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Toxicological potential of acyl glucuronides and its assessment.

Authors
  • Iwamura, Atsushi1
  • Nakajima, Miki2
  • Oda, Shingo3
  • Yokoi, Tsuyoshi3
  • 1 DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda 335-8505, Japan. Electronic address: [email protected] , (Japan)
  • 2 Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. , (Japan)
  • 3 Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. , (Japan)
Type
Published Article
Journal
Drug metabolism and pharmacokinetics
Publication Date
Feb 01, 2017
Volume
32
Issue
1
Pages
2–11
Identifiers
DOI: 10.1016/j.dmpk.2016.11.002
PMID: 28017536
Source
Medline
Keywords
License
Unknown

Abstract

Idiosyncratic drug toxicity (IDT) is a serious problem in drug development. Reactive metabolites are postulated to be one of the causes for IDT. Conjugated metabolites are generally non-reactive except for acyl glucuronides (AGs), which are sufficiently reactive to covalently bind to endogenous proteins. Thus, it has been suggested that AGs would contribute to IDT caused by carboxylic acid-containing drugs. Glucuronidation of a carboxylate residue is catalyzed by UDP-glucuronosyltransferase 1A and 2B isoforms. Unstable AGs undergo intramolecular rearrangements as well as non-enzymatic and enzymatic hydrolysis. The instability and reactivity toward proteins have been well studied for a large number of AGs. Moreover, the half-life of AGs in neutral buffer is becoming a common marker for the prediction of toxicity caused by carboxylic acid-containing drugs in the screening of new chemical entities; however, the underlying mechanisms of the toxicity are not elucidated. Recently, an immunostimulation assay has been proposed for the assessment of the toxicological potential of AGs, which may have a better predictability compared with half-life and peptide adduct assays. In addition to in vitro studies, studies in model animals indicate the in vivo toxicological potential of AGs and help understand the mechanisms of the AG toxicity.

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