Iwamura Atsushi, Nakajima Miki, Oda Shingo, Yokoi Tsuyoshi
DMPK Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda 335-8505, Japan.
Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Drug Metab Pharmacokinet. 2017 Feb;32(1):2-11. doi: 10.1016/j.dmpk.2016.11.002. Epub 2016 Nov 23.
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.
特异质性药物毒性（IDT）是药物研发中的一个严重问题。反应性代谢物被认为是IDT的原因之一。除了酰基葡糖醛酸（AGs）外，共轭代谢物通常无反应性，而AGs具有足够的反应性，能够与内源性蛋白质共价结合。因此，有人提出AGs会导致含羧酸药物引起的IDT。羧酸残基的葡糖醛酸化由UDP-葡糖醛酸基转移酶1A和2B亚型催化。不稳定的AGs会发生分子内重排以及非酶促和酶促水解。对于大量的AGs，其对蛋白质的不稳定性和反应性已得到充分研究。此外，在新化学实体筛选中，AGs在中性缓冲液中的半衰期正成为预测含羧酸药物毒性的常用指标；然而，毒性的潜在机制尚未阐明。最近，有人提出了一种免疫刺激试验来评估AGs的毒理学潜力，与半衰期和肽加合物试验相比，该试验可能具有更好的预测性。除了体外研究外，在模型动物中的研究表明了AGs的体内毒理学潜力，并有助于了解AGs毒性的机制。
