Shimada Hiroaki, Ikuta Hiroyuki, Hashimoto Yu, Yabuuchi Yusuke, Kawase Atsushi, Matzno Sumio, Iwaki Masahiro
Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan.
Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan.
J Pharm Sci. 2025 Feb;114(2):1307-1314. doi: 10.1016/j.xphs.2025.01.014. Epub 2025 Jan 26.
Acyl glucuronide (AG) is a reactive metabolite that causes idiosyncratic drug toxicity (IDT). Although the instability of AG is used to predict the IDT risk of novel drug candidates, it sometimes overestimates the IDT risk. We investigated whether the rate of enzymatic AG hydrolysis in human liver microsomes (HLM) can predict the risk of IDT. We used 16 drugs classified into three categories in terms of IDT risk: drugs withdrawn from the market owing to severe IDT (withdrawn, WDN) and drugs still being on the market, regardless of IDT risk (warning, WA) or not (safe, SA). AG was incubated with HLM, and the resulting parent drugs for AG hydrolysis were quantified using HPLC. The rate of enzymatic AG hydrolysis in the HLM of WDN was higher than that in WA and SA, and no difference was observed between WA and SA. We categorized WA and SA as commercially available (CA) drugs and performed a logistic regression analysis. The rate of enzymatic AG hydrolysis in HLM significantly distinguished WDN drugs from CA drugs, with an estimated classification value of 0.189 nmol/min/mg protein. In conclusion, the rate of enzymatic AG hydrolysis in HLM may be useful for predicting the risk in drug development.
酰基葡萄糖醛酸（AG）是一种会导致特异质性药物毒性（IDT）的反应性代谢产物。尽管AG的不稳定性被用于预测新型候选药物的IDT风险，但它有时会高估IDT风险。我们研究了人肝微粒体（HLM）中AG酶促水解速率是否能够预测IDT风险。我们使用了16种根据IDT风险分为三类的药物：因严重IDT而退市的药物（已退市，WDN）以及无论有无IDT风险仍在市场上的药物（有警示，WA）或无警示（安全，SA）。将AG与HLM一起孵育，使用高效液相色谱法（HPLC）对AG水解产生的母体药物进行定量。WDN的HLM中AG酶促水解速率高于WA和SA，且WA和SA之间未观察到差异。我们将WA和SA归类为市售（CA）药物并进行逻辑回归分析。HLM中AG酶促水解速率显著区分了WDN药物和CA药物，估计分类值为0.189 nmol/分钟/毫克蛋白质。总之，HLM中AG酶促水解速率可能有助于预测药物开发中的风险。
