Wen Dingsheng, Chen Boyu, Deng Mingtong, Wu Shaoyu, Xie Shuilin
Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China.
School of Pharmacy & Clinical Pharmacy (Integrated School of Pharmacy), Guangdong Pharmaceutical University, Guangzhou 510006, China.
Pharmaceutics. 2025 Mar 26;17(4):423. doi: 10.3390/pharmaceutics17040423.
: Triple-negative breast cancer (TNBC) is a major cause of cancer-related deaths among women. The Hedgehog (Hh) signaling pathway plays a critical role in tumor development, and targeting this pathway may provide new therapeutic opportunities for TNBC. TPB15 is a novel smoothened inhibitor of the Hh pathway, showing promising tumor reduction and low-toxicity properties in vivo/vitro. This study aims to evaluate TPB15's protein binding rates, metabolic stability, and metabolism across different species, including mice, rats, dogs, monkeys, and humans. : TPB15 was synthesized, and its pharmacokinetic profile was assessed. Plasma protein binding was determined using ultrafiltration across multiple species. Stability studies were conducted in plasma and liver microsomes from each species. Additionally, metabolic enzymes in human liver microsomes were characterized with selective CYP450 inhibitors, and high-resolution mass spectrometry was employed to identify metabolites. : Plasma protein binding of TPB15 was consistent across species, ranging from 81.5% to 82.4% in humans and rats. After 120 min, TPB15 remained stable in plasma, with retention rates of 97.2-98.3%. The elimination half-life () varied from 88 min in monkeys to 630 min in dogs. In human liver microsomes, metabolism was significantly inhibited by sulfaphenazole and ketoconazole, indicating the involvement of CYP3A4 and CYP2C9 enzymes. TPB15 underwent phase I metabolism, producing a major metabolite with a molecular weight of 468.9. : TPB15 demonstrates stable pharmacokinetic properties across species, with consistent protein binding and significant variability in half-life. The observed differences in metabolism are primarily attributed to CYP2C9 and CYP3A4, offering valuable insights into its drug development potential.
三阴性乳腺癌（TNBC）是女性癌症相关死亡的主要原因。刺猬（Hh）信号通路在肿瘤发展中起关键作用，靶向该通路可能为TNBC提供新的治疗机会。TPB15是一种新型的Hh通路平滑肌抑制剂，在体内/体外显示出有前景的肿瘤缩小和低毒性特性。本研究旨在评估TPB15在不同物种（包括小鼠、大鼠、狗、猴子和人类）中的蛋白质结合率、代谢稳定性和代谢情况。：合成了TPB15，并评估了其药代动力学特征。使用超滤法测定多个物种的血浆蛋白结合情况。在每个物种的血浆和肝微粒体中进行稳定性研究。此外，用选择性CYP450抑制剂对人肝微粒体中的代谢酶进行了表征，并采用高分辨率质谱法鉴定代谢产物。：TPB15的血浆蛋白结合在各物种间一致，在人和大鼠中为81.5%至82.4%。120分钟后，TPB15在血浆中保持稳定，保留率为97.2 - 98.3%。消除半衰期（）从猴子的88分钟到狗的630分钟不等。在人肝微粒体中，磺胺苯吡唑和酮康唑显著抑制代谢，表明涉及CYP3A4和CYP2C9酶。TPB15经历I相代谢，产生一种分子量为468.9的主要代谢产物。：TPB15在各物种中表现出稳定的药代动力学特性，蛋白结合一致，半衰期有显著差异。观察到的代谢差异主要归因于CYP2C9和CYP3A4，为其药物开发潜力提供了有价值的见解。
