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Effects of the Thiol Methyltransferase Inhibitor (±)-2,3-Dichloro-α-Methylbenzylamine (DCMB) on the Pharmacokinetics and Metabolism of Vicagrel in Rats.
Yang, Cheng; Gong, Jingru; Xue, Mingzhen; Huang, Wensi; Yuan, Yali; Chen, Chong; He, Yifei; Yang, Chen; Sun, Hongbin; Liu, Yongqiang; Gong, Yanchun; Wu, Yong; Lai, Xiaojuan; Zhong, Dafang; Diao, Xingxing; Lu, Huiping; Zheng, Yuandong.
Afiliação
  • Yang C; 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 (C
  • Gong J; 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 (C
  • Xue M; 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 (C
  • Huang W; 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 (C
  • Yuan Y; 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 (C
  • Chen C; 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 (C
  • He Y; 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 (C
  • Yang C; 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 (C
  • Sun H; 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 (C
  • Liu Y; 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 (C
  • Gong Y; 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 (C
  • Wu Y; 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 (C
  • Lai X; 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 (C
  • Zhong D; 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 (C
  • Diao X; 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 (C
  • Lu H; 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 (C
  • Zheng Y; 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 (C
Drug Metab Dispos ; 52(9): 988-996, 2024 Aug 14.
Article em En | MEDLINE | ID: mdl-38997155
ABSTRACT
P2Y12 receptor inhibitors are commonly used in clinical antiplatelet therapy, typically alongside other medications. Vicagrel, a promising P2Y12 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-α-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 [14C]vicagrel (100 µCi/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 (C max) decrease and time to reach C max (T max) 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 (t 1/2) 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 C max decrease, T max 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 P2Y12 inhibitors such as clopidogrel, vicagrel, etc.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Microssomos Hepáticos / Ratos Sprague-Dawley / Metiltransferases Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Microssomos Hepáticos / Ratos Sprague-Dawley / Metiltransferases Idioma: En Ano de publicação: 2024 Tipo de documento: Article