Preclinical and Clinical DMPK (C.A.L., C.Y.,V.S., Z.S.), Bioanalytical (D.M.W.), Biology (T.M.O.), Chemistry (J.-L.G.), and Clinical Development (J.H.) Ardea Biosciences, Inc., San Diego, California; and Early Clinical Development, IMED Biotech Unit, Quantitative Clinical Pharmacology (M.G.) AstraZeneca LP, Gaithersburg, Maryland
Preclinical and Clinical DMPK (C.A.L., C.Y.,V.S., Z.S.), Bioanalytical (D.M.W.), Biology (T.M.O.), Chemistry (J.-L.G.), and Clinical Development (J.H.) Ardea Biosciences, Inc., San Diego, California; and Early Clinical Development, IMED Biotech Unit, Quantitative Clinical Pharmacology (M.G.) AstraZeneca LP, Gaithersburg, Maryland.
Drug Metab Dispos. 2018 May;46(5):532-541. doi: 10.1124/dmd.117.078220. Epub 2018 Feb 28.
Verinurad (RDEA3170) is a second generation selective uric acid reabsorption inhibitor for the treatment of gout and asymptomatic hyperuricemia. Following a single oral solution of 10-mg dose of [C]verinurad (500 Ci), verinurad was rapidly absorbed with a median time to occurrence of maximum observed concentration (T) of 0.5 hours and terminal half-life of 15 hours. In plasma, verinurad constituted 21% of total radioactivity. Recovery of radioactivity in urine and feces was 97.1%. Unchanged verinurad was the predominant component in the feces (29.9%), whereas levels were low in the urine (1.2% excreted). Acylglucuronide metabolites M1 (direct glucuronidation) and M8 (glucuronidation of N-oxide) were formed rapidly after absorption of verinurad with terminal half-life values of approximately 13 and 18 hours, respectively. M1 and M8 constituted 32% and 31% of total radioactivity in plasma and were equimolar to verinurad on the basis of AUC ratios. M1 and M8 formed in the liver were biliary cleared with complete hydrolysis in the GI tract, as metabolites were not detected in the feces and/or efflux across the sinusoidal membrane; M1 and M8 accounted for 29.2% and 32.5% of the radioactive dose in urine, respectively. In vitro studies demonstrated that CYP3A4 mediated the formation of the N-oxide metabolite (M4), which was further metabolized by glucuronyl transferases (UGTs) to form M8, as M4 was absent in plasma and only trace levels were present in the urine. Several UGTs mediated the formation of M1, which could also be further metabolized by CYP2C8. Overall, the major clearance route of verinurad is metabolism via UGTs and CYP3A4 and CYP2C8.
维那鲁单抗（RDEA3170）是一种用于治疗痛风和无症状高尿酸血症的第二代选择性尿酸重吸收抑制剂。单次口服 10 毫克剂量的 [C]维那鲁单抗（500 毫居里）后，维那鲁单抗迅速吸收，最大观测浓度（T）的中位时间为 0.5 小时，终末半衰期为 15 小时。在血浆中，维那鲁单抗占总放射性的 21%。尿液和粪便中放射性的回收率为 97.1%。未改变的维那鲁单抗是粪便中的主要成分（29.9%），而尿液中的水平较低（1.2%排泄）。酰基葡萄糖醛酸代谢物 M1（直接葡萄糖醛酸化）和 M8（N-氧化物的葡萄糖醛酸化）在吸收维那鲁单抗后迅速形成，终末半衰期值分别约为 13 和 18 小时。M1 和 M8 构成了血浆中总放射性的 32%和 31%，基于 AUC 比值与维那鲁单抗等摩尔。M1 和 M8 在肝脏中形成并在胃肠道中完全水解被胆汁清除，因为在粪便中未检测到代谢物和/或跨窦状膜外排；M1 和 M8 分别占尿液中放射性剂量的 29.2%和 32.5%。体外研究表明，CYP3A4 介导 N-氧化物代谢物（M4）的形成，M4 进一步被葡萄糖醛酸转移酶（UGTs）代谢形成 M8，因为 M4 在血浆中不存在，仅在尿液中存在微量水平。几种 UGTs 介导 M1 的形成，M1 也可以被 CYP2C8 进一步代谢。总体而言，维那鲁单抗的主要清除途径是通过 UGTs 和 CYP3A4 和 CYP2C8 代谢。
