title: Toxicological evaluation of acyl glucuronides utilizing half-lives, peptide adducts, and immunostimulation assays.
abstract: Chemical reactivity of acyl glucuronides (AGs) is believed to be involved in the toxicity of carboxylic acid-containing drugs. Both direct and immune-mediated toxicity have been suggested as possible mechanisms of toxicity; however, it remains unclear. In the present study, we performed assays of half-lives, peptide adducts, and immunostimulation to evaluate the potential risk of AGs of 21 drugs and analyzed the relationship to the toxic category. AGs of all withdrawn drugs tested in this study showed short half-lives and peptide adducts formation, but so did those of several safe drugs. In contrast, only AGs of withdrawn and warning drugs induced interleukin-8 (IL-8) in human peripheral blood mononuclear cells (hPBMCs). Using a DNA microarray assay, we found that zomepirac AG induced the mRNAs of 5 genes, including IL-8 in hPBMCs. In addition, withdrawn and warning drugs were distinguished from safe drugs by an integrated score of relative mRNA expression levels of 5 genes. The immunostimulation assay showed higher sensitivity, specificity, and accuracy compared with other methods. In preclinical drug development, the evaluation of the reactivity of AGs using half-lives and peptide adducts assays followed by the evaluation of immunostimulation by highly reactive AGs using hPBMCs can contribute to improved drug safety.
authors.affiliation: DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama 335-8505, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa 920-1192, Japan. Electronic address: Iwamura.Atsushi@mf.mt-pharma.co.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwamura
authors.affiliation: Safety Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Chiba 292-0818, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Ito
authors.affiliation: Safety Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Chiba 292-0818, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mitsui
authors.affiliation: Safety Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Chiba 292-0818, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hasegawa
authors.affiliation: DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama 335-8505, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Kosaka
authors.affiliation: DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama 335-8505, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kino
authors.affiliation: DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama 335-8505, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa 920-1192, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Aichi 466-8550, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
authors.affiliation: DMPK Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama 335-8505, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kume
mesh_terms: D002478:Cells, Cultured; D020719:Glucuronides / Q000493:pharmacokinetics / Q000633:toxicity*; D006207:Half-Life; D006801:Humans; D007114:Immunization; D016209:Interleukin-8 / Q000235:genetics; D010455:Peptides / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D020719:Glucuronides; D016209:Interleukin-8; D010455:Peptides; D012333:RNA, Messenger
keywords: Acyl glucuronides; Drug-induced liver injury; Half-lives assay; Immunostimulation assay; Peptide adducts assay