Schulz Simone I, Schultze-Mosgau Marcus-Hillert, Engelen Anna, Singh Nand, Pawsey Steve, Francke Klaus, Lock Ruth, Rottmann Antje
Preclinical Development-Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany.
Early Clinical Development, Bayer AG, Berlin, Germany.
Eur J Drug Metab Pharmacokinet. 2025 Jan;50(1):91-103. doi: 10.1007/s13318-024-00930-3. Epub 2024 Dec 24.
Elinzanetant is a dual neurokinin-1,3 receptor antagonist in development for the treatment of menopausal vasomotor symptoms. The objectives of these studies were to characterize the mass balance and biotransformation of elinzanetant.
In the clinical evaluation, whole blood, plasma, urine, and feces were collected from healthy fasted male volunteers (n = 6) following a single dose of 120 mg [C]-elinzanetant oral suspension for analysis of total radioactivity and metabolite profiling. In vitro reaction phenotyping and kinetics experiments on enzymes involved in elinzanetant metabolism were performed.
On average, 90.8% of the total radioactivity administered was recovered in excreta over 480 h, mostly via the fecal route (feces 90.4%; urine 0.4%). Elinzanetant was rapidly absorbed and extensively metabolized but remained the main circulating species in plasma, accounting for 39.1% of total radioactivity. Known principal and active metabolites M27, M30/34, and M18/21 accounted for 7.6%, 13.7%, and 4.9% of total radioactivity in plasma, respectively. All other radiolabeled plasma components were each < 3.5%, revealing the oxidation product M30/34 as the only metabolite with relevant exposure (> 10% of total radioactivity). In feces, metabolites resulting from oxidative biotransformation accounted, in sum, for ~ 40% of the dose, while elinzanetant remained the primary drug-related moiety. Results of in vitro experiments indicated that metabolism of elinzanetant was primarily mediated by cytochrome P450 3A4, with minor contribution from uridine 5'-diphospho-glucuronosyltransferase.
Elinzanetant is metabolized mainly via oxidative biotransformation mediated by cytochrome P450 3A4, and primarily excreted in feces. The primary oxidation product M30/34 is a major human metabolite of elinzanetant.
NCT04654897.
艾林扎坦是一种正在研发的双重神经激肽-1、3受体拮抗剂，用于治疗绝经后血管舒缩症状。这些研究的目的是描述艾林扎坦的质量平衡和生物转化。
在临床评估中，从健康的空腹男性志愿者（n = 6）中收集全血、血浆、尿液和粪便，这些志愿者在单次口服120 mg [C] - 艾林扎坦口服混悬液后进行总放射性分析和代谢物谱分析。对参与艾林扎坦代谢的酶进行了体外反应表型分析和动力学实验。
在480小时内，平均90.8%的给药总放射性在排泄物中回收，主要通过粪便途径（粪便90.4%；尿液0.4%）。艾林扎坦迅速吸收并广泛代谢，但仍是血浆中的主要循环物质，占总放射性的39.1%。已知的主要活性代谢物M27、M30/34和M18/21分别占血浆总放射性的7.6%、13.7%和4.9%。所有其他放射性标记的血浆成分均<3.5%，表明氧化产物M30/34是唯一具有相关暴露量（>总放射性的10%）的代谢物。在粪便中,氧化生物转化产生的代谢物总计约占剂量的40%，而艾林扎坦仍然是主要的药物相关部分。体外实验结果表明，艾林扎坦的代谢主要由细胞色素P450 3A4介导，尿苷5'-二磷酸葡萄糖醛酸基转移酶的贡献较小。
艾林扎坦主要通过细胞色素P450 介导的氧化生物转化代谢，主要通过粪便排泄。主要氧化产物M30/34是艾林扎坦的主要人体代谢物。
NCT04654897。
