Novo Nordisk A/S, Søborg, Denmark.
Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark.
Eur J Pharm Sci. 2017 Jun 15;104:31-41. doi: 10.1016/j.ejps.2017.03.020. Epub 2017 Mar 16.
Semaglutide is a human glucagon-like peptide-1 analogue in clinical development for the treatment of type 2 diabetes. The absorption, metabolism and excretion of a single 0.5mg/450μCi [16.7MBq] subcutaneous dose of [H]-radiolabelled semaglutide was investigated in healthy human subjects and compared with data from nonclinical studies. Radioactivity in blood, plasma, urine and faeces was determined in humans, rats and monkeys; radioactivity in expired air was determined in humans and rats. Metabolites in plasma, urine and faeces were quantified following profiling and radiodetection. The blood-to-plasma ratio and pharmacokinetics of both radiolabelled semaglutide-related material and of semaglutide (in humans only) were assessed. Intact semaglutide was the primary component circulating in plasma for humans and both nonclinical species, accounting for 69-83% of the total amount of semaglutide-related material, and was metabolised prior to excretion. Recovery of excreted radioactivity was 75.1% in humans, 72.1% in rats and 58.2% in monkeys. Urine and faeces were shown to be important routes of excretion, with urine as the primary route in both humans and animals. Semaglutide was metabolised through proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain, and metabolism was not confined to specific organs. Intact semaglutide in urine accounted for 3.1% of the administered dose in humans and less than 1% in rats; it was not detected in urine in monkeys. The metabolite profiles of semaglutide in humans appear to be similar to the profiles from the nonclinical species investigated.
司美格鲁肽是一种在研的用于治疗 2 型糖尿病的人胰高血糖素样肽-1 类似物。在健康受试者中研究了单次皮下给予 0.5mg/450μCi [16.7MBq]标记的[H]放射性司美格鲁肽后的吸收、代谢和排泄，并与非临床研究数据进行了比较。在人类、大鼠和猴子中测定了血液、血浆、尿液和粪便中的放射性；在人类和大鼠中测定了呼出空气中的放射性。在对其进行分析和放射性检测后，对血浆、尿液和粪便中的代谢物进行了定量。评估了放射性标记的司美格鲁肽相关物质和司美格鲁肽（仅在人类中）的血药比和药代动力学。完整的司美格鲁肽是在人类和两种非临床物种的血浆中循环的主要成分，占司美格鲁肽相关物质总量的 69-83%，并在排泄前被代谢。在人类中，排泄的放射性回收率为 75.1%，在大鼠中为 72.1%，在猴子中为 58.2%。尿液和粪便均为重要的排泄途径，尿液是人类和动物的主要排泄途径。司美格鲁肽通过肽主链的蛋白水解切割和脂肪酸侧链的连续β氧化进行代谢，且代谢不限于特定的器官。尿液中完整的司美格鲁肽占人类给予剂量的 3.1%，大鼠中不到 1%；在猴子中未检测到。人类中司美格鲁肽的代谢物谱似乎与所研究的非临床物种的谱相似。
