Pharmacokinetics,mass balance,and metabolism of[14C]vicagrel,a novel irreversible P2Y12 inhibitor in humans

• 作者: Yuan-dong Zheng Hua Zhang Yan Zhan Yi-cong Bian Sheng Ma Hai-xian Gan Xiao-juan Lai Yong-qiang Liu Yan-chun Gong Xue-fang Liu Hong-bin Sun Yong-guo Li Da-fang Zhong Li-yan Miao Xing-xing Diao
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（9）
• 所属期刊栏目: Drug Absorption,Distribution,Metabolism and Excretion
• 页码范围: 1535-1546
• 页数: 12页
• 语种: 英文

摘要

Vicagrel,a novel irreversible P2Y12 receptor inhibitor,is undergoing phase Ⅲ trials for the treatment of acute coronary syndromes in China.In this study,we evaluated the pharmacokinetics,mass balance,and metabolism of vicagrel in six healthy male Chinese subjects after a single oral dose of 20 mg[14C]vicagrel (120 μCi).Vicagrel absorption was fast (Tmax =0.625 h),and the mean t1/2 of vicagrel-related components was ～38.0 h in both plasma and blood.The blood-to-plasma radioactivity AUCinf ratio was 0.55,suggesting preferential distribution of drug-related material in plasma.At 168 h after oral administration,the mean cumulative excreted radioactivity was 96.71％ of the dose,including 68.03％ in urine and 28.67％ in feces.A total of 22 metabolites were identified,and the parent vicagrel was not detected in plasma,urine,or feces.The most important metabolic spot of vicagrel was on the thiophene ring.In plasma pretreated with the derivatization reagent,M9-2,which is a methylated metabolite after thiophene ring opening,was the predominant drug-related component,accounting for 39.43％ of the radioactivity in pooled AUC0-8h plasma.M4,a mono-oxidation metabolite upon ring-opening,was the most abundant metabolite in urine,accounting for 16.25％ of the dose,followed by M3-1,accounting for 12.59％ of the dose.By comparison,M21 was the major metabolite in feces,accounting for 6.81％ of the dose.Overall,renal elimination plays a crucial role in vicagrel disposition,and the thiophene ring is the predominant metabolic site.