Hiromachi, Shinagawa-ku, Tokyo, Japan.
Drug Metab Dispos. 2010 Oct;38(10):1857-64. doi: 10.1124/dmd.110.034173. Epub 2010 Jul 6.
Acyl glucuronides (AGs) formed from carboxylic acid-containing drugs have been considered to be a cause of idiosyncratic drug toxicity (IDT). Chemical stability of AGs is supposed to relate to their reactivity. In this study, the half-lives of 21 AGs of carboxylic drugs in potassium phosphate buffer (KPB), human serum albumin (HSA) solution, and human fresh plasma were analyzed in relation to the IDT risk derived from these drugs. The carboxylic drugs were classified into three safety categories of "safe," "warning," and "withdrawn" in terms of their IDT risk. As for the results, the half-lives of AGs in KPB correlated with the IDT risk better than those in HSA solution or in human fresh plasma with regard to the separation of the safe drugs from the warning drugs or the withdrawn drugs. In KPB, whereas the half-lives in the safe category were 7.2 h or longer, those in the withdrawn category were 1.7 h or shorter. The classification value of the half-life in KPB, which separated the safe drugs from the withdrawn drugs was calculated to be 3.6 h by regression analysis. In conclusion, this is the first report that clearly shows the relationship between the IDT risk and chemical stability of AGs in several in vitro systems. The KPB system was considered to be the best for evaluating the stability of AGs, and the classification value of the half-life in KPB serves as a useful key predictor for the IDT risk.
酰基葡萄糖醛酸（AGs）是由含有羧酸的药物形成的，被认为是造成药物特异质毒性（IDT）的原因之一。AGs 的化学稳定性被认为与其反应性有关。在这项研究中，分析了 21 种羧酸类药物的 AG 在磷酸钾缓冲液（KPB）、人血清白蛋白（HSA）溶液和人新鲜血浆中的半衰期，与这些药物的 IDT 风险有关。根据 IDT 风险，将羧酸类药物分为“安全”、“警告”和“撤市”三个安全类别。结果表明，就安全药物与警告药物或撤市药物的分离而言，AG 在 KPB 中的半衰期与 IDT 风险的相关性优于在 HSA 溶液或人新鲜血浆中的半衰期。在 KPB 中，安全类别的半衰期为 7.2 小时或更长，撤市类别的半衰期为 1.7 小时或更短。通过回归分析，计算出 KPB 中半衰期的分类值为 3.6 小时，可将安全药物与撤市药物分开。总之，这是第一个明确显示几种体外系统中 IDT 风险与 AG 化学稳定性之间关系的报告。KPB 系统被认为是评估 AG 稳定性的最佳系统，KPB 中半衰期的分类值可作为 IDT 风险的有用关键预测指标。
