol
December 2015
Admescope Ltd. , Typpitie 1, 90620 Oulu, Finland.
Many carboxylic acid-containing drugs are associated with idiosyncratic drug toxicity (IDT), which may be caused by reactive acyl glucuronide metabolites. The rate of acyl migration has been earlier suggested as a predictor of acyl glucuronide reactivity. Additionally, acyl Coenzyme A (CoA) conjugates are known to be reactive.
View Article and Find Full Text PDFXenobiotic carboxylic acids may be metabolized to oxidative metabolites, acyl glucuronides, and/or S-acyl-CoA thioesters (CoA conjugates) in vitro, e.g., in hepatocytes, and in vivo.
View Article and Find Full Text PDFToxicol In Vitro
August 2014
Preclinical Development, Almirall, S.A, Sant Feliu de Llobregat, Barcelona, Spain.
The formation of reactive oxygen species (ROS) could cause cellular damage and eventually lead to apoptosis and necrosis. The ratio between oxidized glutathione and reduced glutathione (GSSG-to-GSH ratio) has been used as an important in vitro and in vivo biomarker of the redox balance in the cell and consequently of cellular oxidative stress. This paper optimizes a LC-MS/MS method for the simultaneous determination of GSH and GSSG.
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