Abstract

1. 8‐[(1H‐1,2,3‐benzotriazol‐1‐yl)amino]octanoic acid (8-BOA) was recently identified as a selective and potent mechanism-based inactivator (MBI) of breast cancer-associated CYP4Z1 and exhibited favourable inhibitory activity in vitro, thus meriting in vivo characterization.

2. The pharmacokinetics and metabolism of 8-BOA in rats was examined after a single IV bolus dose of 10 mg/kg. A biphasic time-concentration profile resulted in relatively low clearance and a prolonged elimination half-life.

3. The major circulating metabolites identified in plasma were products of β-oxidation; congeners losing two and four methylene groups accounted for >50% of metabolites by peak area. The –(CH₂)₂ product was characterized previously as a CYP4Z1 MBI and so represents an active metabolite that may contribute to the desired pharmacological effect.

4. Ex vivo analysis of total CYP content in rat liver and kidney microsomes showed that off-target CYP inactivation was minimal; liver microsomal probe substrate metabolism also demonstrated low off-target inactivation. Standard clinical chemistries provided no indication of acute toxicity.

5. In silico simulations using the free concentration of 8-BOA in plasma suggested that the in vivo dose used here may effectively inactivate CYP4Z1 in a xenografted tumour.

摘要

1. 8-[(1H-1,2,3-苯并三唑-1-基)氨基]辛酸 (8-BOA) 最近被确定为乳腺癌相关 CYP4Z1 的一种选择性且有效的基于机制的灭活剂 (MBI)，并表现出良好的体外抑制活性，因此值得体内表征。

2. 8-BOA 在大鼠中的药代动力学和代谢在单次静脉推注剂量为 10 mg/kg 后进行检查。双相时间-浓度曲线导致相对较低的清除率和较长的消除半衰期。

3. 血浆中鉴定出的主要循环代谢物是β-氧化产物；按峰面积计算，失去两个和四个亚甲基的同类物占代谢物的 50% 以上。–(CH ₂ ) ₂产物之前被表征为 CYP4Z1 MBI，因此代表一种可能有助于实现所需药理作用的活性代谢物。

4. 大鼠肝脏和肾脏微粒体中总 CYP 含量的离体分析表明，CYP 脱靶失活极少；肝微粒体探针底物代谢也表现出低脱靶失活。标准临床化学没有提供急性毒性的迹象。

5. 使用血浆中游离浓度的 8-BOA 的计算机模拟表明，此处使用的体内剂量可以有效地使异种移植肿瘤中的 CYP4Z1 失活。