Shanghai Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (M.X., W.H., Y.Y., C.C., Y.H., Chen Y., D.Z., X.D., Y.Z.); School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China (Cheng Y., Y.Y., C.C., X.D.); Department of Pharmacy, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China (J.G., H.L.); Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China (M.X.); State Key Laboratory of Natural Medicines and Center of Drug Discovery, College of Pharmacy, China Pharmaceutical University, Nanjing, China (H.S.); and Jiangsu Vcare PharmaTech Co. Ltd., Nanjing, China (Y.L., Y.G., Y.W., X.L.).
Shanghai Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (M.X., W.H., Y.Y., C.C., Y.H., Chen Y., D.Z., X.D., Y.Z.); School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China (Cheng Y., Y.Y., C.C., X.D.); Department of Pharmacy, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China (J.G., H.L.); Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China (M.X.); State Key Laboratory of Natural Medicines and Center of Drug Discovery, College of Pharmacy, China Pharmaceutical University, Nanjing, China (H.S.); and Jiangsu Vcare PharmaTech Co. Ltd., Nanjing, China (Y.L., Y.G., Y.W., X.L.)
Drug Metab Dispos. 2024 Aug 14;52(9):988-996. doi: 10.1124/dmd.124.001739.
P2Y receptor inhibitors are commonly used in clinical antiplatelet therapy, typically alongside other medications. Vicagrel, a promising P2Y receptor inhibitor, has submitted a new drug marketing application to the United States Food and Drug Administration. Its primary metabolites and some metabolic pathways are identical to those of clopidogrel. The aim of this study was to investigate the effects of the thiol methyltransferase inhibitor (±)-2,3-dichloro--methylbenzylamine (DCMB) on the metabolism and pharmacokinetics of vicagrel. In vitro incubation with human and rat liver microsomes revealed that DCMB significantly inhibited the methylation of vicagrel's thiol metabolite M15-1. Rats were orally administered 6 mg/kg [C]vicagrel (100 Ci/kg) 1 hour after peritoneal injection with or without DCMB (80 mg/kg). Compared with the control group, the plasma of DCMB-pretreated rats exhibited maximum plasma concentration ( ) decrease and time to reach ( ) delay for all vicagrel-related substances, the methylation product of the thiol metabolite (M9-2), and the derivatization product of the active thiol metabolite (MP-M15-2). However, no significant changes in area under the curve (AUC) or half-life ( ) were observed. DCMB had negligible effect on the total radiological recovery of vicagrel within 72 hours, although the rate of vicagrel excretion slowed down within 48 hours. DCMB had a negligible impact on the metabolic pathway of vicagrel. Overall, the present study found that DCMB did not significantly affect the total exposure, metabolic pathways, metabolite profiles, or total excretion rates of vicagrel-related metabolites in rats, but led to decrease, delay, and slower excretion rate within 48 hours. SIGNIFICANCE STATEMENT: This study used liquid chromatography-tandem mass spectrometry combined with radiolabeling technology to investigate the effects of the thiol methyltransferase inhibitor (±)-2,3-dichloro-α-methylbenzylamine on the absorption, metabolism, and excretion of vicagrel in rats. This work helps to better understand the in vivo metabolism of active thiol metabolites of P2Y inhibitors such as clopidogrel, vicagrel, etc.
P2Y 受体抑制剂常用于临床抗血小板治疗，通常与其他药物联合使用。维卡格雷是一种很有前途的 P2Y 受体抑制剂，已向美国食品和药物管理局提交了新药上市申请。其主要代谢物和一些代谢途径与氯吡格雷相同。本研究旨在探讨硫醇甲基转移酶抑制剂（±）-2,3-二氯-α-甲基苄胺（DCMB）对维卡格雷代谢和药代动力学的影响。体外用人和大鼠肝微粒体孵育表明，DCMB 显著抑制维卡格雷硫醇代谢物 M15-1 的甲基化。大鼠在腹腔注射 DCMB（80mg/kg）1 小时后，口服给予 6mg/kg [C]维卡格雷（100Ci/kg）。与对照组相比，DCMB 预处理大鼠的血浆中所有与维卡格雷相关的物质、硫醇代谢物的甲基化产物（M9-2）和活性硫醇代谢物的衍生化产物（MP-M15-2）的最大血浆浓度（）降低，达峰时间（）延迟。然而，曲线下面积（AUC）或半衰期（）没有明显变化。DCMB 对 72 小时内维卡格雷的总放射性回收率几乎没有影响，尽管在 48 小时内维卡格雷的排泄率减慢。DCMB 对维卡格雷的代谢途径几乎没有影响。总的来说，本研究发现 DCMB 对维卡格雷在大鼠体内的总暴露量、代谢途径、代谢产物谱或相关代谢物的总排泄率没有显著影响，但导致在 48 小时内排泄率下降、达峰时间延迟和排泄率减慢。意义：本研究采用液相色谱-串联质谱联用放射性标记技术，研究了硫醇甲基转移酶抑制剂（±）-2,3-二氯-α-甲基苄胺对维卡格雷在大鼠体内吸收、代谢和排泄的影响。这项工作有助于更好地了解氯吡格雷、维卡格雷等 P2Y 抑制剂的活性硫醇代谢物的体内代谢。
