Abstract

1. The disposition of radioactivity following subcutaneous ¹⁴C-razuprotafib, a Tie2 activator, was explored in multiple species.

2. The absorption and clearance of razuprotafib and total radioactivity in human plasma are rapid and pharmacokinetics support razuprotafib as primary circulating component. Radioactivity is distributed greater to human plasma than whole blood (B:P = 0.36).

3. In pigmented rats, radioactivity distributes to whole-body tissues rapidly and, within 24 h, is localised to elimination pathway end organs and injection site.

4. Overall recovery of radioactivity across species is >93%, with the majority recovered within 24–48 h, and >80% in faeces.

5. The CYP2C8 enzyme contributes significantly to razuprotafib metabolism.

6. A hydrolysis product of razuprotafib (m/z⁻ 380) is the main component in rat plasma at 2 h (49% peak area radioactivity), while razuprotafib (m/z⁻ 585) is the main component in plasma for dog (58%), monkey (99.3%), and human (100%).

7. Razuprotafib is present in dog, monkey, and human faeces, with the greatest percentage of radioactivity as metabolites. The major metabolite (>25%) in monkey and human, m/z⁻ 633, is an S-methylated oxidised derivative of razuprotafib and is localised in faeces.

8. Overall disposition of ¹⁴C-razuprotafib in human is best modelled by monkey over lower order species.

摘要

1. 在多个物种中探索了皮下¹⁴ C-razuprotafib（一种 Tie2 激活剂）后的放射性处置。

2. razuprotafib 的吸收和清除以及人血浆中的总放射性迅速，药代动力学支持 razuprotafib 作为主要循环成分。与全血相比，人类血浆中的放射性分布更大 (B:P = 0.36)。

3. 在有色素的大鼠中，放射性迅速分布到全身组织，并在 24 小时内定位于消除途径末端器官和注射部位。

4. 整个物种的放射性总回收率 > 93%，大多数在 24-48 小时内回收，粪便中 >80%。

5. CYP2C8 酶对 razuprotafib 代谢有显着贡献。

6. razuprotafib (m/z ⁻ 380)的水解产物是 2 h 大鼠血浆中的主要成分（49% 峰面积放射性），而 razuprotafib (m/z ⁻ 585) 是狗血浆中的主要成分（58% )、猴子 (99.3%) 和人类 (100%)。

7. Razuprotafib 存在于狗、猴子和人类粪便中，以代谢物的形式存在最大百分比的放射性。猴子和人类的主要代谢物 (>25%)，m/z ⁻ 633，是 razuprotafib 的 S-甲基化氧化衍生物，位于粪便中。

8. 人类中¹⁴ C-razuprotafib 的总体配置最好由猴子对低阶物种进行建模。