Toxicological evaluation of acyl glucuronides utilizing half-lives, peptide adducts, and immunostimulation assays
| Autor: | Jun Hasegawa, Keigo Kosaka, Tsuyoshi Yokoi, Ichiro Kino, Atsushi Iwamura, Masahito Ito, Miki Nakajima, Toshiyuki Kume, Hideaki Mitsui, Minoru Tsuda |
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| Rok vydání: | 2015 |
| Předmět: |
Drug
Microarray media_common.quotation_subject Peptide Pharmacology Toxicology Peripheral blood mononuclear cell Glucuronides Zomepirac medicine Humans RNA Messenger Interleukin 8 Cells Cultured media_common chemistry.chemical_classification Chemistry Interleukin-8 General Medicine Pre-clinical development Biochemistry Toxicity Immunization Peptides Half-Life medicine.drug |
| Zdroj: | Toxicology in Vitro. 30:241-249 |
| ISSN: | 0887-2333 |
| Popis: | 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 AGs of all withdrawn drugs tested in this study showed short half-lives and peptide adducts formation, but so did those of several safe drugs. In contrast, only AGs of withdrawn and warning drugs induced interleukin-8 (IL-8) in human peripheral blood mononuclear cells (hPBMCs).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 In addition, withdrawn and warning drugs were distinguished from safe drugs by an integrated score of relative mRNA expression levels of 5 genes.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. |
| Databáze: | OpenAIRE |
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