State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of the Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2023 Jan;44(1):221-233. doi: 10.1038/s41401-022-00922-6. Epub 2022 Jun 8.
TPN171 is a novel phosphodiesterase-5 (PDE5) inhibitor used to treat pulmonary arterial hypertension (PAH) and erectile dysfunction (ED), which currently is undergoing phase II clinical trials in China. In this single-center, single-dose, nonrandomized, and open design study, radiolabeled [C]TPN171 was used to investigate the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of TPN171 in 6 healthy Chinese male volunteers. Each volunteer was administered a single oral suspension of 10 mg (100 μCi) of [C]TPN171. We found that TPN171 was absorbed rapidly in humans with a peak time (T) of 0.667 h and a half-life (t) of approximately 9.89 h in plasma. Excretion of radiopharmaceutical-related components was collected 216 h after administration, accounting for 95.21% of the dose (46.61% in urine and 48.60% in feces). TPN171 underwent extensive metabolism in humans. Twenty-two metabolites were detected in human plasma, urine, and feces using a radioactive detector combined with a high-resolution mass spectrometer. According to radiochromatograms, a glucuronide metabolite of O-dealkylated TPN171 exceeded 10% of the total drug-related components in human plasma. However, according to the Food and Drug Administration (FDA) guidelines, no further tests are needed to evaluate the safety of this metabolite because it is a phase II metabolite, but the compound is still worthy of attention. The main metabolic biotransformation of TPN171 was mono-oxidation (hydroxylation and N-oxidation), dehydrogenation, N-dealkylation, O-dealkylation, amide hydrolysis, glucuronidation, and acetylation. Cytochrome P450 3A4 (CYP3A4) mainly catalyzed the formation of metabolites, and CYP2E1 and CYP2D6 were involved in the oxidative metabolism of TPN171 to a lesser extent. According to the incubation data, M1 was mainly metabolized to M1G by UDP-glucuronosyltransferase 1A9 (UGT1A9), followed by UGT1A7 and UGT1A10.
TPN171 是一种新型磷酸二酯酶-5（PDE5）抑制剂，用于治疗肺动脉高压（PAH）和勃起功能障碍（ED），目前正在中国进行 II 期临床试验。在这项单中心、单剂量、非随机、开放设计的研究中，放射性标记的 [C]TPN171 用于研究 6 名健康中国男性志愿者中 TPN171 的代谢机制、药代动力学特征和清除途径。每个志愿者单次口服 10mg（100μCi）[C]TPN171 混悬液。我们发现 TPN171 在人体内吸收迅速，血浆中 T 峰值（T）为 0.667h，半衰期（t）约为 9.89h。给药后 216h 收集放射性药物相关成分的排泄量，占剂量的 95.21%（尿液中 46.61%，粪便中 48.60%）。TPN171 在人体内广泛代谢。使用放射性探测器结合高分辨率质谱仪在人血浆、尿液和粪便中检测到 22 种代谢物。根据放射性色谱图，O-去烷基化 TPN171 的葡萄糖醛酸代谢物在人血浆中的总药物相关成分中超过 10%。然而，根据美国食品和药物管理局（FDA）的指导原则，无需进一步测试来评估该代谢物的安全性，因为它是 II 期代谢物，但该化合物仍值得关注。TPN171 的主要代谢生物转化为单氧化（羟化和 N-氧化）、脱氢、N-去烷基化、O-去烷基化、酰胺水解、葡萄糖醛酸化和乙酰化。细胞色素 P450 3A4（CYP3A4）主要催化代谢物的形成，CYP2E1 和 CYP2D6 较少参与 TPN171 的氧化代谢。根据孵育数据，M1 主要通过 UDP-葡糖醛酸基转移酶 1A9（UGT1A9）代谢为 M1G，然后是 UGT1A7 和 UGT1A10。
