Toxicological potential of acyl glucuronides and its assessment

被引:40
|
作者
Iwamura, Atsushi [1 ]
Nakajima, Miki [2 ]
Oda, Shingo [3 ]
Yokoi, Tsuyoshi [3 ]
机构
[1] Mitsubishi Tanabe Pharma Corp, DMPK Res Labs, 2-2-50 Kawagishi, Toda, Saitama 3358505, Japan
[2] Kanazawa Univ, Fac Pharmaceut Sci, Kakuma Machi, Kanazawa, Ishikawa 9201192, Japan
[3] Nagoya Univ, Grad Sch Med, Dept Drug Safety Sci, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan
关键词
Acyl glucuronide; Drug development; Drug toxicity; In vitro screening; In vivo model; Immune activation; Protein adduct; Reactive metabolite; UDP-glucuronosyltransferase; HUMAN LIVER-MICROSOMES; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; HUMAN SERUM-ALBUMIN; HUMAN UDP-GLUCURONOSYLTRANSFERASE; TANDEM MASS-SPECTROMETRY; RENAL-TRANSPLANT RECIPIENTS; PROTEIN ADDUCT FORMATION; GLYCATION END-PRODUCTS; UGT-MEDIATED BIOACTIVATION; IN-VITRO GLUCURONIDATION;
D O I
10.1016/j.dmpk.2016.11.002
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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. (C) 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
引用
收藏
页码:2 / 11
页数:10
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