Abstract

1. The absorption, metabolism and excretion of pictilisib, a selective small molecule inhibitor of class 1 A phosphoinositide 3-kinase (PI3K), was characterized following a single oral administration of [¹⁴C]pictilisib in rats, dogs and humans at the target doses of 30 mg/kg, 5 mg/kg and 60 mg, respectively.

2. Pictilisib was rapidly absorbed with T_max less than 2 h across species. In systemic circulation, pictilisib represented the predominant total radioactivity greater than 86.6% in all species.

3. Total pictilisib and related radioactivity was recovered from urine and faeces in rats, dogs, and human at 98%, 80% and 95%, respectively, with less than 2% excreted in urine and the rest excreted into faeces.

4. In rat and dog, more than 40% of drug-related radioactivity was excreted into the bile suggesting biliary excretion was the major route of excretion. Unchanged pictilisib was a minor component in rat and dog bile. The major metabolite in bile was O-glucuronide of oxidation on indazole moiety (M20, 21% of the dose) in rats and an oxidative piperazinyl ring-opened metabolite M7 (10.8% of the dose) in dogs.

5. Oxidative glutathione (GSH) conjugates (M18, M19) were novel metabolites detected in rat bile, suggesting the potential generation of reactive intermediates from pictilisib. The structure of M18 was further confirmed by NMR to be a N-hydroxylated and GSH conjugated metabolite on the moiety of the indazole ring.

摘要

1. pictilisib 是 1A 类磷酸肌醇 3-激酶 (PI3K) 的选择性小分子抑制剂，其吸收、代谢和排泄的特点是在大鼠、狗和人中以目标剂量单次口服 [ ¹⁴ C] pictilisib 后分别为 30 mg/kg、5 mg/kg 和 60 mg。

2. Pictilisib 被迅速吸收，T _max跨物种小于 2 小时。在体循环中，pictilisib 代表了所有物种中超过 86.6% 的主要总放射性。

3. 从大鼠、狗和人的尿液和粪便中回收到的总 pictilisib 和相关放射性分别为 98%、80% 和 95%，少于 2% 随尿液排泄，其余排泄到粪便中。

4. 在大鼠和狗中，超过 40% 的与药物相关的放射性物质被排泄到胆汁中，表明胆汁排泄是主要的排泄途径。未改变的 pictilisib 是大鼠和狗胆汁中的次要成分。胆汁中的主要代谢物是大鼠中吲唑部分（M20，剂量的 21%）氧化的O-葡萄糖醛酸和狗中氧化哌嗪基开环代谢物 M7（剂量的 10.8%）。

5. 氧化型谷胱甘肽 (GSH) 偶联物​​（M18、M19）是在大鼠胆汁中检测到的新型代谢物，表明 pictilisib 可能产生反应性中间体。M18 的结构通过 NMR 进一步证实是吲唑环部分上的N-羟基化和 GSH 共轭代谢物。